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Sample records for benzoapyrene diol epoxide

  1. Specificity of chemiluminescence in the metabolism of benzo[a]pyrene to its carcinogenic diol epoxide.

    PubMed Central

    Hamman, J P; Seliger, H H; Posner, G H

    1981-01-01

    The metabolism of 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene results primarily in the ultimate carcinogenic metabolite of benzo[a]pyrene, 7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene and to a lesser extent 7,8-dihydroxy-9,10-dioxetane-7,8,9,10-tetrahydrobenzo[a]pyrene, from which chemiluminescence is observed. This specific microsomal chemiluminescence has been used to establish that the rate-limiting reaction in the metabolism of benzo[a]pyrene to the bay region diol epoxide is the production of the 7,8-diol. The microsome-mediated chemiluminescence of the parent benzo[a]pyrene is therefore an indicator of the activity of the specific sequence of metabolic reactions leading to the ultimate carcinogenic metabolite. PMID:6785756

  2. Further characterization of benzo[a]pyrene diol-epoxide (BPDE)-induced comet assay effects.

    PubMed

    Bausinger, Julia; Schütz, Petra; Piberger, Ann Liza; Speit, Günter

    2016-03-01

    The present study aims to further characterize benzo[a]pyrene diol-epoxide (BPDE)-induced comet assay effects. Therefore, we measured DNA effects by the comet assay and adduct levels by high-performance liquid chromatography (HPLC) in human lymphocytes and A549 cells exposed to (±)-anti-benzo[a]pyrene-7,8-diol 9,10-epoxide [(±)-anti-BPDE] or (+)-anti-benzo[a]pyrene-7,8-diol 9,10-epoxide [(+)-anti-BPDE]. Both, the racemic form and (+)-anti-BPDE, which is the most relevant metabolite with regard to mutagenicity and carcinogenicity, induced DNA migration in cultured lymphocytes in the same range of concentrations to a similar extent in the alkaline comet assay after exposure for 2h. Nevertheless, (+)-anti-BPDE induced significantly enhanced DNA migration after 16 and 18h post-cultivation which was not seen in response to (±)-anti-BPDE. Combination of the comet assay with the Fpg (formamidopyrimidine-DNA glycosylase) protein did not enhance BPDE-induced effects and thus indicated the absence of Fpg-sensitive sites (oxidized purines, N7-guanine adducts, AP-sites). The aphidicolin (APC)-modified comet assay suggested significant excision repair activity of cultured lymphocytes during the first 18h of culture after a 2 h-exposure to BPDE. In contrast to these repair-related effects measured by the comet assay, HPLC analysis of stable adducts did not reveal any significant removal of (+)-anti-BPDE-induced adducts from lymphocytes during the first 22h of culture. On the other hand, HPLC measurements indicated that A549 cells repaired about 70% of (+)-anti-BPDE-induced DNA-adducts within 22h of release. However, various experiments with the APC-modified comet assay did not indicate significant repair activity during this period in A549 cells. The conflicting results obtained with the comet assay and the HPLC-based adduct analysis question the real cause for BPDE-induced DNA migration in the comet assay and the reliability of the APC-modified comet assay for the

  3. Genetic damage induced by benzo[a]pyrene diol epoxide and risk of lung cancer

    SciTech Connect

    Wei, Q.; Cheng, L.; Li, D.

    1997-10-01

    Lung cancer is the paradigm of carcinogen-induced disease. A chemical carcinogen, benzo[a]pyrene, commonly found in tobacco, is both mutagenic and carcinogenic. It is hypothesized that individuals have varying responses to exposure to environmental carcinogens. In this study, we used benzo[a]pyrene diol epoxide (BPDE) as the test mutagen to investigate three in-vitro susceptibility markers in lymphocytes from 51 patients with lung cancer and 172 cancer-free controls. These markers were: BPDE-induced chromosomal aberrations, BPDE-induced DNA adducts, and DNA repair capacity using host cell reactivation assay with BPDE-damaged plasmid. Using the medians of the controls as the cutoff values, increased risk of lung cancer was associated with increased frequency of chromosomal aberrations (OR=6.53; 95% confidence interval (C.I.), 3.74-11.4), increased BPDE-DNA adduct level (odds ratio (OR)=4.7; 95% C.I., 1.2-18.5), and reduced DNA repair capacity (OR=5.7; 95% C.I., 2.1-15.7). In correlation analyses, cellular ability to repair BPDE-induced DNA damage was found to be inversely correlated with the levels of BPDE-induced DNA adducts (n=34; r=0.34; p=0.048) and the levels of BPDE-DNA adducts correlated significantly with the frequency of chromosomal aberrations (n=62; r=0.42; p=0.001). However, cellular ability to repair BPDE-induced DNA damage was not correlated significantly with the frequency of chromosomal aberrations (n=47; r=0.06; p=0.677). These biomarkers have differing sensitivities in measuring repair of damage induced by chemical carcinogens; therefore, the complementary use of these assays should increase the probability of identifying individuals with susceptibility to smoking-related cancers.

  4. Gene-specific repair of benzo[a]pyrene diol epoxide DNA damage in human cells

    SciTech Connect

    Denisenko, M.F.; Venkatachalam, S.; Wani, A.A.

    1995-11-01

    Gene-specific preferential repair of UV damage has been well documented in a variety of organisms. Less is known about many other types of critical DNA lesions, the data available being not numerous and contradictory. To date, the majority of observations with UV were obtained by using T4 endonuclease V system. Recent report questions the applicability of UvrABC nuclease incision method for detecting gene-specific repair. This has stimulated our search for simple and sensitive approach based on a different principle. We have employed the idea of detection by the Southern hybridization of restriction cleavage inhibition at rare sites and developed a method for the analysis of benzo[a]pyrene diol epoxide (anti-BPDE) DNA damage in human H-ras proto-oncogene. Damage-dependent induction of individual facultative bands resulting from cleavage inhibition was observed in in vitro modified (4-50 adducts/10{sup 3}kb) p220-ras plasmid DNA digested with EcoRI/NotI, Xhol/Xbal/PstI, and SstI/XbaI/Pst/I. In vivo lesion formation and removal was monitored at several PstI sites distributed along the 6.4 kb single copy ras sequence. Rapid gene-specific repair was seen in primary culture of normal human fibroblasts and in SV40 transformed GM00637 cells. Surprisingly, SV40 transformed XP12BE (complementation group A) GM4429 fibroblasts also repaired anti-BPDE DNA damage at comparable levels. All investigated sites within ras sequence were repaired faster than the genome overall. The results show the utility of the above approach for fine mapping of anti-BPDE DNA lesions. Data suggests that the xeroderma pigmentosum (group A) fibroblasts have a capacity of removing these bulky adducts at least from the active genes.

  5. INTERACTION OF BENZO(A)PYRENE DIOL EPOXIDE WITH SVAO MINICHROMOSOMES

    SciTech Connect

    Gamper, Howard B.; Yokota, Hisao A.; Bartholomew, James C.

    1980-03-01

    SV40 minichromosomes were reacted with (+)7{beta},8{alpha}-dihydroxy-9{alpha},10{alpha}-epoxy- 7,8,9,10-tetrahydrobenzo[a]pyrene (BaP diol epoxide). Low levels of modification (< 5 DNA adducts/minichromosome) did not detectably alter the structure of the minichromosomes but high levels (> 200 DNA adducts/minichromosome) led to extensive fragmentation. Relative to naked SV40 DNA BaP diol epoxide induced alkylation and strand scission of minichromosomal DNA was reduced or enhanced by factors of 1.5 and 2.0, respectively. The reduction in covalent binding was attributed to the presence of histones, which competed with DNA for the hydrocarbon and reduced the probability of BaP diol epoxide intercalation by tightening the helix. The enhancement of strand scission was probably due to the catalytic effect of histones on the rate of S-elimination at apurinic sites, although an altered adduct profile or the presence of a repair endonuclease were not excluded. Staphylococcal nuclease digestion indicated that BaP dial epoxide randomly alkylated the minichromosomal DNA. This is in contrast to studies with cellular chromatin where internucleosomal DNA was preferentially modified. Differences in the minichromosomal protein complement were responsible for this altered susceptibility.

  6. Comparison of the tumor-initiating activities of benzo(a)pyrene arene oxides and diol-epoxides.

    PubMed

    Slaga, T J; Bracken, W M; Viaje, A; Levin, W; Yagi, H; Jerina, D M; Conney, A H

    1977-11-01

    The ability of arene oxides, and diol epoxides of benzo(a)pyrene to initiate skin tumors in mice was determined by using a two-stage system of tumorigenesis. (+/-)-7beta,8alpha-Dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene was a more effective tumor initiator than was (+/-)-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene when applied topically to CD-1 mice and then followed by twice-weekly applications of the promotor 12-O-tetradecanoylphorbol-13-acetate. (+/-)-7beta,8alpha-Dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene was approximately 20 to 30% as active as benzo(a)pyrene was as a tumor initiator. (+/-)-7beta,8alpha-Dihydroxy-7beta,8beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, benzo(a)pyrene, 9,10-oxide, and benzo(a)pyrene 11, 12-oxide, possessed about 1, 2, and 10%, respectively, of the tumor-initiating activity of benzo(a)pyrene.

  7. Role of diaxial versus diequatorial hydroxyl groups in the tumorigenic activity of a benzo[a]pyrene bay-region diol epoxide.

    PubMed Central

    Chang, R L; Wood, A W; Conney, A H; Yagi, H; Sayer, J M; Thakker, D R; Jerina, D M; Levin, W

    1987-01-01

    Tumorigenic activities of the (7R,8S,9S,10R)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro derivatives of benzo[a]pyrene [(+)-B[a]P diol epoxide-2] and 6-fluorobenzo[a]pyrene (6-FB[a]P diol epoxide-2) were evaluated in newborn CD-1 mice. A total dose of 14 nmol of either diol epoxide was administered to preweanling mice, and tumorigenic activity was determined when the mice were 32 to 36 weeks old. At the termination of the study, 13% of solvent-treated control mice had developed lung tumors with an average of 0.19 tumor per mouse. No other tumors were observed in control animals. (+)-B[a]P diol epoxide-2 induced pulmonary tumors in 60% of the mice with an average of 1.9 tumors per mouse, and 14% of the male mice developed hepatic tumors with an average of 0.18 tumor per mouse. In contrast, 6-FB[a]P diol epoxide-2 had no significant tumorigenic activity at the 14-nmol dose. Although both bay-region diol epoxides have the same absolute configuration, (7R,8S,9S,10R), the hydroxyl groups of (+)-B[a]P diol epoxide-2 prefer the pseudoequatorial conformation whereas the hydroxyl groups of 6-FB[a]P diol epoxide-2 prefer the pseudoaxial conformation. The tumorigenicity results reported here are the first direct demonstration that conformation of the hydroxyl groups in a bay-region diol epoxide, in addition to the documented effect of absolute configuration, is an important determinant in the tumorigenic activity of these ultimate carcinogens. PMID:3479808

  8. Mapping and characterization of mutations induced by benzo[a]pyrene diol epoxide at dihydrofolate reductase locus in CHO cells.

    PubMed

    Carothers, A M; Urlaub, G; Grunberger, D; Chasin, L A

    1988-03-01

    Chinese hamster ovary cells were mutagenized with benzo[a]pyrene diol epoxide (BPDE), an aromatic hydrocarbon carcinogen, and mutants at the dihydrofolate reductase (dhfr) locus were isolated. Of 15 mutants analyzed by Southern blotting, one contained a large deletion that spanned all six exons of the 25-kb dhfr gene; the remaining mutants exhibited no detectable changes. Three of these putative point mutations were localized by the loss of a restriction site: a SacI site in exon III, an MspI site in exon III, and a KpnI site in exon VI. The affected regions in two of these mutants were cloned and sequenced. The SacI- mutant was caused by a G:C----T:A transversion resulting in an amber termination codon. In the MspI- mutant, the deletion of a single C:G resulted in a frameshift and a downstream ochre termination codon. On the basis of overlapping restriction site sequences, the KpnI- mutant was deduced to be a splicing mutant involving the most 3' G in intron V. The location of these and the remaining 11 putative point mutations was sought using RNA heteroduplex mapping. Mismatched bases between riboprobes complementary to wild-type dhfr mRNA and mutant mRNA molecules were detected in 10 of the 14 mutants analyzed. These mutations mapped to four of the six exons or exon splice sites. Surprisingly, over half of these mutants exhibited greatly reduced (approximately 10-fold) steady-state levels of dhfr mRNA.

  9. Skin-tumor-initiating ability of benzo(a)pyrene-7,8-diol-9,10-epoxide (anti) when applied topically in tetrahydrofuran.

    PubMed

    Slaga, T J; Viaje, A; Bracken, W M; Berry, D L; Fischer, S M; Miller, D R; Leclerc, S M

    1977-07-01

    The skin-tumor-initiating abilities of various metabolites of benzo(a)pyrene (BP) were determined in mice by using a two-stage system of tumorigenesis. We previously reported that BP-7,8-dihydrodiol (+/- trans) was approximately as potent as BP, suggesting that it may be a proximate carcinogen, but the alleged ultimate carcinogen of BP [BP-7,8-dihydrodiol-9,10-epoxide (anti)] was a weak tumor initiator (Cancer Lett.2: 115, 1976). Because of its high reactivity, the tumor-initiating ability of the BP-7,8-dihydrodiol-9,10-epoxide (anti) was determined by using acetone, benzene, and tetrahydrofuran (THF) as the solvent vehicles. The 'diol-epoxide' of BP was found to be an effective tumor initiator when applied topically in THF. The effectiveness of the various vehicles for the 'diol-epoxide' was as follows: THF greater than benzene greater than acetone; however, acetone was the best solvent for BP tumor initiation. The BP-9,10-dihydrodiol and BP-3-hydroxy were found to be weak tumor initiators. BP-3-hydroxy was also tested for tumor-promoting ability and was found to be inactive in this capacity.

  10. Quantitation of enantiomers of r-7,t-8,9,c-10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]-pyrene in human urine: evidence supporting metabolic activation of benzo[a]pyrene via the bay region diol epoxide.

    PubMed

    Hecht, Stephen S; Hochalter, Jon Bradley

    2014-09-01

    Benzo[a]pyrene (BaP), a potent polycyclic aromatic hydrocarbon carcinogen, is widely distributed in the human environment. All humans are exposed to BaP through the diet and contact with the general environment; cigarette smokers have higher exposure. An important pathway of BaP metabolism proceeds through formation of diol epoxides including the 'bay region diol epoxide' 7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [BaP-(7R,8S)-diol-(9S,10R)-epoxide] and the 'reverse diol epoxide' 9S,10R-dihydroxy-7R,8S-epoxy-7,8,9,10-tetrahydrobenzo [a]pyrene [BaP-(9S,10R)-diol-(7R,8S)-epoxide]. The bay region diol epoxide is considered a major ultimate carcinogen of BaP based on studies in cell culture and laboratory animals, but the available data in humans are less convincing. The bay region diol epoxide and the reverse diol epoxide react with H2O to produce enantiomeric BaP-tetraols that are excreted in the urine. We used chiral stationary-phase high-performance liquid chromatography and gas chromatography-negative ion chemical ionisation-tandem mass spectrometry to quantify these enantiomeric BaP-tetraols in the urine of 25 smokers and 25 non-smokers. The results demonstrated that the BaP-tetraol enantiomer representing the carcinogenic bay region diol epoxide pathway accounted for 68±6% (range 56-81%) of total BaP-tetraol in smokers and 64±6% (range 46-78%) in non-smokers. Levels of the major BaP-tetraol enantiomer decreased by 75% in smokers who quit smoking. These data provide convincing evidence in support of the bay region diol epoxide mechanism of BaP carcinogenesis in humans.

  11. MODULATION BY IONIC STRENGTH AND SUPERHELICITY OF BENZO[a]PYRENE DIOL EPOXIDE INDUCED DNA ALKYLATION AND UNWINDING

    SciTech Connect

    Gamper, Howard B.; Straub, Kenneth; Calvin, Melvin; Bartholomew, James C.

    1980-01-01

    Superhelical and partially relaxed SV40 DNA were reacted in vitro with (+)7{beta}, 8{alpha}-dihydroxy-9{alpha},10{alpha}-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP diol epoxide). The modified DNA contained N{sup 2} guanine and N{sup 6} adeninte hydrocarbon adducts in the ratio 86:14. Superhelical SV40 DNA was approximately 6% more susceptible to modification than partially relaxed viral DNA. Counterions inhibited DNA alkylation by up to 90%, Mg{sup 2+} being 50-fold more effective than Na{sup +}. The sensitivity of covalent binding to helix stability is consistent with a reaction complex in which BaP diol epoxide is intercalated. The superhelical density of the modified DNA substrates was determined electrophoretically relative to partially relaxed standards and an unwinding angle for the hydrocarbon adducts was calculated. The angle was dependent upon the superhelicity of the DNA molecule and ranged from 330{sup o} to 30{sup o}. This data indicates that the modified base pairs are disrupted and, in the presence of torsional strain, act as centers for the further denaturation of up to 8 adjacent base pairs. In the absence of such strain the alkylation sites have an ordered structure with the attached hydrocarbon probably oriented in the minor or major groove of the helix.

  12. Interaction of benzo[a]pyrene diol epoxide isomers with human serum albumin: Site specific characterisation of adducts and associated kinetics

    PubMed Central

    Motwani, Hitesh V.; Westberg, Emelie; Törnqvist, Margareta

    2016-01-01

    Carcinogenicity of benzo[a]pyrene {B[a]P, a polycyclic aromatic hydrocarbon (PAH)} involves DNA-modification by B[a]P diol epoxide (BPDE) metabolites. Adducts to serum albumin (SA) are not repaired, unlike DNA adducts, and therefore considered advantageous in assessment of in vivo dose of BPDEs. In the present work, kinetic experiments were performed in relation to the dose (i.e. concentration over time) of different BPDE isomers, where human SA (hSA) was incubated with respective BPDEs under physiological conditions. A liquid chromatography (LC) tandem mass spectrometry methodology was employed for characterising respective BPDE-adducts at histidine and lysine. This strategy allowed to structurally distinguish between the adducts from racemic anti- and syn-BPDE and between (+)- and (−)-anti-BPDE, which has not been attained earlier. The adduct levels quantified by LC-UV and the estimated rate of disappearance of BPDEs in presence of hSA gave an insight into the reactivity of the diol epoxides towards the N-sites on SA. The structure specific method and dosimetry described in this work could be used for accurate estimation of in vivo dose of the BPDEs following exposure to B[a]P, primarily in dose response studies of genotoxicity, e.g. in mice, to aid in quantitative risk assessment of PAHs. PMID:27805056

  13. Interaction of benzo[a]pyrene diol epoxide isomers with human serum albumin: Site specific characterisation of adducts and associated kinetics

    NASA Astrophysics Data System (ADS)

    Motwani, Hitesh V.; Westberg, Emelie; Törnqvist, Margareta

    2016-11-01

    Carcinogenicity of benzo[a]pyrene {B[a]P, a polycyclic aromatic hydrocarbon (PAH)} involves DNA-modification by B[a]P diol epoxide (BPDE) metabolites. Adducts to serum albumin (SA) are not repaired, unlike DNA adducts, and therefore considered advantageous in assessment of in vivo dose of BPDEs. In the present work, kinetic experiments were performed in relation to the dose (i.e. concentration over time) of different BPDE isomers, where human SA (hSA) was incubated with respective BPDEs under physiological conditions. A liquid chromatography (LC) tandem mass spectrometry methodology was employed for characterising respective BPDE-adducts at histidine and lysine. This strategy allowed to structurally distinguish between the adducts from racemic anti- and syn-BPDE and between (+)- and (‑)-anti-BPDE, which has not been attained earlier. The adduct levels quantified by LC-UV and the estimated rate of disappearance of BPDEs in presence of hSA gave an insight into the reactivity of the diol epoxides towards the N-sites on SA. The structure specific method and dosimetry described in this work could be used for accurate estimation of in vivo dose of the BPDEs following exposure to B[a]P, primarily in dose response studies of genotoxicity, e.g. in mice, to aid in quantitative risk assessment of PAHs.

  14. Adaptive upregulation of DNA repair genes following benzo(a)pyrene diol epoxide protects against cell death at the expense of mutations

    PubMed Central

    Christmann, Markus; Boisseau, Catherine; Kitzinger, Rebekka; Berac, Christian; Allmann, Sebastian; Sommer, Tina; Aasland, Dorthe; Kaina, Bernd; Tomicic, Maja T.

    2016-01-01

    A coordinated and faithful DNA damage response is of central importance for maintaining genomic integrity and survival. Here, we show that exposure of human cells to benzo(a)pyrene 9,10-diol-7,8-epoxide (BPDE), the active metabolite of benzo(a)pyrene (B(a)P), which represents a most important carcinogen formed during food preparation at high temperature, smoking and by incomplete combustion processes, causes a prompt and sustained upregulation of the DNA repair genes DDB2, XPC, XPF, XPG and POLH. Induction of these repair factors on RNA and protein level enhanced the removal of BPDE adducts from DNA and protected cells against subsequent BPDE exposure. However, through the induction of POLH the mutation frequency in the surviving cells was enhanced. Activation of these adaptive DNA repair genes was also observed upon B(a)P treatment of MCF7 cells and in buccal cells of human volunteers after cigarette smoking. Our data provide a rational basis for an adaptive response to polycyclic aromatic hydrocarbons, which occurs however at the expense of mutations that may drive cancer formation. PMID:27694624

  15. Haplotypes of DNMT1 and DNMT3B are associated with mutagen sensitivity induced by benzo[a]pyrene diol epoxide among smokers.

    PubMed

    Leng, Shuguang; Stidley, Christine A; Bernauer, Amanda M; Picchi, Maria A; Sheng, Xin; Frasco, Melissa A; Van Den Berg, David; Gilliland, Frank D; Crowell, Richard E; Belinsky, Steven A

    2008-07-01

    The mutagen sensitivity assay is an in vitro measure of DNA repair capacity used to evaluate intrinsic susceptibility for cancer. The high heritability of mutagen sensitivity to different mutagens validates the use of this phenotype to predict cancer susceptibility. However, genetic determinants of mutagen sensitivity have not been fully characterized. Recently, several studies found that three major cytosine DNA methyltransferases (DNMTs), especially DNMT1, have a direct role in the DNA damage response, independent of their methyltransferase activity. This study evaluated the hypothesis that sequence variants in DNMT1, DNMT3A and DNMT3B are associated with mutagen sensitivity induced by the tobacco carcinogen benzo[a]pyrene diol epoxide (BPDE) in 278 cancer-free smokers. Single-nucleotide polymorphisms (n = 134) dispersed over the entire gene and regulatory regions of these DNMTs were genotyped by the Illumina Golden Gate Assay. DNA sequence variation in the DNMT1 and DNMT3B loci was globally associated with breaks per cell (P < 0.04 for both). No global association between DNMT3A and breaks per cell was seen (P = 0.09). Two haplotypes in block1 of DNMT1 (H284) and 3B (H70) were associated with 16 and 24% increase in breaks per cell, respectively. Subjects with three or four adverse haplotypes of both DNMT1 and 3B had a 50% elevation in mean level of breaks per cell compared with persons without adverse alleles (P = 0.004). The association between sequence variants of DNMT1 and 3B and mutagen sensitivity induced by BPDE supports the involvement of these DNMTs in protecting the cell from DNA damage.

  16. Benzo[a]pyrene-7,8-diol-9,10-epoxide causes caspase-mediated apoptosis in H460 human lung cancer cell line.

    PubMed

    Xiao, Hui; Rawal, Malika; Hahm, Eun-Ryeong; Singh, Shivendra V

    2007-11-15

    We have shown previously that wild-type p53 renders H460 human lung cancer cells more sensitive to apoptosis induction by environmental carcinogen benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), but the mechanism of cell death is not fully understood. The present study provides insights into the mechanism by which BPDE causes apoptosis in H460 cells. Exposure of H460 cells to BPDE resulted in a concentration-dependent apoptotic cell death characterized by cleavage of poly(ADP-ribose)polymerase, DNA condensation, and apoptotic histone-associated DNA fragments released into the cytosol. The BPDE-mediated release of apoptotic histone-associated DNA fragments into the cytosol was also observed in a normal bronchial epithelial cell line BEAS-2B. The BPDE-induced apoptosis in H460 cells correlated with up-regulation of pro-apoptotic protein Bak, downregulation of anti-apoptotic Bcl-2 family members Bcl-2 and Bcl-xL, release of cytochrome c from mitochondria to the cytosol without a change in mitochondrial membrane potential or mitochondrial morphology (electron microscopy), and cleavage of caspase-8, -9, and -3. Ectopic expression of Bcl-2 failed to confer significant protection against BPDE-induced apoptosis in H460 cells. The SV40 immortalized mouse embryonic fibroblasts (MEFs) derived from Bak and Bax double knockout mice, but not Bid knockout mice, were significantly more resistant to BPDE-induced apoptosis compared with the MEFs derived from wild-type mice. The BPDE-induced apoptosis was partially but statistically significantly attenuated in the presence of specific inhibitors of caspase-9 (z-LEHDfmk) and caspase-8 (z-IETDfmk). In conclusion, the present study reveals that BPDE-induced apoptosis in H460 cells is associated with Bak induction and caspase activation but independent of Bcl-2.

  17. BENZO[A]PYRENE AND BENZO[C]PHENANTHRENE: THE EFFECT OF STRUCTURE ON THE BINDING OF WATER MOLECULES TO THE DIOL EPOXIDES

    EPA Science Inventory

    ABSTRACT
    The interaction with water of the diol epoxides (DEs) of both a planar and a non-planar PAH have been examined using molecular dynamics. To determine probable water locations around the DE for later use in the study of DE protonation, molecular dynamics simulations u...

  18. Black raspberry extracts inhibit benzo(a)pyrene diol-epoxide-induced activator protein 1 activation and VEGF transcription by targeting the phosphotidylinositol 3-kinase/Akt pathway.

    PubMed

    Huang, Chuanshu; Li, Jingxia; Song, Lun; Zhang, Dongyun; Tong, Qiangsong; Ding, Min; Bowman, Linda; Aziz, Robeena; Stoner, Gary D

    2006-01-01

    Previous studies have shown that freeze-dried black raspberry extract fractions inhibit benzo(a)pyrene [B(a)P]-induced transformation of Syrian hamster embryo cells and benzo(a)pyrene diol-epoxide [B(a)PDE]-induced activator protein-1 (AP-1) activity in mouse epidermal Cl 41 cells. The phosphotidylinositol 3-kinase (PI-3K)/Akt pathway is critical for B(a)PDE-induced AP-1 activation in mouse epidermal Cl 41 cells. In the present study, we determined the potential involvement of PI-3K and its downstream kinases on the inhibition of AP-1 activation by black raspberry fractions, RO-FOO3, RO-FOO4, RO-ME, and RO-DM. In addition, we investigated the effects of these fractions on the expression of the AP-1 target genes, vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS). Pretreatment of Cl 41 cells with fractions RO-F003 and RO-ME reduced activation of AP-1 and the expression of VEGF, but not iNOS. In contrast, fractions RO-F004 and RO-DM had no effect on AP-1 activation or the expression of either VEGF or iNOS. Consistent with inhibition of AP-1 activation, the RO-ME fraction markedly inhibited activation of PI-3K, Akt, and p70 S6 kinase (p70(S6k)). In addition, overexpression of the dominant negative PI-3K mutant delta p85 reduced the induction of VEGF by B(a)PDE. It is likely that the inhibitory effects of fractions RO-FOO3 and RO-ME on B(a)PDE-induced AP-1 activation and VEGF expression are mediated by inhibition of the PI-3K/Akt pathway. In view of the important roles of AP-1 and VEGF in tumor development, one mechanism for the chemopreventive activity of black raspberries may be inhibition of the PI-3K/Akt/AP-1/VEGF pathway.

  19. Preferential repair and strand-specific repair of benzo[a]pyrene diol epoxide adducts in the HPRT gene of diploid human fibroblasts.

    PubMed Central

    Chen, R H; Maher, V M; Brouwer, J; van de Putte, P; McCormick, J J

    1992-01-01

    If excision repair-proficient human cells are allowed time for repair before onset of S phase, the premutagenic lesions formed by (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy- 7,8,9,10-tetrahydrobenzo[a]pyrene (benzo[a]pyrene diol epoxide, BPDE) are lost from the transcribed strand of the hypoxanthine (guanine) phosphoribosyltransferase (HPRT) gene faster than from the nontranscribed strand. No change in strand distribution is seen with repair-deficient cells. These results suggest strand-specific repair of BPDE-induced DNA damage in human cells. To test this, we measured the initial number of BPDE adducts formed in each strand of the actively transcribed HPRT gene and the rate of repair, using UvrABC excinuclease in conjunction with Southern hybridization and strand-specific probes. We also measured the rate of loss of BPDE adducts from the inactive 754 locus. The frequencies of adducts formed by exposure to BPDE (1.0 or 1.2 microM) in either strand of a 20-kilobase fragment that lies entirely within the transcription unit of the HPRT gene were similar; the frequency in the 14-kilobase 754 fragment was approximately 20% lower. The rates of repair in the two strands of the HPRT fragment differed significantly. Within 7 hr after treatment with 1.2 microM BPDE, 53% of the adducts had been removed from the transcribed strand, but only 26% from the nontranscribed strand; after 20 hr, these values were 87% and 58%, respectively. In contrast, only approximately 14% of the BPDE adducts were lost from the 754 locus in 20 hr, a value even lower than the rate of loss from the overall genome (i.e., 38%). These results demonstrate strand-specific and preferential repair of BPDE adducts in human cells. They suggest that the heterogeneous repair of BPDE adducts in the human genome cannot be accounted for merely by the greatly increased rate of the repair specific to the transcribed strand of the active genes, and they point to a role for the chromatin structure. Images

  20. Genetic polymorphisms in biotransformation enzymes for benzo[a]pyrene and related levels of benzo[a]pyrene-7,8-diol-9,10-epoxide-DNA adducts in Goeckerman therapy.

    PubMed

    Beranek, Martin; Fiala, Zdenek; Kremlacek, Jan; Andrys, Ctirad; Hamakova, Kvetoslava; Chmelarova, Marcela; Palicka, Vladimir; Borska, Lenka

    2016-07-25

    Goeckerman therapy (GT) for psoriasis combines the therapeutic effect of crude coal tar (CCT) and ultraviolet radiation (UVR). CCT contains polycyclic aromatic hydrocarbons, some of which can form DNA adducts that may induce mutations and contribute to carcinogenesis. The aim of our work was to evaluate the relationship between concentrations of benzo[a]pyrene-7,8-diol-9,10-epoxide-DNA adducts (BPDE-DNA adducts) and rs4646903 (CYP1A1 gene), rs1048943 (CYP1A1), rs1056836 (CYP1B1), rs1051740 (EPHX1), rs2234922 (EPHX1) and rs8175347 (UGT1A1) polymorphic sites, and GSTM1 null polymorphism in 46 patients with chronic stable plaque psoriasis who underwent GT. The level of BPDE-DNA adducts was determined using the OxiSelect BPDE-DNA Adduct ELISA Kit. Polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis (rs4646903, rs1048943, rs1051740, and rs2234922), fragment analysis (rs8175347), real-time PCR (rs1056836), and digital droplet PCR polymorphism (GSTM1) were used. CYP1B1*1/*1 wild-type subjects and CYP1B1*3/*1 heterozygotes for rs1056836 formed significantly higher amounts of BPDE-DNA adducts than CYP1B1*3/*3 homozygotes (p=0.031 and p=0.005, respectively). Regarding rs1051740, individuals with EPHX1*3/*1 heterozygosity revealed fewer adducts than EPHX1*1/*1 wild-type subjects (p=0.026). Our data suggest that CYP1B1/EPHX1 genotyping could help to predict the risk of DNA damage and to optimize doses of coal tar and UVR exposure in psoriatic patients in whom GT was applied.

  1. The enzymatic conjugation of glutathione with bay-region diol-epoxides of benzo[a]pyrene, benz[a]anthracene and chrysene.

    PubMed

    Robertson, I G; Jernström, B

    1986-10-01

    The kinetics of the enzymatic conjugation of glutathione (GSH) with the anti-diastereoisomers of trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (BPDE), trans-3,4-dihydroxy-1,2-epoxy-1,2,3, 4-tetrahydrobenz[a]anthracene (BADE) and trans-1,2- dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrochrysene (CDE) catalyzed by transferase 4-4 from rat liver have been compared. When the concentration of these diol-epoxides was varied (using 2 mM GSH) the apparent Vmax values were 560, 2100 and 1500 nmol/mg/min for (+/-)-anti-BPDE, (+/-)-anti-BADE and (+/-)-anti-CDE, respectively, with corresponding apparent Km values of 11, 125 and 105 microM. The catalytic efficiency of transferase 4-4 in the GSH conjugation of (+/-)-anti-BADE and (+/-)-anti-CDE is thus approximately one-third of (+/-)-anti-BPDE (0.014 and 0.012 s-1 microM-1 respectively versus 0.042 s-1 microM-1). Similar non-linear Lineweaver-Burk plots were obtained with each diol-epoxide when the concentration of GSH was varied, and two apparent Km values of 0.02-0.04 and 0.4-0.9 mM GSH were estimated. The GSH-conjugates formed with the individual enantiomers of the racemic substrates used were resolved by h.p.l.c. The data indicate that with each diol-epoxide transferase 4-4 is highly selective (greater than or equal to 95%) towards the biologically most active (+)-enantiomer.

  2. Tumorigenicity of the optical enantiomers of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides in newborn mice: exceptional activity of (+)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.

    PubMed Central

    Buening, M K; Wislocki, P G; Levin, W; Yagi, H; Thakker, D R; Akagi, H; Koreeda, M; Jerina, D M; Conney, A H

    1978-01-01

    The tumorigenicities of benzo[a]pyrene and each optical enantiomer of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides derived from trans-7,8-dihydroxy-7,8-dihydrobenzol[a]pyrene were tested by sequential intraperitoneal injection of mice with 1,2, and 4 nmol, or with 2, 4, and 8 nmol of each compound on the 1st, 8th, and 15th day of life, respectively. The experiment was terminated when the animals were 34--37 weeks old. (+)-7beta, 8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzol[a]pyrene [(+)-BP-7beta,8alpha-diol-9alpha,10alpha-epoxide 2] had exceptional tumorigenicity, whereas benzo[a]-pyrene and the other three optically pure isomers of the benzo[a]pyrene 7,8-diol,9,10-epoxides had little or no activity. These results demonstrate differences in the carcinogenic activities of optically active isomers of a polycyclic hydrocarbon diol epoxide. Eleven percent of control mice had pulmonary tumors, whereas 71% and 100% of the mice treated with a total dose of 7 or 14 nmol of (+)-BP-7beta,8alpha-diol-9alpha,10alpha-epoxide 2, respectively, had pulmonary tumors. Control mice had an average of 0.12 pulmonary tumors per mouse, whereas mice treated with a total dose of 7 or 14 nmol of (+)-BP-7beta,8alpha-diol-9alpha,10alpha-epoxide 2 had 1.72 and 7.67 pulmonary tumors per mouse, respectively. Mice treated with 14 nmol of (-)-BP-7alpha,8beta-diol-9beta,10beta-epoxide 2, (-)-BP-7beta,8alpha-diol-9beta,10beta-epoxide 1, or (+)-BP-7alpha,8beta-diol-9alpha,10alpha-epoxide 1 had 0.13, 0.25, and 0.34 pulmonary tumors per animal, respectively. PMID:281685

  3. Mutability of p53 hotspot codons to benzo(a)pyrene diol epoxide (BPDE) and the frequency of p53 mutations in nontumorous human lung.

    PubMed

    Hussain, S P; Amstad, P; Raja, K; Sawyer, M; Hofseth, L; Shields, P G; Hewer, A; Phillips, D H; Ryberg, D; Haugen, A; Harris, C C

    2001-09-01

    p53 mutations are common in lung cancer. In smoking-associated lung cancer,the occurrence of G:C to T:A transversions at hotspot codons, e.g., 157, 248, 249,and 273, has been linked to the presence of carcinogenic chemicalsin tobacco smoke including polycyclic aromatic hydrocarbons suchas benzo(a)pyrene (BP). In the present study, we have used a highly sensitive mutation assay to determine the p53 mutation load in nontumorous human lung and to study the mutability of p53 codons 157, 248, 249, and 250 to benzo(a)pyrene-diol-epoxide (BPDE), an active metabolite of BP in human bronchial epithelial BEAS-2B cells. We determined the p53 mutational load at codons 157, 248, 249, and 250 in nontumorous peripheral lung tissue either from lung cancer cases among smokers or noncancer controls among smokers and nonsmokers. A 5-25-fold higher frequency of GTC(val) to TTC(phe) transversions at codon 157 was found in nontumorous samples (57%) from cancer cases (n = 14) when compared with noncancer controls (n = 8; P < 0.01). Fifty percent (7/14) of the nontumorous samples from lung cancer cases showed a high frequency of codon 249 AGG(arg) to AGT(ser) mutations (P < 0.02). Four of these seven samples with AGT(ser) mutations also showed a high frequency of codon 249 AGG(arg) to ATG(met) mutations, whereas only one sample showed a codon 250 CCC to ACC transversion. Tumor tissue from these lung cancer cases (38%) contained p53 mutations but were different from the above mutations found in the nontumorous pair. Noncancer control samples from smokers or nonsmokers did not contain any detectable mutations at codons 248, 249, or 250. BEAS-2B bronchial epithelial cells exposed to doses of 0.125, 0.5, and 1.0 microM BPDE, showed G:C to T:A transversions at codon 157 at a frequency of 3.5 x 10(-7), 4.4 x 10(-7), and 8.9 x 10(-7), respectively. No mutations at codon 157 were found in the DMSO-treated controls. These doses of BPDE induced higher frequencies, ranging from 4-12-fold, of G:C to

  4. Benzo[a]pyrene-7,8-diol-9,10-epoxide inhibits gap junction intercellular communication via phosphorylation of tumor progression locus 2 in WB-F344 rat liver epithelial cells.

    PubMed

    Lee, Bo Kyung; Chung, Min-Yu; Lee, Ki Won

    2015-05-01

    Benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE), a major metabolite of benzo[a]pyrene, has been reported to function as a human carcinogen. However, the molecular mechanism of how B[a]PDE regulates signaling pathways during tumor promotion remains unclear. In this study, we investigated the effects of B[a]PDE on the regulation of gap junction intercellular communication (GJIC), one of the major carcinogenic processes, and its main regulatory signaling pathways using WB-F344 rat liver epithelial (WB-F344 RLE) cells. Treatment of benzo[a]pyrene or B[a]PDE resulted in GJIC inhibition, and B[a]PDE was more active at lower concentrations than benzo[a]pyrene in the suppression of GJIC. This suggests that B[a]PDE is a stronger GJIC inhibitor. B[a]PDE at 1 µM reversibly inhibited GJIC in WB-F344 RLE cells, which was attributable to hyperphosphorylation of connexin43 (Cx43) via phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK). We found that B[a]PDE induced phosphorylation of tumor progression locus 2 (Tpl2), a direct upstream regulator of MEK. Tpl2 inhibitor recovered B[a]PDE-induced GJIC inhibition and attenuated B[a]PDE-induced MEK/ERK phosphorylation in WB-F344 RLE cells. Collectively, our results suggest that B[a]PDE suppresses GJIC by activating Tpl2 and subsequently the MEK/ERK pathway and Cx43 phosphorylation in WB-F344 RLE cells. These results outline the potential importance of Tpl2 as a novel therapeutic target for B[a]PDE-induced GJIC inhibition during cancer promotion.

  5. Oxidative damage to nucleic acids and benzo(a)pyrene-7,8-diol-9,10-epoxide-DNA adducts and chromosomal aberration in children with psoriasis repeatedly exposed to crude coal tar ointment and UV radiation.

    PubMed

    Borska, Lenka; Andrys, Ctirad; Krejsek, Jan; Palicka, Vladimir; Chmelarova, Marcela; Hamakova, Kvetoslava; Kremlacek, Jan; Fiala, Zdenek

    2014-01-01

    The paper presents a prospective cohort study. Observed group was formed of children with plaque psoriasis (n=19) treated by Goeckerman therapy (GT). The study describes adverse (side) effects associated with application of GT (combined exposure of 3% crude coal tar ointment and UV radiation). After GT we found significantly increased markers of oxidative stress (8-hydroxy-2'-deoxyguanosine, 8-hydroxyguanosine, and 8-hydroxyguanine), significantly increased levels of benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) DNA adducts (BPDE-DNA), and significantly increased levels of total number of chromosomal aberrations in peripheral lymphocytes. We found significant relationship between (1) time of UV exposure and total number of aberrated cells and (2) daily topical application of 3% crude coal tar ointment (% of body surface) and level of BPDE-DNA adducts. The findings indicated increased hazard of oxidative stress and genotoxic effects related to the treatment. However, it must be noted that the oxidized guanine species and BPDE-DNA adducts also reflect individual variations in metabolic enzyme activity (different extent of bioactivation of benzo[a]pyrene to BPDE) and overall efficiency of DNA/RNA repair system. The study confirmed good effectiveness of the GT (significantly decreased PASI score).

  6. Suppressive activities of OGG1 and MYH proteins against G:C to T:A mutations caused by 8-hydroxyguanine but not by benzo[a]pyrene diol epoxide in human cells in vivo.

    PubMed

    Yamane, Arito; Shinmura, Kazuya; Sunaga, Noriaki; Saitoh, Takayuki; Yamaguchi, Satoru; Shinmura, Yumi; Yoshimura, Kimio; Murakami, Hirokazu; Nojima, Yoshihisa; Kohno, Takashi; Yokota, Jun

    2003-06-01

    8-Hydroxyguanine (8OHG), an oxidatively damaged base, and benzo[a]pyrene-diol-epoxide (BPDE), a metabolite of benzo[a]pyrene found in cigarette smoke, are thought to be major causes for G:C to T:A transversions in DNA of human cells. In this study, we assessed the abilities of OGG1, MYH and APE1 proteins, which are components of a base excision repair pathway, to suppress G:C to T:A transversions caused by 8OHG or BPDE by a bacterial suppressor tRNA (supF) forward mutation assay using a shuttle plasmid, pMY189. The introduction of a single 8OHG residue at position 159 of the supF gene and treatment with BPDE led to a 65- and 34-fold increase in mutation frequencies of the pMY189 plasmid, respectively, after replication in the NCI-H1299 human lung cancer cell line. G:C to T:A transversions were predominantly induced in these plasmids. Both the mutation frequency of the 8OHG-containing plasmid in NCI-H1299 cells and the occurrence of G:C to T:A transversions at position 159 in the supF gene were significantly reduced by overexpression of OGG1 and MYH proteins, but not by that of APE1 protein. In contrast, neither mutation frequency nor the occurrence of G:C to T:A transversion of the BPDE-treated plasmid was reduced by overexpression of OGG1, MYH and APE1 proteins. These results indicate that OGG1 and MYH function as suppressors for G:C to T:A transversions by 8OHG but not by BPDE in human cells.

  7. Skin tumor initiating ability of benzo(a)pyrene 4,5- 7,5- and 7,8-diol-9,10-epoxides and 7,8-diol.

    PubMed

    Slaga, T J; Viaje, A; Betty, D L; Brachen, W; Buty, S G; Scribner, J D

    1976-11-01

    The skin tumor initiating abilities of both K-region and non-K-region epoxides of benzo(a)pyrene(BP) were determined in mice using a two-stage system of tumorigenesis. BP-4,5-epoxide and BP-7,8-dihydrodiol-9,10-epoxide (anti) were found to be weak tumor initiators whereas BP-7,8-epoxide had about a third of the activity as the parent hydrocarbon, BP. However, the 7,8-dihydrodiol of BP was found to be approximately as potent as BP suggesting that it may be a proximate carcinogen.

  8. Influence of Na+ on DNA reactions with aromatic epoxides and diol epoxides: evidence that DNA catalyzes the formation of benzo[a]pyrene and benz[a]anthracene adducts at intercalation sites.

    PubMed

    Fernando, H; Huang, C R; Milliman, A; Shu, L; LeBreton, P R

    1996-12-01

    Reactions of the benzo[a]pyrene (BP) and benz[a]anthracene (BA) metabolites, (+/-)-trans-7 8-dihydroxy-anti-9, 10-epoxy-7, 8, 9, 10-tetrahydro-BP (BPDE), (+/-)-trans-3, 4-dihydroxy-anti- 1,2-epoxy-1,2,3,4-tetrahydro-BA (BADE), (+/-)-BP-4,5-oxide (BPO), and (+/-)-BA-5, 6-oxide (BAO), were examined under pseudo-first-order conditions at varying Na+ (2.0-100 Mm) and native calf thymus DNA (ctDNA) concentrations. In 0.2 mM ctDNA and 2.0 mM Na+, at a pH of 7.3 most BPDE, BADE, BPO, and BAO (87-95%) undergo DNA catalyzed hydrolysis or rearrangement. For BPDE and BPO, overall, pseudo-first-order rate constants, k, in 2.0 mM Na+ and 0.2 mM ctDNA are 21-72 times larger than values obtained without DNA. For BADE and BAO, the rate constants are less strongly influenced by DNA; k values in 0.2 mM ctDNA are only 9-12 times larger than values obtained without DNA. Kinetic data for BPDE, BPO, BADE, and BAO and DNA intercalation association constants (KA) for BP and BA diols which are model compounds indicate that KA values for BPDE and BPO in 2.0 mM Na+ are 6.6-59 times larger than those of BADE and BAO. The greater DNA enhancement of rate constants for BPDE and BPO, versus BADE and BAO, correlates with the larger KA values of the BP metabolites. DNA adducts, which account for less than 10% of the yields, also form. For BPDE in 0.20 mM ctDNA, k decreases 5.1 times as the Na+ concentration increases from 2.0 to 100 mM. Nevertheless, the DNA adduct level remains constant over the range of Na+ concentrations examined. These results provide evidence that, for BPDE in 0.20 mM DNA and 2.0 mM Na+, ctDNA adduct formation follows a mechanism which is similar to that for DNA catalyzed hydrolysis. The pseudo-first-order rate constant for adduct formation, kAd, given approximately by kAd approximately equal to (kcat,AdKA[DNA])/(1 + KA[DNA]), where kcat,Ad is a catalytic rate constant. for BADE, BPO, and BAO, the influence of varying DNA and Na+ concentrations on k values is similar to that

  9. Detection and characterization of human serum antibodies to polycyclic aromatic hydrocarbon diol-epoxide DNA adducts.

    PubMed Central

    Newman, M J; Light, B A; Weston, A; Tollurud, D; Clark, J L; Mann, D L; Blackmon, J P; Harris, C C

    1988-01-01

    The presence of serum antibodies to the diol-epoxide DNA adducts of representative polycyclic aromatic hydrocarbons (PAH), chrysene, benz[a]anthracene and benzo[a]pyrene, was determined by ELISA using serum samples obtained from normal healthy individuals. Antibodies that reacted against PAH adducted-DNA, but not against PAH-adducted protein, were found in the serum of approximately 40% of the test individuals. Specificity analysis of the antibodies demonstrated that serological cross-reactions between the benzo[a]pyrene and the chrysene diol-epoxide adducts were present. Similar cross-reactivity between the benz[a]anthracene and the chrysene adducts was observed. Sera containing antibodies that were apparently specific for each of the three PAH-DNA adducts were also identified. The presence of antibodies to PAH-DNA adducts indicates both past exposure to these carcinogenic PAH and their metabolic activation to the DNA damaging metabolites. These antibodies may prove to be useful in both retrospective and prospective epidemiological studies of various diseases associated with PAH exposure. PMID:3392204

  10. Influence of adduct stereochemistry and hydrogen-bonding solvents on photoinduced charge transfer in a covalent benzo[a]pyrene diol epoxide-nucleoside adduct on picosecond time scales

    SciTech Connect

    O'Connor, D. ); Shafirovich, V.Y.; Geacintov, N.E. )

    1994-09-29

    Photoinduced electron transfer occurs with different rate constants upon picosecond laser pulse excitation of the stereoisomeric (+)-trans- and (-)-cis-benzo[a]pyrene diol epoxide-N[sup 2]-deoxyguanosine covalently linked adducts (BPDE-N[sup 2]-dG, bond with 10S absolute configuration) in polar solvents (N,N[prime]-dimethylformamide (DMF), and the hydrogen-bonding liquids H[sub 2]O, D[sub 2]O, formamide (FA), and N-methylformamide (NMF)). In the case of (+)-trans-BPDE-dG in DMF, photoinduced electron transfer occurs in the normal Marcus region, from dG to the pyrenyl residue singlet with a rate constant k[sub s] = (9.1 [+-] 0.9) x 10[sup 9] s[sup [minus]1], which is followed by a slower recombination (k[sub r] = (1.8 + 0.5) x 10[sup 9] s[sup [minus]1]) in the inverted Marcus region. In the cis-stereoisomeric adduct, both rate constants are enhanced by a factor of approximately 5. The presence of the hydrogen-bonding network in NMF and FA exerts opposite effects on these rate constants, decreasing k[sub s] and increasing k[sub r] by factors of 2-5. In aqueous solutions these effects are even more pronounced, and radical ions are not observed since k[sub r] [much gt] k[sub s]. A kinetic isotope effect on the delay of the pyrenyl singlets in H[sub 2]O and D[sub 2]O (k[sub s](H[sub 2]O)/k[sub s](D[sub 2]O) = 1.3-1.5) suggests that a proton-coupled electron transfer mechanism may be operative in aqueous solutions. 51 refs., 10 figs., 2 tabs.

  11. Mutagenicity and tumorigenicity of the four enantiopure bay-region 3,4-diol-1,2-epoxide isomers of dibenz[a,h]anthracene.

    PubMed

    Chang, Richard L; Wood, Alexander W; Huang, Mou Tuan; Xie, Jian Guo; Cui, Xiao Xing; Reuhl, Kenneth R; Boyd, D R; Lin, Yong; Shih, Weichung Joe; Balani, Suresh K; Yagi, Haruhiko; Jerina, Donald M; Conney, Allan H

    2013-09-01

    Each enantiomer of the diastereomeric pair of bay-region dibenz[a,h]anthracene 3,4-diol-1,2-epoxides in which the benzylic 4-hydroxyl group and epoxide oxygen are either cis (isomer 1) or trans (isomer 2) were evaluated for mutagenic activity. In strains TA 98 and TA 100 of Salmonella typhimurium, the diol epoxide with (1S,2R,3S,4R) absolute configuration [(-)-diol epoxide-1] had the highest mutagenic activity. In Chinese hamster V-79 cells, the diol epoxide with (1R,2S,3S,4R) absolute configuration [(+)-diol epoxide-2] had the highest mutagenic activity. The (1R,2S,3R,4S) diol epoxide [(+)-diol epoxide-1] also had appreciable activity, whereas the other two bay-region diol epoxide enantiomers had very low activity. In tumor studies, the (1R,2S,3S,4R) enantiomer was the only diol epoxide isomer tested that had strong activity as a tumor initiator on mouse skin and in causing lung and liver tumors when injected into newborn mice. This stereoisomer was about one-third as active as the parent hydrocarbon, dibenz[a,h]anthracene as a tumor initiator on mouse skin; it was several-fold more active than dibenz[a,h]anthracene as a lung and liver carcinogen when injected into newborn mice. (-)-(3R,4R)-3β,4α-dihydroxy-3,4-dihydro-dibenz[a,h]anthracene [(-)-3,4-dihydrodiol] was slightly more active than dibenz[a,h]anthracene as a tumor initiator on mouse skin, whereas (+)-(3S,4S)-3α,4β-dihydroxy-3,4-dihydro-dibenz[a,h]anthracene [(+)-3,4-dihydrodiol] had only very weak activity. The present investigation and previous studies with the corresponding four possible enantiopure bay-region diol epoxide enantiomers/diastereomers of benzo[a]pyrene, benz[a]anthracene, chrysene, benzo[c]phenanthrene, dibenz[c,h]acridine, dibenz[a,h]acridine and dibenz[a,h]anthracene indicate that the bay-region diol epoxide enantiomer with [R,S,S,R] absolute stereochemistry has high tumorigenic activity on mouse skin and in newborn mice.

  12. COMPARATIVE STUDIES OF THE EFFECT OF POLYCYCLIC AROMATIC HYDROCARBON GEOMETRY ON THE HYDROLYSIS OF DIOL EPOXIDES

    EPA Science Inventory

    Comparative studies of the effect of polycyclic aromatic hydrocarbon geometry on the hydrolysis of diol epoxides

    The interaction of the diol epoxides (DEs) of both planar and non-planar PAHs with water have been examined using quantum mechanical and molecular dynamics. Th...

  13. Oxidation of benzo(a)pyrene-7,8-diol by methemoglobin and hydrogen peroxide

    SciTech Connect

    Catalano, C.E.; Ortiz, de Montellano, P.R.

    1986-05-01

    Methemoglobin catalyzes the hydrogen peroxide dependent oxidation of styrene to styrene oxide. An alkylperoxy radical formed from the combination of molecular oxygen with an amino acid radical at the protein surface has been proposed as the actual oxidant. This model predicts that access to the heme crevice is not a requirement for oxidation. The oxidation of benzo(a)pyrene-7.8-dihydro-diol, a substrate whose steric bulk makes access into the heme crevice unlikely, has been examined to further test this hypothesis. Anti-trans-benzo(a)pyrene-7,8,9,10-tetrol is isolated from the incubation of B(a)P-diol in the presence of methemoglobin and H/sub 2/O/sub 2/. The exclusive formation of this tetrol supports a peroxidative epoxidation mechanism analogous to that for lipid peroxy radical oxidation of the title compound. The oxidation of conjugated fatty acids by the methemoglobin/H/sub 2/O/sub 2/ system further supports the hypothesis that oxidation of compounds occurs at protein surface and not in the heme crevice as previously suspected.

  14. In vitro metabolism of benzo[a]pyrene-7,8-dihydrodiol and dibenzo[def,p]chrysene-11,12 diol in rodent and human hepatic microsomes.

    PubMed

    Smith, Jordan N; Mehinagic, Denis; Nag, Subhasree; Crowell, Susan R; Corley, Richard A

    2017-03-05

    Polycyclic aromatic hydrocarbons (PAHs) are contaminants that are ubiquitously found in the environment, produced through combustion of organic matter or petrochemicals, and many of which are procarcinogens. The prototypic PAH, benzo[a]pyrene (B[a]P) and the highly carcinogenic dibenzo[def,p]chrysene (DBC) are metabolically activated by isoforms of the P450 enzyme superfamily producing benzo[a]pyrene-7,8-dihydrodiol (B[a]P diol), dibenzo[def,p]chrysene-11,12 diol (DBC diol). Each of these diols can be further metabolized by cytochrome P450 enzymes to highly reactive diol-epoxide metabolites that readily react with DNA or by phase II conjugation facilitating excretion. To complement prior in vitro metabolism studies with parent B[a]P and DBC, both phase I metabolism and phase II glucuronidation of B[a]P diol and DBC diol were measured in hepatic microsomes from female B6129SF1/J mice, male Sprague-Dawley rats, and female humans. Metabolic parameters, including intrinsic clearance and Michaelis-Menten kinetics were calculated from substrate depletion data. Mice and rats demonstrated similar B[a]P diol phase I metabolic rates. Compared to rodents, human phase I metabolism of B[a]P diol demonstrated lower overall metabolic capacity, lower intrinsic clearance at higher substrate concentrations (>0.14μM), and higher intrinsic clearance at lower substrate concentrations (<0.07μM). Rates of DBC diol metabolism did not saturate in mice or humans and were highest overall in mice. Higher affinity constants and lower capacities were observed for DBC diol glucuronidation compared to B[a]P diol glucuronidation; however, intrinsic clearance values for these compounds were consistent within each species. Kinetic parameters reported here will be used to extend physiologically based pharmacokinetic (PBPK) models to include the disposition of B[a]P and DBC metabolites in animal models and humans to support future human health risk assessments.

  15. Influence of C-5 substituted cytosine and related nucleoside analogs on the formation of benzo[a]pyrene diol epoxide-dG adducts at CG base pairs of DNA.

    PubMed

    Guza, Rebecca; Kotandeniya, Delshanee; Murphy, Kristopher; Dissanayake, Thakshila; Lin, Chen; Giambasu, George Madalin; Lad, Rahul R; Wojciechowski, Filip; Amin, Shantu; Sturla, Shana J; Hudson, Robert H E; York, Darrin M; Jankowiak, Ryszard; Jones, Roger; Tretyakova, Natalia Y

    2011-05-01

    Endogenous 5-methylcytosine ((Me)C) residues are found at all CG dinucleotides of the p53 tumor suppressor gene, including the mutational 'hotspots' for smoking induced lung cancer. (Me)C enhances the reactivity of its base paired guanine towards carcinogenic diolepoxide metabolites of polycyclic aromatic hydrocarbons (PAH) present in cigarette smoke. In the present study, the structural basis for these effects was investigated using a series of unnatural nucleoside analogs and a representative PAH diolepoxide, benzo[a]pyrene diolepoxide (BPDE). Synthetic DNA duplexes derived from a frequently mutated region of the p53 gene (5'-CCCGGCACCC GC[(15)N(3),(13)C(1)-G]TCCGCG-3', + strand) were prepared containing [(15)N(3), (13)C(1)]-guanine opposite unsubstituted cytosine, (Me)C, abasic site, or unnatural nucleobase analogs. Following BPDE treatment and hydrolysis of the modified DNA to 2'-deoxynucleosides, N(2)-BPDE-dG adducts formed at the [(15)N(3), (13)C(1)]-labeled guanine and elsewhere in the sequence were quantified by mass spectrometry. We found that C-5 alkylcytosines and related structural analogs specifically enhance the reactivity of the base paired guanine towards BPDE and modify the diastereomeric composition of N(2)-BPDE-dG adducts. Fluorescence and molecular docking studies revealed that 5-alkylcytosines and unnatural nucleobase analogs with extended aromatic systems facilitate the formation of intercalative BPDE-DNA complexes, placing BPDE in a favorable orientation for nucleophilic attack by the N(2) position of guanine.

  16. In vitro metabolism of benzo[a]pyrene-7,8-dihydrodiol and dibenzo[def,p]chrysene-11,12 diol in rodent and human hepatic microsomes

    DOE PAGES

    Smith, Jordan N.; Mehinagic, Denis; Nag, Subhasree; ...

    2017-01-21

    Polycyclic aromatic hydrocarbons (PAHs) are contaminants that are ubiquitously found in the environment, produced through combustion of organic matter or petrochemicals, and many of which are procarcinogens. The prototypic PAH, benzo[a]pyrene (B[a]P) and the highly carcinogenic dibenzo[def,p]chrysene (DBC) are metabolically activated by isoforms of the P450 enzyme superfamily producing benzo[a]pyrene-7,8-dihydrodiol (B[a]P diol), dibenzo[def,p]chrysene-11,12 diol (DBC diol). Each of these diols can be further metabolized by cytochrome P450 enzymes to highly reactive diol-epoxide metabolites that readily react with DNA or by phase II conjugation facilitating excretion. To complement prior in vitro metabolism studies with parent B[a]P and DBC, both phase Imore » metabolism and phase II glucuronidation of B[a]P diol and DBC diol were measured in this paper in hepatic microsomes from female B6129SF1/J mice, male Sprague-Dawley rats, and female humans. Metabolic parameters, including intrinsic clearance and Michaelis-Menten kinetics were calculated from substrate depletion data. Mice and rats demonstrated similar B[a]P diol phase I metabolic rates. Compared to rodents, human phase I metabolism of B[a]P diol demonstrated lower overall metabolic capacity, lower intrinsic clearance at higher substrate concentrations (>0.14 μM), and higher intrinsic clearance at lower substrate concentrations (<0.07 μM). Rates of DBC diol metabolism did not saturate in mice or humans and were highest overall in mice. Higher affinity constants and lower capacities were observed for DBC diol glucuronidation compared to B[a]P diol glucuronidation; however, intrinsic clearance values for these compounds were consistent within each species. Finally, kinetic parameters reported here will be used to extend physiologically based pharmacokinetic (PBPK) models to include the disposition of B[a]P and DBC metabolites in animal models and humans to support future human health risk assessments.« less

  17. Highly selective hydrolytic kinetic resolution of terminal epoxides catalyzed by chiral (salen)Co(III) complexes. Practical synthesis of enantioenriched terminal epoxides and 1,2-diols.

    PubMed

    Schaus, Scott E; Brandes, Bridget D; Larrow, Jay F; Tokunaga, Makoto; Hansen, Karl B; Gould, Alexandra E; Furrow, Michael E; Jacobsen, Eric N

    2002-02-20

    The hydrolytic kinetic resolution (HKR) of terminal epoxides catalyzed by chiral (salen)Co(III) complex 1 x OAc affords both recovered unreacted epoxide and 1,2-diol product in highly enantioenriched form. As such, the HKR provides general access to useful, highly enantioenriched chiral building blocks that are otherwise difficult to access, from inexpensive racemic materials. The reaction has several appealing features from a practical standpoint, including the use of H(2)O as a reactant and low loadings (0.2-2.0 mol %) of a recyclable, commercially available catalyst. In addition, the HKR displays extraordinary scope, as a wide assortment of sterically and electronically varied epoxides can be resolved to > or = 99% ee. The corresponding 1,2-diols were produced in good-to-high enantiomeric excess using 0.45 equiv of H(2)O. Useful and general protocols are provided for the isolation of highly enantioenriched epoxides and diols, as well as for catalyst recovery and recycling. Selectivity factors (k(rel)) were determined for the HKR reactions by measuring the product ee at ca. 20% conversion. In nearly all cases, k(rel) values for the HKR exceed 50, and in several cases are well in excess of 200.

  18. Inactivation of the thymidine kinase gene after in vitro modification with benzo(a)pyrene-diol-epoxide and transfer to LTK- cells as a eukaryotic test for carcinogens.

    PubMed

    Schaefer-Ridder, M; Moeroey, T; Engelhardt, U

    1984-12-01

    A recombinant plasmid containing the thymidine kinase (TK) gene (pAGO; 6.36 kilobases) was reacted in vitro with (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, an ultimate carcinogenic metabolite of benzo(a)pyrene. The covalent binding of the metabolite to the circular forms of pAGO was visible by a drastic change in their mobility during agarose gel electrophoresis. The 4% modified DNA was only partially restricted by different endonucleases. Modification and limited restriction were correlated to the biological activity by transfer of the plasmid (TK gene), modified and unmodified, to TK-deficient cells. Upon transfection of mouse LTK- cells with modified plasmid or modified TK gene, no or only a few TK-positive cells were obtained, in contrast to the formation of many colonies after transfection with the unmodified plasmid (gene). Benzo(a)-pyrene itself and phenanthrene oxide, a weakly reactive but noncarcinogenic chemical, did not induce this effect. The reactive diol-epoxides of noncarcinogenic benzo(a)acridine and carcinogenic benzo(c)acridine showed a weaker but similar decreasing effect on the formation of TK+ clones. This inhibition of transformation efficiency suggests inactivation of the gene by chemical modification. Our experimental approach challenges the repair capacity of the eukaryotic cell and thus renders the strategy suitable not only as a eukaryotic test for carcinogens but also as a tool for the study of carcinogenesis as aberrant gene expression.

  19. Benzo(a)pyrene dione-benzo(a)pyrene diol oxidation-reduction couples; involvement in DNA damage, cellular toxicity, and carcinogenesis

    SciTech Connect

    Lesko, S.A.; Lorentzen, R.J.

    1985-01-01

    Three isomeric quinone metabolites of the environmental carcinogen benzo(a)pyrene undergo reversible, univalent oxidation-reduction cycles involving the corresponding benzo(a)pyrene diols and intermediate semiquinone radicals. Under anaerobic conditions, benzo(a)pyrene 1,6-dione, benzo(a)pyrene 3,6-dione, and benzo(a)pyrene 6,12-dione are readily reduced by mild biological agents such as NADH and glutathione. The benzo(a)pyrene diols, in turn, are very rapidly autooxidized to diones when exposed to air. Substantial amounts of hydrogen peroxide are produced during these autooxidations. The benzo(a)pyrene diol/benzo(a)pyrene dione interconversions proceed by one-electron steps; the corresponding semiquinone radicals were detected as intermediates when the reactions were carried out at high pH. Benzo(a)pyrene diones are electron-acceptor substrates for NADHdehydrogenase. Catalytic amounts of these metabolites, together with this respiratory enzyme, function as cyclic oxidation-reduction couples to link NADH and molecular oxygen in the continuous production of hydrogen peroxide. Benzo(a)pyrene diones induce strand scissions when incubated with T7 DNA. The damage is modified by conditions that indicate that reduced oxygen species propagate the reactions responsible for strand scission. Benzo(a)pyrene diones are cytotoxic at low concentrations to cultured hamster cells. The cytotoxic effect can be substantially reduced by depletion of oxygen from the growth medium and the atmosphere in which the cells are incubated. The results support the hypothesis that the biological activity of benzo(a)pyrene diones is due to the regenerative oxidation-reduction cycles involving quinone and hydroquinone forms; activated oxygen species and semiquinone radicals formed during these cycles are most likely responsible for the observed cytotoxic action. The role of activated oxygen species in carcinogenesis is discussed.

  20. Molecular mechanics and antibody binding in the structural analysis of polycyclic aromatic hydrocarbon-diol-epoxide--DNA adducts.

    PubMed

    Weston, A; Newman, M J; Mann, D L; Brooks, B R

    1990-05-01

    Analysis of polycyclic aromatic hydrocarbon (PAH)-DNA adducts using monoclonal antibodies raised against DNA that had been modified with (+-)-r-7-,t-8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene in an enzyme-linked immunosorbent assay, as well as analysis using human serum antibodies and antibodies raised in laboratory animals, have suggested the presence on these adducts of both common and unique immunological epitopes. The molecular mechanics studies reported here establish a model for the analysis of PAH-DNA adducts through the identification of energetically favored binding conformations and they further reveal structural alterations in DNA due to the presence of carcinogen adducts. The data explain the antibody reactivity patterns by defining different molecular presenting surfaces that are available for antibody binding. The preferred orientation of the aromatic portions of the adducts, which align either 3' or 5' in the minor groove, were found to be correlated with antibody reactivity patterns. Examination of the topographical characteristics of the adducts facilitated correlation of adduct-antibody recognition and adduct presenting surface. Significant differences were found between benzo[a]pyrene-diol-epoxide (BPDE)-DNA adducts, which align 5' in the minor groove, and benz[a]anthracene-diol-epoxide (BADE)-DNA and dibenz[a,c]anthracene-diol-epoxide-DNA adducts, which align 3' within the minor groove. Chrysene-diol-epoxide-DNA adducts were found to have only a weak preference for 5' alignment and therefore share topographical characteristics with both BPDE-DNA and BADE-DNA adducts.

  1. Methylation of cytosine at C5 in a CpG sequence context causes a conformational switch of a benzo[a]pyrene diol epoxide-N2-guanine adduct in DNA from a minor groove alignment to intercalation with base displacement.

    SciTech Connect

    Zhang, N.; Lin, C.; Huang, X.; Kolbanovskiy, A.; Hingerty, Brian E; Amin, S.; Broyde, S.; Geactinov, N. E.; Patel, D. J.

    2005-03-01

    It is well known that CpG dinucleotide steps in DNA, which are highly methylated at the 5-position of cytosine (meC) in human tissues, exhibit a disproportionate number of mutations within certain codons of the p53 gene. There is ample published evidence indicating that the reactivity of guanine with anti-B[a]PDE (a metabolite of the environmental carcinogen benzo[a]pyrene) at CpG mutation hot spots is enhanced by the methylation of the cytosine residue flanking the target guanine residue on the 5'-side. In this work we demonstrate that such a methylation can also dramatically affect the conformational characteristics of an adduct derived from the reaction of one of the two enantiomers of anti-B[a]PDE with the exocyclic amino group of guanine ([BP]G adduct). A detailed NMR study indicates that the 10R (-)-trans-anti-[BP]G adduct undergoes a transition from a minor groove-binding alignment of the aromatic BP ring system in the unmethylated C-[BP]G sequence context, to an intercalative BP alignment with a concomitant displacement of the modified guanine residue into the minor groove in the methylated meC-[BP]G sequence context. By contrast, a minor groove-binding alignment was observed for the stereoisomeric 10S (+)-trans-anti-[BP]G adduct in both the C-[BP]G and meC-[BP]G sequence contexts. This remarkable conformational switch resulting from the presence of a single methyl group at the 5-position of the cytosine residue flanking the lesion on the 5'-side, is attributed to the hydrophobic effect of the methyl group that can stabilize intercalated adduct conformations in an adduct stereochemistry-dependent manner. Such conformational differences in methylated and unmethylated CpG sequences may be significant because of potential alterations in the cellular processing of the [BP]G adducts by DNA transcription, replication, and repair enzymes.

  2. Chemopreventive activity of chlorophyllin against mouse skin carcinogenesis by benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide.

    PubMed

    Park, K K; Surh, Y J

    1996-04-19

    Chlorophyllin (CHL), the sodium and copper salt of chlorophyll, was tested for its chemopreventive activity against tumorigenesis induced by benzo[a]pyrene (B[a]P) and its ultimate electrophilic and carcinogenic metabolite, benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide(BPDE). Administration of CHL (15 mg/kg body wt) by gavage to female ICR mice 30 min prior to a topical application of B[a]P or BPDE resulted in significant reduction in both incidence and multiplicity of skin tumors initiated by these carcinogens. CHL was rapidly distributed in the skin and other tissues of mice after oral administration. Taken together, these results suggest that CHL is a potential chemopreventive agent.

  3. Oxidized metabolites from benzo[a]pyrene, benzo[e]pyrene, and aza-benzo[a]pyrenes. A computational study of their carbocations formed by epoxide ring opening reactions.

    PubMed

    Borosky, Gabriela L; Laali, Kenneth K

    2007-07-21

    A DFT study aimed at understanding structure-reactivity relationships and fluorine substitution effects on carbocation stability in benzo[a]pyrene (BaP), benzo[e]pyrene (BeP), and aza-benzo[a]pyrene (aza-BaP) derivatives are reported. The relative energies of the resulting carbocations are examined and compared, taking into account the available biological activity data on these compounds. O-Protonation of the epoxides and diol epoxides leads to carbocation formation by barrierless processes. Charge delocalization modes in the resulting carbocations were deduced via NPA-derived changes in charges, and fluorine substitution effects were analyzed on the basis of charge density at different carbocation positions. Thus, fluorine substitution at sites bearing negative charge generated inductive destabilization of the carbocation, whereas a fluorine atom at a ring position which presented significant positive charge density produced a less pronounced destabilization due to fluorine p-pi back-bonding. Protonation reactions were also studied for the azaBaPs. In selected cases, the covalent adducts generated via bond formation with the exocyclic nitrogen of cytosine were computed and relative energies and geometries of the resulting adducts were examined.

  4. ON BENZO[A]PYRENE DERIVED DNA ADDUCTS FORMED IN LUNG TISSUE OF MICE

    EPA Science Inventory

    On Benzo [a] pyrene Derived DNA Adducts Formed in Lung Tissue of Mice
    The previously identified major DNA adducts of benzo[a]pyrene (BP) in vitro and in vivo are the stable and unstable adducts formed by reaction of the bay-region diol epoxide of BP (BPDE) and BP radical catio...

  5. BENZO[A]PYRENE AND ITS K-REGION DIOL INDUCE DNA DAMAGE IN C3H10T1/2C18 CELLS AS MEASURED BY THE ALKALINE SINGLE CELL GEL (COMET) ASSAY

    EPA Science Inventory


    160. Benzo[a]pyrene and its K-region diol induce DNA damage in C3HlOTl/2Cl8 cells as measured by the alkaline single cell gel (Comet) assay

    In a continuing series of studies on the genotoxicity ofK-region dihydrodiols of polycyclic aromatic hydrocarbons, we have repo...

  6. Lack of contribution of covalent benzo[a]pyrene-7,8-quinone-DNA adducts in benzo[a]pyrene-induced mouse lung tumorigenesis

    EPA Science Inventory

    Benzo[a]pyrene (B[a]P) is a potent human and rodent lung carcinogen. This activity has been ascribed in part to the formation of anti-trans-B[a]P-7,8-diol-9,10-epoxide (BPDE)-DNA adducts. Other carcinogenic mechanisms have been proposed: 1.] The induction of apurinic sites from r...

  7. Fragmentation patterns of DNA-benzo(a)pyrene diol epoxide adducts characterized by nanoflow LC/quadrupole time-of-flight mass spectrometry

    NASA Astrophysics Data System (ADS)

    Wang, Jin J.; Marshall, William D.; Law, Brandon; Lewis, Daniel M.

    2003-11-01

    Polycyclic aromatic hydrocarbons are a pervasive and abundant class of environmental and workplace pollutants. Formation of covalent DNA adducts has been considered to be a useful dosimeter or molecular biomarker for assessing the exposure to such pollutants. The establishment of prospective models for the formation of DNA adducts may help to understand the mechanisms of the effects. To identify the DNA adducts in this study, the fragmentation patterns of DNA-benzo(a)pyrene diol epoxide adducts were characterized by nanoflow liquid chromatography (LC) coupled to hybrid quadrupole orthogonal acceleration time-of-flight mass spectrometry (Q-TOF-MS). In the experiment, the DNA adducts were synthesized by reaction of calf thymus DNA with anti-benzo(a)pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide(+/-) (anti-BPDE). The major adducts of N2-deoxyguanosine-benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (N2-dG-BPDE), N6-deoxyadenosine-benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (N6-dA-BPDE), N4-deoxycytidine-benzo(a)pyrene-7,8-epoxide (N4-dC-BPDE), and N3-deoxythymidine-benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide adduct (N3-dT-BPDE) were identified by electrospray positive ionization with TOF-MS/MS scan mode. The results of this study demonstrated that the approach that utilizes collision-induced dissociation leading to a characteristic fragmentation pattern offers a distinct advantage for identification and elucidation of molecular structural features of the DNA adducts. The fragmentation patterns established in this study may be applied to identify DNA adducts in biological systems.

  8. Preferential Formation of Benzo[a]pyrene Adducts at Lung Cancer Mutational Hotspots in P53

    NASA Astrophysics Data System (ADS)

    Denissenko, Mikhail F.; Pao, Annie; Tang, Moon-Shong; Pfeifer, Gerd P.

    1996-10-01

    Cigarette smoke carcinogens such as benzo[a]pyrene are implicated in the development of lung cancer. The distribution of benzo[a]pyrene diol epoxide (BPDE) adducts along exons of the P53 gene in BPDE-treated HeLa cells and bronchial epithelial cells was mapped at nucleotide resolution. Strong and selective adduct formation occurred at guanine positions in codons 157, 248, and 273. These same positions are the major mutational hotspots in human lung cancers. Thus, targeted adduct formation rather than phenotypic selection appears to shape the P53 mutational spectrum in lung cancer. These results provide a direct etiological link between a defined chemical carcinogen and human cancer.

  9. Low-dose benzo(a)pyrene and its epoxide metabolite inhibit myogenic differentiation in human skeletal muscle-derived progenitor cells.

    PubMed

    Chiu, Chen-Yuan; Yen, Yuan-Peng; Tsai, Keh-Sung; Yang, Rong-Sen; Liu, Shing-Hwa

    2014-04-01

    The risk of low birth weights is elevated in prenatal exposure to polycyclic aromatic hydrocarbons (PAHs), which are ubiquitous environmental pollutants generated from combustion of organic compounds, including cigarette smoke. We hypothesized that benzo(a)pyrene (BaP), a member of PAHs existing in cigarette smoke, may affect the myogenesis to cause low birth weights. We investigated the effects of BaP and its main metabolite, benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), on the myogenic differentiation of human skeletal muscle-derived progenitor cells (HSMPCs). HSMPCs were isolated by a modified preplate technique and cultured in myogenic differentiation media with or without BaP and BPDE (0.25 and 0.5 μM) for 4 days. The multinucleated myotube formation was morphologically analyzed by hematoxylin and eosin staining. The expressions of myogenic differentiation markers and related signaling proteins were determined by Western blotting. Both BaP and BPDE at the submicromolar concentrations (0.25 and 0.5 μM) dose-dependently repressed HSMPCs myogenic differentiation without obvious cell toxicity. Both BaP and BPDE inhibited the muscle-specific protein expressions (myogenin and myosin heavy chain) and phosphorylation of Akt (a known modulator in myogenesis), which could be significantly reversed by the inhibitors for aryl hydrocarbon receptor (AhR), estrogen receptor (ER), and nuclear factor (NF)-κB. BaP- and BPDE-activated NF-κB-p65 protein phosphorylation could also be attenuated by both AhR and ER inhibitors. The inhibitory effects of BaP and BPDE on myogenesis were reversed after withdrawing BaP exposure, but not after BPDE withdrawal. These results suggest that both BaP and BPDE are capable of inhibiting myogenesis via an AhR- or/and ER-regulated NF-κB/Akt signaling pathway.

  10. Both (+/-)syn- and (+/-)anti-7,12-dimethylbenz[a]anthracene-3,4-diol-1,2-epoxides initiate tumors in mouse skin that possess -CAA- to -CTA- mutations at Codon 61 of c-H-ras.

    PubMed

    Tang, M S; Vulimiri, S V; Viaje, A; Chen, J X; Bilolikar, D S; Morris, R J; Harvey, R G; Slaga, T J; DiGiovanni, J

    2000-10-15

    We have determined the tumor-initiating activity of (+/-)syn- and (+/-)anti-7,12-dimethylbenz[a]anthracene-3,4-diol-1,2-epoxide (syn- and anti-DMBADE), the two metabolically formed bay-region diol epoxides of DMBA, and we have also analyzed mutations in the H-ras gene from tumors induced by these compounds. Using a two-stage, initiation-promotion protocol for tumorigenesis in mouse skin, we have found that both syn- and anti-DMBADE are active tumor initiators, and that the occurrence of papillomas is carcinogen dose dependent. All of the papillomas induced by syn-DMBADE (a total of 40 mice), 96% of those induced by anti-DMBADE (a total of 25 mice), and 94% of those induced by DMBA (a total of 16 mice) possessed a -CAA- to -CTA- mutation at codon 61 of H-ras. No mutations in codons 12 or 13 were detected in any tumor. Topical application of syn- and anti-DMBADE produced stable adducts in mouse epidermal DNA, most of which comigrated with stable DNA adducts formed after topical application of DMBA. Further analysis of the data showed that levels of the major syn- and anti-DMBADE-deoxyadenosine adducts formed after topical application of DMBA are sufficient to account for the tumor-initiating activity of this carcinogen on mouse skin. Previously, we showed that both the syn- and anti-DMBADE bind to the adenine (A182) at codon 61 of H-ras. Collectively, these results indicate that the adenine adducts induced by both bay-region diol epoxides of DMBA lead to the mutation at codon 61 of H-ras and, consequently, initiate tumorigenesis in mouse skin.

  11. Totally selective ring-opening of amino epoxides with ketones: a general entry to enantiopure (2R,3S)- and (2S,3S)-3-aminoalkano-1,2-diols.

    PubMed

    Concellón, José M; Suárez, José Ramón; García-Granda, Santiago; Díaz, M Rosario

    2005-01-20

    [Reaction: see text] Transformation of enantiopure diastereoisomers (2R,1'S)- and (2S,1'S)-2-(1-aminoalkyl)epoxides into the corresponding 4-(1-aminoalkyl)-1,3-dioxolanes is achieved by reaction with different ketones in the presence of BF3.Et2O. The conversion takes place in very high yields, total selectivity, and without epimerization. A mechanism to explain this transformation is proposed. The obtained 1,3-dioxolanes can be deprotected, and (2R,3S)- and (2S,3S)-3-aminoalkano-1,2-diols were isolated.

  12. Quantitation of a minor enantiomer of phenanthrene tetraol in human urine: correlations with levels of overall phenanthrene tetraol, benzo[a]pyrene tetraol, and 1-hydroxypyrene.

    PubMed

    Hochalter, J Bradley; Zhong, Yan; Han, Shaomei; Carmella, Steven G; Hecht, Stephen S

    2011-02-18

    Polycyclic aromatic hydrocarbons (PAH) are well established carcinogens that are likely to play a role in causing some human cancers. One accepted pathway of PAH metabolic activation is the formation of bay region diol epoxides. Some individuals may be particularly susceptible to PAH carcinogenesis because they metabolically activate PAH more effectively than others. We have used the measurement of urinary phenanthrene tetraols (Phe-tetraols) as a biomarker of PAH exposure plus metabolic activation since bay region diol epoxides are hydrolyzed to tetraols. Because of stereoselectivity in Phe metabolism, Phe-(1R,2S,3R,4S)-tetraol (4) results mainly from the bay region diol epoxide pathway, and Phe-(1S,2R,3S,4R)-tetraol (7) is formed mainly from the reverse diol epoxide pathway, not generally associated with carcinogenicity. The latter pathway accounts for more than 95% of human urinary Phe-tetraol. In most previous studies, Phe-tetraol was quantified without enantiomeric resolution, using a relatively rapid and practical method, applicable to large studies. It was not clear, however, whether measurement of overall unresolved Phe-tetraol would accurately represent the bay region diol epoxide metabolic activation pathway. Therefore, in this study we specifically quantified Phe-(1R,2S,3R,4S)-tetraol (4) by supplementing our usual analysis with chiral HPLC separations and using [(13)C(6)]Phe-(1R,2S,3R,4S)-tetraol as internal standard. We then investigated the relationship of urinary levels of 4 to those of Phe-tetraols (4 + 7), quantified without enantiomeric resolution. We applied these methods to urine samples from cigarette smokers and highly PAH-exposed creosote workers. The results were also compared to levels of benzo[a]pyrene-7,8,9,10-tetraol and 1-hydroxypyrene in the same samples. Levels of 4 were highly correlated with those of 4 + 7 (r > 0.9, P < 0.0001) in both types of urine samples. Strong correlations of 4 and 4 + 7 with benzo[a]pyrene-7,8,9,10-tetraol

  13. Role of base sequence context in conformational equilibria and nucleotide excision repair of benzo[a]pyrene diol epoxide-adenine adducts.

    PubMed

    Yan, Shixiang; Wu, Min; Buterin, Tonko; Naegeli, Hanspeter; Geacintov, Nicholas E; Broyde, Suse

    2003-03-04

    We investigate the influence of base sequence context on the conformations of the 10S (+)- and 10R (-)-trans-anti-[BP]-N(6)-dA adducts through molecular dynamics (MD) simulations with free energy calculations, and relate the structural findings to results of nucleotide excision repair (NER) assays in human cell extracts. In previous studies, these adducts were studied in the CA*A sequence context, and here we report results for the CA*C sequence. Our simulations indicate that the base sequence context affects the syn-anti conformational equilibrium in the 10S (+) adduct by modulating the barrier heights between these states on the energy surface, with a higher barrier in the CA*C case. Our nucleotide excision repair assay finds greater NER susceptibilities in the 10S (+) adduct for the CA*C sequence context. A structural rationale ties together these results. A sequence specific hydrogen bond, accompanied by a significantly increased roll and consequent bending in the 10S (+) adduct, has been found in our simulations for the CA*C sequence, which could account for the enhanced nucleotide excision repair as well as the syn-anti equilibrium difference we observe in this isomer and sequence. Such sequence specific differential repair could contribute to the existence of mutational hotspots and thereby contribute to the complexity of cancer initiation.

  14. The roles of diol epoxide and o-quinone pathways in mouse lung tumorigenesis induced by benzo(a)pyrene: relevance to human lung carcinogenesis

    EPA Science Inventory

    There is sufficient epidemiological evidence supported by experimental data that some PAH-containing complex environmental mixtures pose risks to human health by increasing lung cancer incidence. The International Agency for Research on Cancer has determined that human respirator...

  15. Characterization of molecular association of poly(2-oxazoline)s-based micelles with various epoxides and diols via the Flory-Huggins theory: a molecular dynamics simulation approach.

    PubMed

    Chun, Byeong Jae; Lu, Jie; Weck, Marcus; Jang, Seung Soon

    2015-11-21

    The hydrolytic kinetic resolution (HKR) of epoxides has been performed in a shell-crosslinked micellar (SCM) nanoreactor consisting of amphiphilic triblock copolymers based on poly(2-oxazline)s polymer derivatives with attached Co(iii)-salens to the micelle core. To investigate the effect of the molecular interaction of reactant/product molecules with the SCM nanoreactor on the rate of HKR, we calculated the Flory-Huggins interaction parameters (χ) using the molecular dynamics simulation method. For this, the blend systems were constructed with various compositions such as 15, 45, and 70 wt% of the reactant/product molecules with respect to the polymers such as poly(2-methyl-2-oxazoline) (PMOX), poly(2-(3-butinyl)2-oxazoline) (PBOX), and poly(methyl-3-oxazol-2-yl)pentanoate with Co(iii)-salen (PSCoX). From the χ parameters, we demonstrate that the miscibility of reactants/products with polymers has a strong correlation with the experimental reaction rate of the HKR: phenyl glycidyl ether (Reac-OPh) > epoxyhexane (Reac-C4) > styrene oxide (Reac-Ph) > epichlorohydrin (Reac-Cl). To validate this finding, we also conducted the potential of mean force analysis using steered molecular dynamics simulation for the molecular displacement of Reac-Cl and Reac-OPh through PMOX and PSCoX, revealing that the free energy reduction was greater when Reac-OPh molecule enters the polymer phase compared to Reac-Cl, which agrees with the findings from the χ parameters calculations.

  16. Metabolic activation of benzo(a)pyrene in SENCAR and BALB/c mouse embryo cell cultures.

    PubMed Central

    Baird, W M; Sebti, S M; Reinsvold, L A

    1986-01-01

    The metabolism and DNA binding of benzo(a)pyrene [B(a)P] were compared in early passage mouse embryo cell cultures prepared from SENCAR mice, a strain especially susceptible to two-stage tumorigenesis, and BALB/c mice, a strain relatively resistant to two-stage tumorigenesis. Cultures from both strains metabolized similar amounts of B(a)P; however, the proportion of water-soluble metabolites formed was higher in the BALB/c cultures than in the SENCAR cultures. The major metabolites formed in cultures from both strains were B(a)P-9,10-diol, B(a)P-7,8-diol and the glucuronic acid conjugate of 3-hydroxy-B(a)P. The level of binding of B(a)P to DNA was greater in the SENCAR mouse embryo cell cultures than in the BALB/c cultures after 5, 24, and 48 hr exposure. The major B(a)P-DNA adduct formed in B(a)P-treated cultures from both strains was the adduct formed by reaction of (+)anti-B(a)P-7,8-diol-9,10-epoxide [anti-B(a)PDE, the isomer with the epoxide and the benzylic hydroxyl on opposite faces of the molecule] with the exocyclic amino group of deoxyguanosine. Immobilized boronate chromatography followed by high-performance liquid chromatography demonstrated the presence of small amounts of syn-B(a)PDE (the isomer with the epoxide and benzylic hydroxyl on the same face of the molecule)-DNA adducts. The proportions of these amounts were similar in cultures from both strains. The results suggest that SENCAR mouse embryo cell cultures may convert less B(a)P to water-soluble metabolites and more to DNA-binding metabolites than BALB/c mouse embryo cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3780631

  17. In vitro replication by prokaryotic and eukaryotic polymerases on DNA templates containing site-specific and stereospecific benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide adducts.

    PubMed Central

    Chary, P; Lloyd, R S

    1995-01-01

    DNA adducts of the environmental carcinogen benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) interact stereospecifically with prokaryotic and eukaryotic polymerases in vitro. Toward understanding the capacity to replicate past different diastereomers of BPDE at specific sites in DNA, six deoxyoligonucleotides, each 33 bases long, were constructed with stereochemically defined BPDE adducts on adenine N6 at position two of the human N-ras codon 61. Four polymerases that were studied under single encounters with the template-primer complex terminated synthesis one base 3' to the lesion with all the adducted templates. When multiple encounters between polymerase and substrate were permitted, each of the polymerases analyzed revealed a unique pattern for a given adducted template. The general replication pattern was encompassed under two categories, reflecting the significance of the R and S configurations of C10 of the pyrenyl ring attached to the single-stranded DNA template. Furthermore, within each of these categories, every polymerase demonstrated distinct quantitative differences in product accumulation at a given site, for the various adducted templates. Among the polymerases utilized in this study, exonuclease-deficient Klenow fragment of polymerase I (exo- KF) exhibited the most efficient translesion synthesis resulting in approximately 16% full-length products with the modified templates bearing adducts with C10-S configuration. In contrast, chain elongation with bacteriophage T4 DNA polymerase bearing an active 3'-->5' exonucleolytic activity was most strongly inhibited by all six BPDE-adducted templates. Misincorporation of A opposite the adduct occurred in all the templates when polymerized with Sequenase, whereas exo- KF preferentially incorporated C opposite the C10-R BPDE adducts and A opposite the C10-S BPDE adducts. Images PMID:7753632

  18. Direct Copolymerization of CO2 and Diols

    NASA Astrophysics Data System (ADS)

    Tamura, Masazumi; Ito, Kazuki; Honda, Masayoshi; Nakagawa, Yoshinao; Sugimoto, Hiroshi; Tomishige, Keiichi

    2016-04-01

    Direct polymerization of CO2 and diols is promising as a simple and environmental-benign method in place of conventional processes using high-cost and/or hazardous reagents such as phosgene, carbon monoxide and epoxides, however, there are no reports on the direct method due to the inertness of CO2 and severe equilibrium limitation of the reaction. Herein, we firstly substantiate the direct copolymerization of CO2 and diols using CeO2 catalyst and 2-cyanopyridine promotor, providing the alternating cooligomers in high diol-based yield (up to 99%) and selectivity (up to >99%). This catalyst system is applicable to various diols including linear C4-C10 α,ω-diols to provide high yields of the corresponding cooligomers, which cannot be obtained by well-known methods such as copolymerization of CO2 and cyclic ethers and ring-opening polymerization of cyclic carbonates. This process provides us a facile synthesis method for versatile polycarbonates from various diols and CO2 owing to simplicity of diols modification.

  19. Direct Copolymerization of CO2 and Diols

    PubMed Central

    Tamura, Masazumi; Ito, Kazuki; Honda, Masayoshi; Nakagawa, Yoshinao; Sugimoto, Hiroshi; Tomishige, Keiichi

    2016-01-01

    Direct polymerization of CO2 and diols is promising as a simple and environmental-benign method in place of conventional processes using high-cost and/or hazardous reagents such as phosgene, carbon monoxide and epoxides, however, there are no reports on the direct method due to the inertness of CO2 and severe equilibrium limitation of the reaction. Herein, we firstly substantiate the direct copolymerization of CO2 and diols using CeO2 catalyst and 2-cyanopyridine promotor, providing the alternating cooligomers in high diol-based yield (up to 99%) and selectivity (up to >99%). This catalyst system is applicable to various diols including linear C4-C10 α,ω-diols to provide high yields of the corresponding cooligomers, which cannot be obtained by well-known methods such as copolymerization of CO2 and cyclic ethers and ring-opening polymerization of cyclic carbonates. This process provides us a facile synthesis method for versatile polycarbonates from various diols and CO2 owing to simplicity of diols modification. PMID:27075987

  20. UVA photoirradiation of benzo[a]pyrene metabolites: induction of cytotoxicity, reactive oxygen species, and lipid peroxidation.

    PubMed

    Xia, Qingsu; Chiang, Hsiu-Mei; Yin, Jun-Jie; Chen, Shoujun; Cai, Lining; Yu, Hongtao; Fu, Peter P

    2015-10-01

    Benzo[a]pyrene (BaP) is a prototype for studying carcinogenesis of polycyclic aromatic hydrocarbons (PAHs). We have long been interested in studying the phototoxicity of PAHs. In this study, we determined that metabolism of BaP by human skin HaCaT keratinocytes resulted in six identified phase I metabolites, for example, BaP trans-7,8-dihydrodiol (BaP t-7,8-diol), BaP t-4,5-diol, BaP t-9,10-diol, 3-hydroxybenzo[a]pyrene (3-OH-BaP), BaP (7,10/8,9)tetrol, and BaP (7/8,9,10)tetrol. The photocytotoxicity of BaP, 3-OH-BaP, BaP t-7,8-diol, BaP trans-7,8-diol-anti-9,10-epoxide (BPDE), and BaP (7,10/8,9)tetrol in the HaCaT keratinocytes was examined. When irradiated with 1.0 J/cm(2) UVA light, these compounds when tested at doses of 0.1, 0.2, and 0.5 μM, all induced photocytotoxicity in a dose-dependent manner. When photoirradiation was conducted in the presence of a lipid (methyl linoleate), BaP metabolites, BPDE, and three related PAHs, pyrene, 7,8,9,10-tetrahydro-BaP trans-7,8-diol, and 7,8,9,10-tetrahydro-BaP trans-9,10-diol, all induced lipid peroxidation. The formation of lipid peroxides by BaP t-7,8-diol was inhibited by NaN3 and enhanced by deuterated methanol, which suggests that singlet oxygen may be involved in the generation of lipid peroxides. The formation of lipid hydroperoxides was partially inhibited by superoxide dismutase (SOD). Electron spin resonance spin trapping experiments indicated that both singlet oxygen and superoxide radical anion were generated from UVA photoirradiation of BPDE in a light dose responding manner.

  1. Molecular characterization of mutation and comparison of mutation profiles in the hprt gene of Chinese hamster ovary cells treated with benzo[a]pyrene trans-7,8-diol-anti-9,10-epoxide, 1-nitrobenzol[a]pyrene trans-7,8-diol-anti-9,10-epoxide, and 3-nitrobenzol[a]pyrene trans-7,8-diol-anti-9,10-epoxide

    SciTech Connect

    Zhan, D.J.; Heflich, R.H.; Fu, P.P.

    1996-12-31

    Both 1- and 3-nitrobenzol[a] pyrene (nitro-BaP) are environmental contaminants, potent mutagens in Salmonella, and moderate mutagens in Chinese hamster ovary (CHO) cells. The mutagenicity of their oxidized metabolites, trans-7,8-dihydroxy-anti-9, 10-epoxy-7,8,9,10-tetrahydro-1-nitrobenzol[a]pyrene (1-nitro-BaP-DE) and trans-7,8-dihydroxy-anti-9, 10-epoxy-7,8,9,10-tetrahydro-3-nitrobenzo[a]pyrene (3-nitro-BaP-DE), together with trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzol[a]pyren (BaP-DE), was determined in CHO-K1 cells, and the resulting mutations at the hprt locus were characterized by polymerase chain reaction (PCR) amplification of reverse-transcribed hprt mRNA, followed by DNA sequence analysis. The mutant frequencies, in mutants/10{sup 6} clonable cells, at 30 and 100 ng/ml, were BaP-DE, 248 and 456; 1-nitro-BaP-DE, 68 and 260; 3-nitro-BaP-DE, 81 and 232, respectively. In general, the three diolepoxides exhibited similar mutational spectra: (1) 64% (23/36 sequenced mutants) of BaP-DE, 53% (19/36) of 1-nitro-BaP-DE, and 64% (23/36) of 3-nitro-BaP-DE mutants resulted from simple base pair substitution, with the predominant mutation being G{r_arrow}T transversion: (2) 90%, 100%, and 100% of mutations at G:C had the mutated dG on the nontranscribed DNA strand; and (3) about one quarter of the mutants produced by each mutagen had one or more PCR products with partial or complete exon deletions. 61 refs., 1 fig., 7 tabs.

  2. Molecular characterization of mutation and comparison of mutation profiles in the hprt gene of Chinese hamster ovary cells treated with benzo[a]pyrene trans-7,8-diol-anti-9,10-epoxide, 1-nitrobenzo[a]pyrene trans-7,8-diol-anti-9,10-epoxide, and 3-nitrobenzo[a]pyrene trans-7,8- diol-anti-9,10-epoxide.

    PubMed

    Zhan, D J; Heflich, R H; Fu, P P

    1996-01-01

    Both 1- and 3-nitrobenzo[a]pyrene (nitro-BaP) are environmental contaminants, potent mutagens in Salmonella, and moderate mutagens in Chinese hamster ovary (CHO) cells. The mutagenicity of their oxidized metabolites,trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-epoxy -7,8,9,10-tetrahydro-1-nitrobenzo[a]pyrene (1-nitro-BaP-DE) and trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-3-nitrobenzo[a]- pyrene (3-nitro-BaPDE), together with trans-7,8-dihydroxy-anti-9, 10-ep- oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP-DE), was determined in CHO-K1 cells, and the resulting mutations at the hprt locus were characterized by polymerase chain reaction (PCR) amplification of reverse-transcribed hprt mRNA, followed by DNA sequence analysis. The mutant frequencies, in mutants/10(6) clonable cells, at 30 and 100 ng/ml, were BaP-DE, 248 and 456; 1-nitro-BaP-DE, 68 and 260; 3-nitro-BaP-DE, 81 and 232, respectively. In general, the three diolepoxides exhibited similar mutational spectra: 1) 64% (23/36 sequenced mutants) of BaP-DE, 53% (19/36) of 1-nitro-BaP-DE, and 64% (23/36) of 3-nitro-BaP-DE mutants resulted from simple base pair substitution, with the predominant mutation being G-->T transversion; 2) 90%, 100%, and 100% of mutations at G:C had the mutated dG on the nontranscribed DNA strand; and 3) about one quarter of the mutants produced by each mutagen had one or more PCR products with partial or complete exon deletions. The mutagens induced few frameshifts or complex mutations. Among the differences in mutational specificity for the three diolepoxides, the proportion of substituted dGs with 3' purines was significant (P < 0.05) for BaP-DE (16/19, 84%) and 3-nitro-BaP-DE (17/20, 85%), but not significant for 1-nitro-BaP-DE-induced mutants (11/17, 65%, P > 0.05). Also, high proportions of BaP-DE and 3-nitro-BaP-DE base pair substitutions at G:C occurred in DNA sequence contexts of 5'-GG-3', 5'-GGA-3', and 5'-TGGA-3', while the proportions of 1-nitro-BaP-DE mutants in these contexts were often lower. The results indicate that nitro substitution at C1 or C3 of BaP-DE reduces mutational potency in CHO cells and appears to have only subtle effects upon the mutational pattern in the hprt gene.

  3. Epoxide-derived organosulfates

    NASA Astrophysics Data System (ADS)

    Schwier, A. N.; Woo, J.; McNeill, V. F.

    2011-12-01

    Organosulfates (OS) are a significant fraction of secondary organic aerosol (SOA) material in the atmosphere. OS are typically surface-active, and have been suggested to cause surface tension depression in aerosols. Recent field studies suggest that epoxide-derived OS are the most abundant OS type in aerosols. Time-dependent surface tension measurements and Aerosol-CIMS characterization of two epoxides and their organosulfate products are shown. α-pinene oxide, derived from α-pinene, shows significant surface tension depression in H2O and ammonium sulfate. Results from cis-2,3-epoxybutane-1,4-diol (BEPOX), a butadiene-derived analog to isoprene-derived epoxydiols, are also shown. In addition, using GAMMA, a photochemical box model using coupled gas- and aqueous-phase chemistry developed in the McNeill laboratory, we show the dominance of epoxide-derived OS formation over other competing OS formation mechanisms, such as radical chemistry, under both high-NOx and low-NOx scenarios.

  4. Photocatalytic degradation of polycyclic aromatic hydrocarbon benzo[a]pyrene by iron oxides and identification of degradation products.

    PubMed

    Gupta, Himanshu; Gupta, Bina

    2015-11-01

    Photocatalytic decay profiles of polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (B[a]P) have been investigated on various synthesized iron oxides and on soil surfaces under a set of diverse conditions. Samples were analysed using the developed HPLC procedure. Results of the present study demonstrate fastest photodisintegration of B[a]P on goethite followed by haematite, magnetite, akaganeite and maghemite, respectively. The effect of soil pH, irradiation wavelength and iron oxide and oxalic acid dose on the degradation of B[a]P was evaluated. The studies revealed enhancement in photodegradation in the presence of oxalic acid due to the occurrence of fenton like reaction. The results showed faster B[a]P degradation under short wavelength UV radiation. Rate constants in acidic, neutral and alkaline soils under optimum dissipation conditions were 1.11×10(-2), 7.69×10(-3) and 9.97×10(-3) h(-1), respectively. The study indicates that iron oxides along with oxalic acid are effective photocatalyst for the remediation of benzo[a]pyrene contaminated soil surfaces. The degradation products of B[a]P in the soils of different pH in presence of goethite were identified and degradation pathways proposed. Peaks due to toxic metabolites such as diones, diols and epoxides disappear after 120 h in all the three soils.

  5. Overexpression of Catalase Enhances Benzo(a)pyrene Detoxification in Endothelial Microsomes

    PubMed Central

    Yang, Fang; Yang, Hong; Ramesh, Aramandla; Goodwin, J. Shawn; Okoro, Emmanuel U.; Guo, ZhongMao

    2016-01-01

    We previously reported that overexpression of catalase upregulated xenobiotic- metabolizing enzyme (XME) expression and diminished benzo(a)pyrene (BaP) intermediate accumulation in mouse aortic endothelial cells (MAECs). Endoplasmic reticulum (ER) is the most active organelle involved in BaP metabolism. To examine the involvement of ER in catalase-induced BaP detoxification, we compared the level and distribution of XMEs, and the profile of BaP intermediates in the microsomes of wild-type and catalase transgenic endothelial cells. Our data showed that endothelial microsomes were enriched in cytochrome P450 (CYP) 1A1, CYP1B1 and epoxide hydrolase 1 (EH1), and contained considerable levels of NAD(P)H: quinone oxidoreductase-1 (NQO1) and glutathione S-transferase-pi (GSTP). Treatment of wild-type MAECs with 1μM BaP for 2 h increased the expression of microsomal CYP1A1, 1B1 and NQO1 by ~300, 64 and 116%, respectively. However, the same treatment did not significantly alter the expression of EH1 and GSTP. Overexpression of catalase did not significantly increase EH1, but upregulated BaP-induced expression of microsomal CYP1A1, 1B1, NQO1 and GSTP in the following order: 1A1>NQO1>GSTP>1B1. Overexpression of catalase did not alter the distribution of each of these enzymes in the microsomes. In contrast to our previous report showing lower level of BaP phenols versus BaP diols/diones in the whole-cell, this report demonstrated that the sum of microsomal BaP phenolic metabolites were ~60% greater than that of the BaP diols/diones after exposure of microsomes to BaP. Overexpression of catalase reduced the concentrations of microsomal BaP phenols and diols/diones by ~45 and 95%, respectively. This process enhanced the ratio of BaP phenol versus diol/dione metabolites in a potent manner. Taken together, upregulation of phase II XMEs and CYP1 proteins, but not EH1 in the ER might be the mechanism by which overexpression of catalase reduces the levels of all the BaP metabolites

  6. Editor's Highlight: Interactive Genotoxicity Induced by Environmentally Relevant Concentrations of Benzo(a)Pyrene Metabolites and Arsenite in Mouse Thymus Cells.

    PubMed

    Xu, Huan; Lauer, Fredine T; Liu, Ke Jian; Hudson, Laurie G; Burchiel, Scott W

    2016-11-01

    Arsenic and polycyclic aromatic hydrocarbon (PAH) exposures affect many people worldwide leading to cancer and other diseases. Arsenite (As(+3)) and certain PAHs are known to cause genotoxicity. However, there is limited information on the interactions between As(+3) and PAHs at environmentally relevant concentrations. The thymus is the primary immune organ for T cell development in mammals. Our previous studies showed that environmentally relevant concentrations of As(+3) induce genotoxicity in mouse thymus cells through Poly(ADP-ribose) polymerase (PARP) inhibition. Certain PAHs, such as the metabolites of benzo(a)pyrene (BaP), are known to cause DNA damage by forming DNA adducts. In the present study, primary mouse thymus cells were examined for DNA damage following 18 hr in vitro treatments with 5 or 50 nM As(+3) and 100 nM BaP, benzo[a]pyrene-7,8-dihydrodiol (BP-Diol), or benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). An interactive increase in genotoxicity and apoptosis were observed following treatments with 5 nM As (+)  (3 )+( )100 nM BP-diol and 50 nM As (+)  (3 )+( )100 nM BPDE. We attribute the increase in DNA damage to inhibition of PARP inhibition leading to decreased DNA repair. To further support this hypothesis, we found that a PARP inhibitor, 3,4-dihydro-5[4-(1-piperindinyl) butoxyl]-1(2H)-isoquinoline (DPQ), also interacted with BP-diol to produce an increase in DNA damage. Interestingly, we also found that As(+3) and BP-diol increased CYP1A1 and CYP1B1 expression, suggesting that increased PAH metabolism may also contribute to genotoxicity. In summary, these results show that the suppression of PARP activity and induction of CYP1A1/CYP1B1 may act together to increase DNA damage produced by As(+3) and PAHs.

  7. Biotechnological production of enantiopure epoxides by enzymatic kinetic resolution.

    PubMed

    Choi, Won Jae

    2009-08-01

    Enantiopure epoxides are high value-added synthons for the production of pharmaceuticals, agrochemicals, as well as versatile fine chemicals and have broad scope of market demand for their applications. A major challenge in conventional organic synthesis is to generate such compounds in high enantiopurity with reasonable yield. Among possible chemical and biological technologies for enantiopure epoxide preparation, enzymatic kinetic resolution has been paid much attention with respect to its high enantioselectivity. Epoxide hydrolase (EH) has shown promising characteristics for the preparation of enantiopure epoxides and vicinal diols during enantioselective hydrolysis of racemic epoxides. EH is readily available from microbial resources thus it is being employed for biohydrolysis of a variety of epoxides. Recent technical progress in EH-catalyzed enantioselective hydrolysis is summarized in terms of exploration of novel EH, its functional improvement, high throughput assay, and preparative scale resolution process.

  8. Potent Urea and Carbamate Inhibitors of Soluble Epoxide Hydrolases

    NASA Astrophysics Data System (ADS)

    Morisseau, Christophe; Goodrow, Marvin H.; Dowdy, Deanna; Zheng, Jiang; Greene, Jessica F.; Sanborn, James R.; Hammock, Bruce D.

    1999-08-01

    The soluble epoxide hydrolase (sEH) plays a significant role in the biosynthesis of inflammation mediators as well as xenobiotic transformations. Herein, we report the discovery of substituted ureas and carbamates as potent inhibitors of sEH. Some of these selective, competitive tightbinding inhibitors with nanomolar Ki values interacted stoichiometrically with the homogenous recombinant murine and human sEHs. These inhibitors enhance cytotoxicity of trans-stilbene oxide, which is active as the epoxide, but reduce cytotoxicity of leukotoxin, which is activated by epoxide hydrolase to its toxic diol. They also reduce toxicity of leukotoxin in vivo in mice and prevent symptoms suggestive of acute respiratory distress syndrome. These potent inhibitors may be valuable tools for testing hypotheses of involvement of diol and epoxide lipids in chemical mediation in vitro or in vivo systems.

  9. Effect of heavy metals on the metabolism of benzo(a)pyrene in rats

    SciTech Connect

    Honey, S.A.; Yuan, Zhi-Xin; Kumar, S.; Sikka, H.C.

    1996-12-31

    In order to investigate the interaction of heavy metals and PAHs, we have examined the effect of methylmercuric chloride and cadmium chloride on the oxidative metabolism by rats of benzo(a)pyrene [BaP], a model carcinogenic PAR Treatment of male rats with 2.5 or 5.0 mg/kg methylmercury (ip) reduced the rate of metabolism of BaP by liver microsomes by 38.7 and 62.2%, respectively. Cadmium was more potent than methylmercury, decreasing the rate of metabolism of BaP by 28.4, 52.2, and 69.7% by liver microsomes of rats treated with 0.5, 1.0, and 1.5 mg/kg of cadmium, respectively. The liver microsomes from animals treated with methylmercury or cadmium produced a greater proportion of BP-phenols and a lower portion of BP-diols than did the microsomes from untreated animals, suggesting that both metals also inhibit the activity of epoxide hydrase. Neither methylmercury nor cadmium had an effect on the proportion of BP-quinones formed by liver microsomes. Treatment of rats with methylmercury or cadmium did not inhibit the metabolism of BaP by liver microsomes from animals treated with 3-methylcholanthrene (3-MC) prior to metal administration, suggesting that 3-MC treatment protects against the effect of methylmercury or cadmium on the oxidative metabolism of BaP.

  10. Metabolically Competent Human Skin Models: Activation and Genotoxicity of Benzo[a]pyrene

    PubMed Central

    Henkler, Frank

    2013-01-01

    The polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (BP) is metabolized into a complex pattern of BP derivatives, among which the ultimate carcinogen (+)-anti-BP-7,8-diol-9,10-epoxide (BPDE) is formed to certain extents. Skin is frequently in contact with PAHs and data on the metabolic capacity of skin tissue toward these compounds are inconclusive. We compared BP metabolism in excised human skin, commercially available in vitro 3D skin models and primary 2D skin cell cultures, and analyzed the metabolically catalyzed occurrence of seven different BP follow-up products by means of liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). All models investigated were competent to metabolize BP, and the metabolic profiles generated by ex vivo human skin and skin models were remarkably similar. Furthermore, the genotoxicity of BP and its derivatives was monitored in these models via comet assays. In a full-thickness skin, equivalent BP-mediated genotoxic stress was generated via keratinocytes. Cultured primary keratinocytes revealed a level of genotoxicity comparable with that of direct exposure to 50–100nM of BPDE. Our data demonstrate that the metabolic capacity of human skin ex vivo, as well as organotypic human 3D skin models toward BP, is sufficient to cause significant genotoxic stress and thus cutaneous bioactivation may potentially contribute to mutations that ultimately lead to skin cancer. PMID:23148024

  11. Heptachlor epoxide

    Integrated Risk Information System (IRIS)

    Heptachlor epoxide ; CASRN 1024 - 57 - 3 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogen

  12. Diversity and Biocatalytic Potential of Epoxide Hydrolases Identified by Genome Analysis†

    PubMed Central

    van Loo, Bert; Kingma, Jaap; Arand, Michael; Wubbolts, Marcel G.; Janssen, Dick B.

    2006-01-01

    Epoxide hydrolases play an important role in the biodegradation of organic compounds and are potentially useful in enantioselective biocatalysis. An analysis of various genomic databases revealed that about 20% of sequenced organisms contain one or more putative epoxide hydrolase genes. They were found in all domains of life, and many fungi and actinobacteria contain several putative epoxide hydrolase-encoding genes. Multiple sequence alignments of epoxide hydrolases with other known and putative α/β-hydrolase fold enzymes that possess a nucleophilic aspartate revealed that these enzymes can be classified into eight phylogenetic groups that all contain putative epoxide hydrolases. To determine their catalytic activities, 10 putative bacterial epoxide hydrolase genes and 2 known bacterial epoxide hydrolase genes were cloned and overexpressed in Escherichia coli. The production of active enzyme was strongly improved by fusion to the maltose binding protein (MalE), which prevented inclusion body formation and facilitated protein purification. Eight of the 12 fusion proteins were active toward one or more of the 21 epoxides that were tested, and they converted both terminal and nonterminal epoxides. Four of the new epoxide hydrolases showed an uncommon enantiopreference for meso-epoxides and/or terminal aromatic epoxides, which made them suitable for the production of enantiopure (S,S)-diols and (R)-epoxides. The results show that the expression of epoxide hydrolase genes that are detected by analyses of genomic databases is a useful strategy for obtaining new biocatalysts. PMID:16597997

  13. An approach based on liquid chromatography/electrospray ionization–mass spectrometry to detect diol metabolites as biomarkers of exposure to styrene and 1,3-butadiene

    PubMed Central

    Shen, Shuijie; Zhang, Fan; Zeng, Su; Zheng, Jiang

    2012-01-01

    Styrene and 1,3-butadiene are important intermediates used extensively in the plastics industry. They are metabolized mainly through cytochrome P450-mediated oxidation to the corresponding epoxides, which are subsequently converted to diols by epoxide hydrolase or through spontaneous hydration. The resulting styrene glycol and 3-butene-1,2-diol have been suggested as biomarkers of exposure to styrene and 1,3-butadiene, respectively. Unfortunately, poor ionization of the diols within electrospray mass spectrometers becomes an obstacle to the detection of the two diols by liquid chromatography/electrospray ionization–mass spectrometry (LC/ESI–MS). We developed an LC/ESI–MS approach to analyze styrene glycol and 3-butene-1,2-diol by means of derivatization with 2-bromopyridine-5-boronic acid (BPBA), which not only dramatically increases the sensitivity of diol detection but also facilitates the identification of the diols. The analytical approach developed was simple, quick, and convincing without the need for complicated chemical derivatization. To evaluate the feasibility of BPBA as a derivatizing reagent of diols, we investigated the impact of diol configuration on the affinity of a selection of diols to BPBA using the established LC/ESI–MS approach. We found that both cis and trans diols can be derivatized by BPBA. In conclusion, BPBA may be used as a general derivatizing reagent for the detection of vicinal diols by LC/MS. PMID:19111668

  14. Hydrolytic and aminolytic kinetic resolution of terminal bis-epoxides.

    PubMed

    Bredihhina, Jevgenia; Villo, Piret; Andersons, Kārlis; Toom, Lauri; Vares, Lauri

    2013-03-15

    Hydrolytic and aminolytic kinetic resolution of terminal bis-epoxides catalyzed by (salen)Co(III) complexes affords epoxy-diols and N-protected epoxy-amino alcohols with excellent enantio- and diastereoselectivity and good yields. An operationally simple procedure gives instant access to valuable building blocks containing two remote stereocenters in highly enantioenriched form.

  15. LC/MSMS STUDY OF BENZO[A]PYRENE-7,8-QUINONE ADDUCTION TO GLOBIN TRYPTIC PEPTIDES AND N-ACETYLAMINO ACIDS

    EPA Science Inventory

    Benzo[a]pyrene-7,8-quinone (BPQ) is regarded as a reactive genotoxic compound enzymatically formed from a xenobiotic precursor benzo[a]pyrene-7,8-diol by aldo-keto-reductase family of enzymes. Because BPQ, a Michael electrophile, was previously shown to react with oligonucleotide...

  16. Benzo[a]pyrene increases DNA double strand break repair in vitro and in vivo: a possible mechanism for benzo[a]pyrene-induced toxicity.

    PubMed

    Tung, Emily W Y; Philbrook, Nicola A; Belanger, Christine L; Ansari, Saad; Winn, Louise M

    2014-01-15

    Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon and carcinogen that is released into the environment through natural and anthropogenic sources. BaP toxicity is dependent on its metabolism by cytochrome P450s to the reactive metabolite benzo[a]pyrene diol epoxide (BPDE), which is strongly associated with increased mutation frequency. BaP can also be metabolized to benzo[a]pyrene quinones that can undergo redox cycling and induce oxidative stress. The purpose of this study was to examine if BaP exposure induces DNA double strand breaks (DSBs) and subsequently activate DNA DSB repair pathways in the CHO 3-6 cell line and pKZ1 mouse model. In vitro assessment of homologous recombination (HR) showed significantly increased HR frequency following exposure to 10μM of BaP. In vivo evaluations of BaP-induced DNA DSB repair demonstrated positive staining for intrachromosomal recombination events, which are associated with non-homologous end joining (NHEJ), in the lung and thymus of exposed animals that were statistically significant in the thymus when quantified by Western blotting. Gene expression analyses from mouse tissues showed significantly decreased expression of ATM and Xrcc6 in BaP-treated liver and lung. In addition, BaP exposure significantly reduced the expression of Xrcc5, p53, and DNA-PKcs in lung. Taken together, our results demonstrate that BaP increases DNA DSB repair in vitro and in vivo, and induces expression changes in DNA repair pathway genes. As repair of DNA DSBs is not error-free, aberrant DNA repair may be contributing to the mechanism of BaP-induced toxicity.

  17. Mutagenic activity of the 4,5- and 9,10-dihydrodiols of benzo[i]fluoranthene and their syn- and anti-dihydrodiol epoxides in Salmonella typhimurium

    SciTech Connect

    Marshall, M.V. ); He, Z.M.; Weyand, E.H.; Rice, J.E.; LaVoie, E.J. )

    1993-01-01

    The objective of this study was to determine the relative mutagenic activities of the major dihydrodiol metabolites of benzo[i]fluoranthene (B[i]F) and their corresponding syn- and anti-dihydrodiol epoxides. Salmonella typhimurium tester strains TA97a, TA98, and TA100 were used to evaluate the mutagenic potencies of the parent hydrocarbon and these suspect proximate and ultimate mutagenic metabolites. B[i]F and the trans-dihydrodiol metabolites were active only in the presence of an external metabolic activation system (S9) with the exception of the B[i]F-4,5-diol, which was weakly active in TA98 and TA100 in the absence of S9. The B[i]F-4,5-diol was more mutagenic than the B[i]F-9,10-diol in tester strains TA98 and TA100, whereas the opposite effect was observed in TA97a. In the absence of S9, the anti-B[i]F-4,5-diol epoxide was more mutagenic than the syn-B[i]F-4,5-diol epoxide and the syn- and anti-B[i]F-9,10-diol epoxides in tester strains TA97a and TA100. The exceptional mutagenic potency of the anti-B[i]F-4,5-diol epoxide in TA100 resembles that observed by epoxides located within a fjord, or by the anti-diol epoxides of bay region methylated polycyclic aromatic hydrocarbons. In contrast, the mutagenicity of the pseudo bay region dihydrodiol epoxides arising from the B[i]F-9,10-diol more closely resembles that observed with the classical bay region dihydrodiol epoxides of chrysene. In summary, both dihydrodiol metabolites of B[i]F are mutagenic in S. typhimurium, and the relative potency varies among the tester strains. The highest mutagenic response was achieved in tester strain TA100, which detects base-pair substitutions. The most potent direct-acting dihydrodiol epoxide in this tester strain was the anti-B[i]F-4,5-diol epoxide, which agrees with the results of mouse skin painting studies that indicate that the B[i]F-4,5-diol is more tumorigenic than the parent hydrocarbon or the B[i]F-9,10-diol. 34 refs., 7 figs., 2 tabs.

  18. Metabolism of benzo(a)pyrene by subcellular fractions of gastrointestinal (GI) tract and liver in Apc(Min) mouse model of colon cancer.

    PubMed

    Mantey, Jane A; Rekhadevi, Perumalla V; Diggs, Deacqunita L; Ramesh, Aramandla

    2014-05-01

    Given the fact that increased dietary intake of polycyclic aromatic hydrocarbons (PAHs; a family of environmental toxicants) leads to the formation and development of colon tumors, the ability of the gastrointestinal tract to process these compounds is important from the viewpoint of toxicity/carcinogenesis. Benzo(a)pyrene (BaP), a prototypical PAH compound is released into the environment from automobile exhausts, cigarette smoke, and industrial emissions. Additionally, considerable intake of BaP is expected in people who consume barbecued foods and a diet rich in saturated fat. In exposed animals, BaP becomes activated to potent metabolites that interfere with target organ function and as a consequence cause toxicity and cancer. Therefore, knowledge of BaP metabolism in the digestive system will be of importance in the management of cancers of the digestive tract. The objective of our study was to study the metabolism of BaP by subcellular fractions (nuclear, cytosolic, mitochondrial, and microsomal) of the gastrointestinal tract and liver. Subcellular fractions were isolated by differential centrifugation from the stomach, jejunum, colon, and liver tissues of Apc(Min) mice that received a subchronic dose of 25 μg/kg BaP. The fractions were incubated with 1 and 3 μM BaP. Subsequent to incubation, samples were extracted with ethyl acetate and analyzed for BaP metabolites by reverse-phase HPLC equipped with fluorescence detection. Among the different fractions tested, microsomal BaP metabolism was higher than the rest of the fractions in all the samples analyzed. Additionally, a BaP exposure concentration-dependent effect on metabolite levels generated by the subcellular fractions was recorded. The BaP metabolites identified were the following: BaP-9,10-diol; BaP-4,5-diol; BaP-7,8-diol; 9(OH) BaP; 3(OH) BaP; BaP-3,6-dione; and BaP-6,12-dione. While the diol group of metabolites was frequently detected, among diones, the 3,6 and 6,12-dione metabolites were

  19. Specificity in interaction of benzo[a]pyrene with nuclear macromolecules: implication of derivatives of two dihydrodiols in protein binding.

    PubMed Central

    MacLeod, M C; Kootstra, A; Mansfield, B K; Slaga, T J; Selkirk, J K

    1980-01-01

    Benzo[a]pyrene (B[a]P), 7,8-dihydroxy-7,8-dihydro-B[a]P, and 9,10-dihydro-B[a]P are metabolized by hamster embryo cells to derivatives that bind to nuclear macromolecules. The selectivity for different classes of macromolecules varies depending on the compound analyzed. The ratio of DNA specific activity to protein specific activity (pmol bound/mg of macromolecules) is high (1.51) for 7,8-dihydroxy-7,8-dihydro-B[a]P, extremely low (0.03) for 9,10-dihydroxy-9,10-dihydro-B[a]P, and intermediate (0.26) for B[a]P. Histones H3 and H2A are the major targets of 7,8-dihydroxy-7,8-dihydro-B[a]P; a protein(s) with a mobility similar to that of histone H1 is heavily labeled by 9,10-dihydroxy-9,10-dihydro-B[a]P, with minor labeling of other (nonhistone) bands. The labeling pattern seen with B[a]P is a combination of the patterns seen with the two dihydrodiol metabolites studied. Analysis of the ethyl acetate-soluble metabolites suggests that hamster embryo cells produce 9,10-dihydroxy-7,8-oxy-7,8,9,10-tetrahydro-B[a]P from 9,10-dihydroxy-9,10-dihydro-B[a]P and raise the possibility that this vicinal diol epoxide is an intermediate in the binding of 9,10-dihydroxy-9,10-dihydro-B[a]P to nuclear proteins. The differences seen suggest that factors other than the intrinsic chemical reactivity of the epoxide group are extremely important in the interaction of potential ultimate carcinogens with biological systems. Images PMID:6935653

  20. Single amino acid mutations, but not common polymorphisms, decrease the activity of CYP1B1 against (-)benzo[a]pyrene-7R-trans-7,8-dihydrodiol.

    PubMed

    Mammen, Jennifer S; Pittman, Gary S; Li, Ying; Abou-Zahr, Fadi; Bejjani, Bassem A; Bell, Douglas A; Strickland, Paul T; Sutter, Thomas R

    2003-07-01

    Genetic differences that underlie inter-individual variation in the metabolism of common carcinogens are important potential sources of cancer susceptibility. Cytochrome P450 1B1 (CYP1B1), a central enzyme in the activation of the ubiquitous environmental carcinogen benzo[a]pyrene (B[a]P), has several genetic variants. This study investigated six rare mutations and four common polymorphisms for their effects on B[a]P metabolism. Five missense mutations associated with congenital glaucoma (Gly61Glu, Gly365Trp, Asp374Asn, Pro437Leu and Arg469Tryp) dramatically decreased the capacity of CYP1B1 to convert (-)benzo[a]pyrene-7R-trans-7,8-dihyrodiol (B[a]P-7,8-diol) to (+/-)benzo[a]pyrene-r-7,t-8-dihydrodiol-9,10-epoxides. These five mutations resulted in enzymes with 3-12% of normal activity when assayed in vitro using an Saccharomyces cerevisiae microsomal expression system. A 10 bp deletion mutation produced no detectable protein or activity. In contrast, proteins containing all possible combinations of four common single nucleotide polymorphisms (Arg48Gly, Ala199Ser, Val432Leu, Asn453Ser) had modest effects on B[a]P-7,8-diol metabolism. Michaelis-Menten analysis suggested that two alleles, Arg48, Ala119, Val432, Ser453 (RAVS) and Arg48, Ala119, Leu432, Ser453 (RALS), have KM values 2-fold lower than Arg48, Ala119, Val432, Ser453 (RAVN): 1.4+/-0.3 and 1.3+/-0.4 microM, respectively, compared with 2.8+/-0.8 microM (P<0.05). However, these differences could not be confirmed with direct measurements of rate at low substrate concentration. There were no significant differences for either of two other kinetic parameters, kcat or kcat/KM. Allele frequency analysis in three populations reveals the Ser453 variant is rare among those of Asian (<1%) and African ancestry (<4%), and more common in individuals of European ancestry (16%). Haplotypes containing the Ser453 variant were uncommon; only RALS was detectable in our small populations. The RALS allele occurred between 0

  1. Asymmetric catalysis with water: efficient kinetic resolution of terminal epoxides by means of catalytic hydrolysis.

    PubMed

    Tokunaga, M; Larrow, J F; Kakiuchi, F; Jacobsen, E N

    1997-08-15

    Epoxides are versatile building blocks for organic synthesis. However, terminal epoxides are arguably the most important subclass of these compounds, and no general and practical method exists for their production in enantiomerically pure form. Terminal epoxides are available very inexpensively as racemic mixtures, and kinetic resolution is an attractive strategy for the production of optically active epoxides, given an economical and operationally simple method. Readily accessible synthetic catalysts (chiral cobalt-based salen complexes) have been used for the efficient asymmetric hydrolysis of terminal epoxides. This process uses water as the only reagent, no added solvent, and low loadings of a recyclable catalyst (<0.5 mole percent), and it affords highly valuable terminal epoxides and 1, 2-diols in high yield with high enantiomeric enrichment.

  2. Co(III)(salen)-catalyzed HKR of two stereocentered alkoxy- and azido epoxides: a concise enantioselective synthesis of (S,S)-reboxetine and (+)-epi-cytoxazone.

    PubMed

    Reddy, R Santhosh; Chouthaiwale, Pandurang V; Suryavanshi, Gurunath; Chavan, Vilas B; Sudalai, Arumugam

    2010-07-21

    The HKR of racemic syn- or anti- alkoxy- and azido epoxides catalyzed by Co(salen) complex affords a practical access to a series of enantioenriched syn- or anti- alkoxy- and azido epoxides and the corresponding 1,2-diols. This strategy has been successfully employed in the concise, enantioselective synthesis of bioactive molecules such as (S,S)-reboxetine and (+)-epi-cytoxazone.

  3. Benzo(a)pyrene metabolism by murine spleen microsomes

    SciTech Connect

    Kawabata, T.T.; White, K.L. Jr. )

    1989-11-01

    The immunosuppressive actions of benzo(a)pyrene have been proposed to be mediated by reactive metabolites rather than the parent compound. Reactive metabolites which suppress splenic humoral immune responses are thought to be generated within the spleen rather than in distant tissues. Although the spleen has been shown to be capable of metabolizing benzo(a)pyrene, the relative amounts and types of metabolites generated have not been determined. In this study, high-pressure liquid chromatography was used to separate benzo(a)pyrene metabolites generated by splenic microsomes. The major metabolites generated by the splenic microsomal preparations of untreated female B6C3F1 mice were found to be the 9,10- and 7,8-dihydrodiols and 9-, 7-, and 3-hydroxy benzo(a)pyrene. The 1,3-, 3,6-, and 6,12-diones and 4,5-dihydrodiol constituted only a small fraction of the metabolites generated. The generation of all metabolites were inhibited by alpha-naphthoflavone and antiserum to NADPH-cytochrome P-450 reductase, whereas SKF 525-A had only a minimal effect. Dihydrodiol production was completely inhibited by the epoxide hydrolase inhibitor, trichloropropylene oxide. Benzo(a)pyrene pretreatment of mice produced a dramatic increase in the amount of metabolites formed; however, the pattern of metabolites remained similar to that generated by splenic microsomes of untreated mice. The role of prostaglandin synthetase in generating these metabolites was also examined. The addition of arachidonic acid in place of NADPH resulted in the formation of only quinones. Dihydrodiols and phenols were undetectable. The results of this study indicate that splenocytes may be capable of generating the 7,8-dihydrodiol, the precursor to the highly reactive 7,8-dihydrodiol-9,10-epoxide.

  4. Studies on the mutagenic mechanisms of the potent environmental carcinogen, benzo[a]pyrene

    SciTech Connect

    Rodriguez, H.

    1993-01-01

    Environmental chemicals that cause cancer have previously been shown to become chemically linked to the genetic substance, DNA, to give DNA adducts. These adducts appear foreign to the cell and mutations occur when the DNA is being duplicated during cell replication. Mutations in proto-oncogenes can change a normal cell into a cancerous cell. Benzo[a]pyrene is one example of a potent mutagen/carcinogen found ubiquitously in the environment: For example, in the soot from internal combustion engines and power plants, in cigarette smoke, and on charred meat. Benzo[a]pyrene is an indirect-acting mutagen/carcinogen, which must be metabolized inside the body to its ultimate mutagen/carcinogen, the corresponding (+)-anti-diol epoxide ((+)-anti-B[a]PDE) which forms many adducts in DNA. By using a newly developed forward mutation assay (ES87/pUB3) mutations induced by (+)-anti-B[a]PDE were isolated and characterized. SOS induction was shown to enhance frameshift and base pairing mutagenesis; G:C->T:A mutations were preferentially enhanced (approximately twelve-fold). Nearest neighbor analysis was performed assuming a guanine (underlined) was being mutated; SOS enhanced (+)-anti-B[a]PDE base pairing mutagenesis in 5[prime]-(A/T)G-3[prime] sequences more than in 5[prime]-G(A/T)-3[prime] sequences, and in 5[prime]-G(C/G)-3[prime] sequences more than in 5[prime]-G(A/T)-3[prime] sequences. Sequence content affected mutagenesis quantitatively where hot-spots for (+)-anti-B[a]PDE was heated prior to transformation into ES87 cells, an approximately two-fold decrease in mutation frequency was observed. In general, heating did not affect mutagenic specificity. Models are proposed to explain these results. Freeze/thawing pUB3 adducted with (+)-anti-B[a]PDE, also caused both an approximately two-fold decrease in mutation frequency and changes similar to those caused by heating.

  5. Lack of contribution of covalent benzo[a]pyrene-7,8-quinone-DNA adducts in benzo[a]pyrene-induced mouse lung tumorigenesis.

    PubMed

    Nesnow, Stephen; Nelson, Garret; Padgett, William T; George, Michael H; Moore, Tanya; King, Leon C; Adams, Linda D; Ross, Jeffrey A

    2010-07-30

    Benzo[a]pyrene (B[a]P) is a potent human and rodent lung carcinogen. This activity has been ascribed in part to the formation of anti-trans-7,8-dihydroxy-7,8-dihydroB[a]P-9,10-epoxide (BPDE)-DNA adducts. Other carcinogenic mechanisms have been proposed: (1) the induction of apurinic sites from radical cation processes, and (2) the metabolic formation of B[a]P-7,8-quinone (BPQ) that can form covalent DNA adducts or reactive oxygen species which can damage DNA. The studies presented here sought to examine the role of stable BPQ-DNA adducts in B[a]P-induced mouse lung tumorigenesis. Male strain A/J mice were injected intraperitoneally once with BPQ or trans-7,8-dihydroxy-7,8-dihydroB[a]P (BP-7,8-diol) at 30, 10, 3, or 0mg/kg. Lungs and livers were harvested after 24h, the DNA extracted and subjected to (32)P-postlabeling analysis. Additional groups of mice were dosed once with BPQ or BP-7,8-diol each at 30 mg/kg and tissues harvested 48 and 72 h later, or with B[a]P (50mg/kg, a tumorigenic dose) and tissues harvested 72 h later. No BPQ or any other DNA adducts were observed in lung or liver tissues 24, 48, or 72 h after the treatment with 30 mg/kg BPQ. BP-7,8-diol gave BPDE-DNA adducts at all time points in both tissues and B[a]P treatment gave BPDE-DNA adducts in the lung. In each case, no BPQ-DNA adducts were detected. Mouse body weights significantly decreased over time after BPQ or BP-7,8-diol treatments suggesting that systemic toxicity was induced by both agents. Model studies with BPQ and N-acetylcysteine suggested that BPQ is rapidly inactivated by sulfhydryl-containing compounds and not available for DNA adduction. We conclude that under these treatment conditions BPQ does not form stable covalent DNA adducts in the lungs or livers of strain A/J mice, suggesting that stable BPQ-covalent adducts are not a part of the complex of mechanisms involved in B[a]P-induced mouse lung tumorigenesis.

  6. Immunoassay procedures to detect exposure to aflatoxin B1 and benzo(a)pyrene in animals and man at the DNA level.

    PubMed

    Garner, R C; Dvorackova, I; Tursi, F

    1988-01-01

    Immunological methods were used to examine human liver for the presence of aflatoxin-DNA adducts and human lung for benzo(a)pyrene diol-epoxide DNA (BPDE-DNA) adducts. Eight liver samples obtained from Czechoslovakian patients with primary hepatocellular carcinoma were studied, seven of which had detectable anti-aflatoxin inhibitory material. Values ranged between 0.63 and 3.51 picomoles aflatoxin per mg DNA. In a separate, independent study performed in another laboratory the one sample with no aflatoxin bound to DNA also had no free aflatoxin present in the liver. In the case of the human lung DNA samples, 12 samples were examined, the samples having been removed during thoracic surgery, and five had detectable anti-BPDE-DNA antibody activity. The positive samples were all from smokers and had inhibitory values ranging from 4 to 12 femtomoles per mg DNA. Samples were prepared by immunoconcentration prior to analysis. These preliminary results support the view that immunological methods can be used to examine human tissue DNA for carcinogen adducts.

  7. Identification and characterization of a new epoxide hydrolase from mouse liver microsomes.

    PubMed

    Guenthner, T M; Oesch, F

    1983-12-25

    A new microsomal epoxide hydrolase (mEH2) has been identified and characterized. This enzyme has properties which distinguish it from previously described cytosolic (cEH) or membrane-bound (mEH1) epoxide hydrolases. The enzyme is an integral microsomal protein which is not dissociated from the membrane by repeated washing, high ionic strength salt, or chaotropic agent solutions, or by sonication. It is very different from the normally described microsomal epoxide hydrolase (mEH1) as shown by its different substrate specificity and kinetic properties and by immunological criteria. In contrast to the hitherto described microsomal epoxide hydrolase, mEH1, the new enzyme effectively catalyzes the hydration of transdisubstituted oxiranes such as trans-stilbene oxide and trans-beta-ethyl styrene oxide and has no appreciable activity toward benzo(a)pyrene 4,5-oxide. It is also structurally distinct, in that it does not cross-react with antibodies raised against the normally described microsomal epoxide hydrolase mEH1. This newly described microsomal epoxide hydrolase probably represents an important factor in the control of reactive epoxides; its location in the membrane ensures access to lipophilic epoxides generated by membrane-bound monooxygenases, and its substrate specificity is such that it can hydrolyze epoxides poorly metabolized by the previously described microsomal epoxide hydrolase.

  8. The extreme variety of genotoxic response to benzo[a]pyrene in three different human cell lines from three different organs.

    PubMed

    Genies, Camille; Maître, Anne; Lefèbvre, Emmanuel; Jullien, Amandine; Chopard-Lallier, Marianne; Douki, Thierry

    2013-01-01

    Polycyclic aromatic hydrocarbons (PAHs) are associated with occupational exposure and urban atmospheric pollution. Determination of the genotoxic properties of these compounds is thus of outmost importance. For this purpose a variety of cellular models have been widely used. Reliable results can however only be obtained with models reflecting the specific sensitivity of different organs towards PAHs. In this work, we compared the response to benzo[a]pyrene in cell lines from human lungs (A549) and bladder (T24); two important target organs for PAHs-induced cancer. Human hepatocytes (HepG2) were used as a reference, although liver is not a concern for PAHs carcinogenesis. Adducts arising from the ultimate diol-epoxide metabolite of B[a]P, BPDE, were found to be produced in a dose-dependent manner in HepG2. BPDE DNA adducts were not detected in T24 and in A549 their formation was found to be most efficient at the lowest concentration studied (0.2 µM). These results are probably explained by differences in induction and activity of phase I metabolization enzymes, as well as by proteins eliminating the B[a]P epoxide in A549. In addition to BPDE adducts, oxidative DNA damage, namely strand breaks and oxidized purines were measured and found to be produced only in minute amounts in all three cell lines. In summary, our results emphasize the large differences in the response of cells originating from different organs. Our data also point out the importance of carefully selecting the doses used in in vitro toxicological experiments. The example of A549 shows that working at high doses may lead to an underestimation of the risk. Finally, the choice of method for evaluating genotoxicity appears to be of crucial importance. The comet assay does not seem to be the best method for a compound like B[a]P which induces stable adducts causing limited oxidative damage.

  9. Data set of optimal parameters for colorimetric red assay of epoxide hydrolase activity.

    PubMed

    de Oliveira, Gabriel Stephani; Adriani, Patricia Pereira; Borges, Flavia Garcia; Lopes, Adriana Rios; Campana, Patricia T; Chambergo, Felipe S

    2016-09-01

    The data presented in this article are related to the research article entitled "Epoxide hydrolase of Trichoderma reesei: Biochemical properties and conformational characterization" [1]. Epoxide hydrolases (EHs) are enzymes that catalyze the hydrolysis of epoxides to the corresponding vicinal diols. This article describes the optimal parameters for the colorimetric red assay to determine the enzymatic activity, with an emphasis on the characterization of the kinetic parameters, pH optimum and thermal stability of this enzyme. The effects of reagents that are not resistant to oxidation by sodium periodate on the reactions can generate false positives and interfere with the final results of the red assay.

  10. Soluble epoxide hydrolase: Gene structure, expression and deletion

    PubMed Central

    Harris, Todd R.; Hammock, Bruce D.

    2013-01-01

    Mammalian soluble epoxide hydrolase (sEH) converts epoxides to their corresponding diols through the addition of a water molecule. sEH readily hydrolyzes lipid signaling molecules, including the epoxyeicosatrienoic acids (EETs), epoxidized lipids produced from arachidonic acid by the action of cytochrome p450s. Through its metabolism of the EETs and other lipid mediators, sEH contributes to the regulation of vascular tone, nociception, angiogenesis and the inflammatory response. Because of its central physiological role in disease states such as cardiac hypertrophy, diabetes, hypertension, and pain sEH is being investigated as a therapeutic target. This review begins with a brief introduction to sEH protein structure and function. sEH evolution and gene structure are then discussed before human small nucleotide polymorphisms and mammalian gene expression are described in the context of several disease models. The review ends with an overview of studies that have employed the sEH knockout mouse model. PMID:23701967

  11. Reactions of epoxide monomers in food simulants used to test plastics for migration.

    PubMed

    Philo, M R; Damant, A P; Castle, L

    1997-01-01

    The reactions of four epoxides used as monomers for food contact plastics were studied in the food simulants distilled water, 15% aqueous ethanol, 3% aqueous acetic acid and olive oil. Loss of the parent substance and formation of products was monitored to establish the transformation products to be expected in each simulant following migration testing of plastics. Each epoxide was stable in olive oil but suffered extensive loss in the three aqueous simulants. Reaction half-lives were from < 1 to 10 h in aqueous acetic acid, 25-63 h in distilled water, and 33-87 h in aqueous ethanol simulant. Hydrolysis to the diol was the main reaction pathway. Epoxide ring opening in aqueous ethanol simulant gave the diol and also the diol monoethyl ether. It is concluded that, for aqueous simulants and by implication for most foods, testing plastics against specific migration limits for epoxides is not likely to give reliable results due to their reactivity. The present EC mode of control for these reactive monomers, via compositional limits in food contact plastics, is more practical since the hydrolysis products are less toxic than the parent epoxide.

  12. Cytosolic and microsomal epoxide hydrolases are immunologically distinguishable from each other in the rat and mouse.

    PubMed

    Guenthner, T M; Hammock, B D; Vogel, U; Oesch, F

    1981-04-10

    Antibodies raised to homogeneous rat liver microsomal epoxide hydrolase were used to distinguish microsomal epoxide hydrolase from epoxide hydrolase of cytosolic origin in mice and rats. Using double diffusion analysis in agarose gels, we show that anti-rat liver microsomal epoxide hydrolase forms a single precipitin line with solubilized microsomes from rat and mouse liver, but no reaction is seen with the corresponding cytosolic fractions. Rat or mouse microsomal epoxide hydrolase activity (using benzo[a]pyrene 4,5-oxide as substrate) can be completely precipitated out of solubilized preparations by the antibody, which is equipotent against rat and mouse microsomal epoxide hydrolase. No precipitation of cytosolic hydrolase activity (using trans-beta-ethyl styrene oxide as substrate) is seen with any concentration of the antibody tested. Thus, in the case of microsomal epoxide hydrolase, extensive immunological cross-reactivity exists between the two species, rat and mouse. In contrast, no cross-reactivity is detectable between cytosolic and microsomal epoxide hydrolase, even when enzymes from the same species are compared. We conclude that microsomal and cytosolic epoxide hydrolase activities represent distinct and immunologically non-cross-reactive protein species.

  13. Selective inhibition and selective induction of multiple microsomal epoxide hydrolases.

    PubMed

    Guenthner, T M

    1986-03-01

    The inhibition in vitro and induction in vivo of microsomal trans-stilbene oxide hydrolase have been studied. This microsomal epoxide hydrolase activity is distinguishable from the previously well-defined microsomal arene oxide hydrolase by a number of catalytic criteria. Two substituted chalcone oxides, 4-phenylchalcone oxide and 4'-phenylchalcone oxide, are potent inhibitors of microsomal trans-stilbene oxide hydrolase, but have no apparent activity against benzo[a]pyrene 4,5-oxide hydrolase. Conversely, compounds that are potent inhibitors of benzo[a]pyrene 4,5-oxide hydrolase, including styrene oxide, cyclohexene oxide, and trichloropropene oxide, inhibit microsomal trans-stilbene oxide hydrolase only at very high (millimolar) concentrations. The chalcone oxides inhibit microsomal trans-stilbene oxide hydrolase noncompetitively, and have micromolar or nanomolar affinity constants for the enzyme. Attempts were made to induce microsomal trans-stilbene oxide hydrolase in vivo. Compounds that induced microsomal benzo[a]pyrene 4,5-oxide hydrolase levels in mice did not simultaneously induce trans-stilbene oxide hydrolase levels. Clofibrate was an exception; it induced levels of both enzymes to a small but statistically significant degree. The two microsomal hydrolase activities have, therefore, very different catalytic sites and appear to be under separate genetic control. 4-Phenylchalcone oxide and 4'-phenylchalcone oxide are selective inhibitors of microsomal trans-stilbene oxide hydrolase and may prove to be very useful in assessing the involvement of this enzyme in the metabolism of endogenous or xenobiotic epoxides.

  14. Effect of 3,3{prime},4,4{prime}5 pentachlorobiphenyl (PCB{number_sign}126) on benzo(a)pyrene induced DNA-damage in the fish hepatoma cell line PLHC-1

    SciTech Connect

    Smeets, J.; Berg, M. van den; Seinen, W.; Everaarts, J.

    1995-12-31

    Benzo(a)pyrene (BaP) can be transformed to 7,8 diol-9,10 epoxide BaP which is a major carcinogen. The cytochrome P45OIAI isoenzyme is playing an important role in this bioactivation. The coplanar PCB{number_sign}126 is a strong inducer of CYPIAI in vivo but also in the PLHC-1 fish cell line. This CYPIAI inducing property of PCB{number_sign}L26 could increase the BaP induced DNA-damage. In this study dose-response relationships for PCB{number_sign}126, BaP and their combination are presented, measured either as CYPIAI (EROD) induction or as DNA strand breaks. Strand breaks were measured by means of an alkaline unwinding assay. BaP is readily metabolized in this cell line and induces strand breaks dose-dependently. PCB induces EROD in a dose-dependant way but does not cause DNA strand breaks significantly. PLHC-1 cells were pre-treated with PCB{number_sign}126 (LOEL,ED50 and maximal EROD induction) and then dosed with BaP (LOEL,ED5 and maximal strand break induction). DNA-strand breaks in the pre-treated cells were compared to cells treated with BaP alone. Results of these combined exposures will be presented and discussed.

  15. Epoxidation catalyst and process

    DOEpatents

    Linic, Suljo; Christopher, Phillip

    2010-10-26

    Disclosed herein is a catalytic method of converting alkenes to epoxides. This method generally includes reacting alkenes with oxygen in the presence of a specific silver catalyst under conditions suitable to produce a yield of the epoxides. The specific silver catalyst is a silver nanocrystal having a plurality of surface planes, a substantial portion of which is defined by Miller indices of (100). The reaction is performed by charging a suitable reactor with this silver catalyst and then feeding the reactants to the reactor under conditions to carry out the reaction. The reaction may be performed in batch, or as a continuous process that employs a recycle of any unreacted alkenes. The specific silver catalyst has unexpectedly high selectivity for epoxide products. Consequently, this general method (and its various embodiments) will result in extraordinarily high epoxide yields heretofore unattainable.

  16. Succinic anhydrides from epoxides

    DOEpatents

    Coates, Geoffrey W.; Rowley, John M.

    2013-07-09

    Catalysts and methods for the double carbonylation of epoxides are disclosed. Each epoxide molecule reacts with two molecules of carbon monoxide to produce a succinic anhydride. The reaction is facilitated by catalysts combining a Lewis acidic species with a transition metal carbonyl complex. The double carbonylation is achieved in single process by using reaction conditions under which both carbonylation reactions occur without the necessity of isolating or purifying the product of the first carbonylation.

  17. Mutual in vivo interactions between benzo[a]pyrene and tributyltin in brook trout (Salvelinus fontinalis)

    SciTech Connect

    Padros, J.; Pelletier, E.; Reader, S.; Denizeau, F.

    2000-04-01

    Tributyltin (TBT), an organometal used as an antifouling biocide, has been reported to inhibit cytochrome P450 (P450) 1A isozyme. Benzo[a]pyrene (BaP), a widespread carcinogenic polycyclic aromatic hydrocarbon, is both metabolized and bioactivated to carcinogenic BaP diol-epoxide (BPDE) metabolites primarily by hepatic P450 1A. Hence, TBT may inhibit the metabolism and bioactivation of BaP. This study was therefore designed to examine the potential in vivo interactions between BaP and TBT in a model fish. Male brook trout (Salelinus fontinalis) were given a single intraperitoneal injection of either BaP, TBT, or both in combination. After 48 h, blood, bile, and liver samples were collected and analyzed for a suite of biomarkers associated with P450 activity, BaP metabolism and bioactivation, and TBT metabolism. The results showed that TBT significantly inhibited (a) the induction of hepatic P450 1A-mediated ethoxyresorufin O-deethylase (EROD) and P450-mediated 3-cyano-7-ethoxycoumarin-O-deethylase (CN-ECOD) activities by BaP, (b) the formation of biliary BaP metabolites, and (c) the formation of (+)-anti-BPDE-plasma albumin adducts as measured by high-performance liquid chromatography-fluorescence. Notably, TBT alone did not inhibit EROD activity but induced CN-ECOD activity. Gas chromatography-mass spectrometry analysis indicated that the combined BaP + TBT dose resulted in higher levels of dibutyltin metabolites in the bite (p < 0.05). The present study supports the hypothesis that a single, high dose of TBT can antagonize the metabolism and bioactivation of BaP at least by inhibiting the induction of P4501A. On the other hand, BaP unexpectedly potentiated the metabolism of TBT, suggesting that hepatic isoforms other than P3501A may be responsible for TBT metabolism. Finally, this study supports the utility of a biomarker approach to screen potential xenobiotic interactions in aquatic organisms and to obtain mechanistic insights.

  18. Bioactive lipid profiling reveals drug target engagement of a soluble epoxide hydrolase inhibitor in a murine model of tobacco smoke exposure.

    PubMed

    Nording, Malin L; Yang, Jun; Hoang, Laura; Zamora, Vanessa; Uyeminami, Dale; Espiritu, Imelda; Pinkerton, Kent E; Hammock, Bruce D; Luria, Ayala

    2015-04-01

    The inflammatory process underlying chronic obstructive pulmonary disease (COPD) may be caused by tobacco smoke (TS) exposure. Previous studies show that epoxyeicosatrienoic acids (EETs) possess promising anti-inflammatory properties, therefore stabilization of EETs and other fatty acid epoxides through inhibition of soluble epoxide hydrolase (sEH) was investigated in mouse models of acute and sub-chronic inflammation caused by TS exposure. During the entire TS exposure, the potent sEH inhibitor 1-(1-methylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS) was given via drinking water. To assess drug target engagement of TUPS, a tandem mass spectrometry method was used for bioactive lipid profiling of a broad range of fatty acid metabolites, including EETs, and their corresponding diols (DHETs) derived from arachidonic acid, as well as epoxides and diols derived from other fatty acids. Several, but not all, plasma epoxide/diol ratios increased in mice treated with sEH inhibitor, compared to non-treated mice suggesting a wider role for sEH involving more fatty acid precursors besides arachidonic acid. This study supports qualitative use of epoxide/diol ratios explored by bioactive lipid profiling to indicate drug target engagement in mouse models of TS exposure relevant to COPD, which may have ramifications for future therapeutic interventions of sEH.

  19. Exported Epoxide Hydrolases Modulate Erythrocyte Vasoactive Lipids during Plasmodium falciparum Infection

    PubMed Central

    Dalmia, Varun K.

    2016-01-01

    ABSTRACT Erythrocytes are reservoirs of important epoxide-containing lipid signaling molecules, including epoxyeicosatrienoic acids (EETs). EETs function as vasodilators and anti-inflammatory modulators in the bloodstream. Bioactive EETs are hydrolyzed to less active diols (dihydroxyeicosatrienoic acids) by epoxide hydrolases (EHs). The malaria parasite Plasmodium falciparum infects host red blood cells (RBCs) and exports hundreds of proteins into the RBC compartment. In this study, we show that two parasite epoxide hydrolases, P. falciparum epoxide hydrolases 1 (PfEH1) and 2 (PfEH2), both with noncanonical serine nucleophiles, are exported to the periphery of infected RBCs. PfEH1 and PfEH2 were successfully expressed in Escherichia coli, and they hydrolyzed physiologically relevant erythrocyte EETs. Mutations in active site residues of PfEH1 ablated the ability of the enzyme to hydrolyze an epoxide substrate. Overexpression of PfEH1 or PfEH2 in parasite-infected RBCs resulted in a significant alteration in the epoxide fatty acids stored in RBC phospholipids. We hypothesize that the parasite disruption of epoxide-containing signaling lipids leads to perturbed vascular function, creating favorable conditions for binding and sequestration of infected RBCs to the microvascular endothelium. PMID:27795395

  20. Synthesis of phenol and quinone metabolites of benzo[a]pyrene, a carcinogenic component of tobacco smoke implicated in lung cancer.

    PubMed

    Xu, Daiwang; Penning, Trevor M; Blair, Ian A; Harvey, Ronald G

    2009-01-16

    Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants produced in the combustion of organic matter. PAHs are present in automobile exhaust and tobacco smoke, and they have recently been designated as human carcinogens. Current evidence indicates that PAHs are activated enzymatically to mutagenic metabolites that interact with DNA. There is evidence for three pathways of activation: the diol epoxide path, the radical-cation path, and the quinone path. The relative importance of these paths for human lung cancer has not been established. We now report syntheses of the principal phenol and quinone isomers of the prototype PAH carcinogen benzo[a]pyrene (BP) that are known or are suspected to be formed as metabolites of BP in human bronchoalveolar cells. The methods of synthesis were designed to be adaptable to the preparation of the (13)C-labeled analogues of the BP metabolites. These compounds are needed as standards for sensitive LC-MS/MS methods for analysis of BP metabolites formed in lung cells. Efficient novel syntheses of the 1-, 3-, 6-, 9-, and 12-BP phenols and the BP 1,6-, 3,6-, 6,12-, and 9,10-quinones are now reported. The syntheses of the BP phenols (except 6-HO-BP) involve the key steps of Pd-catalyzed Suzuki-Miyaura cross-coupling of a naphthalene boronate ester with a substituted aryl bromide or triflate ester. The BP quinones were synthesized from the corresponding BP phenols by direct oxidation with the hypervalent iodine reagents IBX or TBI. These reagents exhibited different regiospecificities. IBX oxidation of the 7- and 9-BP phenols provided the ortho-quinone isomers (BP 7,8- and 9,10-diones, respectively), whereas TBI oxidation of the 1-, 3-, and 12-BP phenols furnished BP quinone isomers with carbonyl functions in separate rings (BP 1,6-, 3,6-, and 6,12-diones, respectively).

  1. Synthesis of Phenol and Quinone Metabolites of Benzo[a]pyrene, a Carcinogenic Component of Tobacco Smoke Implicated in Lung Cancer

    PubMed Central

    Xu, Daiwang; Penning, Trevor M.; Blair, Ian A.; Harvey, Ronald G.

    2009-01-01

    Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants produced in the combustion of organic matter. PAHs are present in automobile exhaust and tobacco smoke, and they have recently been designated as human carcinogens. Current evidence indicates that PAHs are activated enzymatically to mutagenic metabolites that interact with DNA. There is evidence for three pathways of activation, the diol epoxide path, the radical-cation path, and the quinone path. The relative importance of these paths for human lung cancer has not been established. We now report syntheses of the principal phenol and quinone isomers of the prototype PAH carcinogen benzo[a]pyrene (BP) that are known or are suspected to be formed as metabolites of BP in human bronchoalveolar cells. The methods of synthesis were designed to be adaptable to preparation of the 13C-labelled analogues of the BP metabolites. These compounds are needed as standards for sensitive LC-MS/MS methods for analysis of BP metabolites formed in lung cells. Efficient novel syntheses of the 1-, 3-, 6-, 9-, and 12-BP phenols, and the BP 1,6-, 3,6-, 6,12-, and 9,10-quinones are now reported. The syntheses of the BP phenols (except 6-HO-BP) involve in the key steps Pd-catalyzed Suzuki-Miyaura cross-coupling of a naphthalene boronate ester with a substituted aryl bromide or triflate ester. The BP quinones were synthesized from the corresponding BP phenols by direct oxidation with the hypervalent iodine reagents IBX or TBI. These reagents exhibited different regiospecificities. IBX oxidation of the 7- and 9- BP phenols provided the ortho-quinone isomers (BP 7,8-, and 9.10-dione), whereas TBI oxidation of the 1-, 3-, and 12-BP phenols furnished BP quinone isomers with carbonyl functions in separate rings (BP 1,6-, 3,6-, and 6,12-dione). PMID:19132942

  2. CHARACTERIZATION OF STABLE BENZO(A)PYRENE-7,8-QUINONE-DNA ADDUCTS IN CALF THYMUS DNA

    EPA Science Inventory

    Benzo[alpyrene-7,8-dione (BPQ) is a reactive aldo-keto reductase-mediated product of B[a]P-7,8-diol, a major P450/epoxide hydrolase metabolite of the multi-species carcinogen, B[a]P. The role of BPQ in B[a]P's genotoxicity and carcinogenesis is evolving. Toxicity pathways involvi...

  3. One step synthesis of 6-oxo-cholestan-3β,5α-diol

    SciTech Connect

    Voisin, Maud; Silvente-Poirot, Sandrine; Poirot, Marc

    2014-04-11

    Highlights: • Cholesterol-5,6-epoxides are metabolized into cholestane-3β,5α,6β-triol (CT) in cancer cells. • 6-Oxo-cholestan-3β,5α-diol (OCDO) is a putative metabolite of CT. • The one step syntheses of CT and OCDO from cholesterol are reported. • The one step syntheses of labelled CT and OCDO are reported. - Abstract: Cholesterol metabolism has been recently linked to cancer, highlighting the importance of the characterization of new metabolic pathways in the sterol series. One of these pathways is centered on cholesterol-5,6-epoxides (5,6-ECs). 5,6-ECs can either generate dendrogenin A, a tumor suppressor present in healthy mammalian tissues, or the carcinogenic cholestane-3β,5α,6β-triol (CT) and its putative metabolite 6-oxo-cholestan-3β,5α-diol (OCDO) in tumor cells. We are currently investigating the identification of the enzyme involved in OCDO biosynthesis, which would be highly facilitated by the use of commercially unavailable [{sup 14}C]-cholestane-3β,5α,6β-triol and [{sup 14}C]-6-oxo-cholestan-3β,5α-diol. In the present study we report the one-step synthesis of [{sup 14}C]-cholestane-3β,5α,6β-triol and [{sup 14}C]-6-oxo-cholestan-3β,5α-diol by oxidation of [{sup 14}C]-cholesterol with iodide metaperiodate (HIO{sub 4})

  4. Synthesis of cyclic carbonates from diols and CO2 catalyzed by carbenes.

    PubMed

    Bobbink, Felix D; Gruszka, Weronika; Hulla, Martin; Das, Shoubhik; Dyson, Paul J

    2016-09-14

    The synthesis of cyclic carbonates from epoxides and CO2 is a well-established reaction, whereas the synthesis of cyclic carbonates from diols and CO2 is considerably more challenging, and few efficient catalysts are available. Here, we describe heterocyclic carbene catalysts, including one derived from a cheap and efficient thiazolium salt, for this latter reaction. The reaction proceeds at atmospheric pressure in the presence of an alkyl halide and Cs2CO3. Reaction mechanisms for the transformations involved are also proposed.

  5. Characterization of multiple epoxide hydrolase activities in mouse liver nuclear envelope.

    PubMed

    Guenthner, T M

    1986-10-01

    A nuclear envelope-associated epoxide hydrolase in mouse liver that hydrates trans-stilbene oxide has been identified and characterized. This epoxide hydrolase is distinct from the enzyme in nuclear envelopes that hydrates benzo[a]pyrene 4,5-oxide and other arene oxides. This distinction was demonstrated by the criteria of pH optima, response to specific inhibitors in vitro, and precipitation by specific antibodies. The new epoxide hydrolase had a pH optimum of 6.8, was poorly inhibited by trichloropropene oxide, was potently inhibited by 4-phenylchalcone oxide, and did not bind to antiserum against benzo[a]pyrene 4,5-oxide hydrolase. This nuclear enzyme is similar in many of its properties to cytosolic and microsomal trans-stilbene oxide hydrolases and may be nuclear envelope-bound form of these other epoxide hydrolases. It differed from these other trans-stilbene oxide hydrolases in that its affinities for both trans-stilbene oxide (measured as apparent Km) and 4-phenylchalcone oxide (measured as I50) were 4- to 20-fold lower than those of either the cytosolic or microsomal forms.

  6. Mechanistic aspects of metal valence change in SalenCo(III)OAc-catalyzed hydrolytic kinetic resolution of racemic epoxides.

    PubMed

    Ren, Wei-Min; Wang, Yi-Ming; Zhang, Rong; Jiang, Jing-Yang; Lu, Xiao-Bing

    2013-05-17

    The chiral SalenCo(III)OAc-catalyzed hydrolytic kinetic resolution (HKR) of racemic terminal epoxides to afford both enantioenriched epoxides and diols presents one of the most important achievements in asymmetric synthesis chemistry. Previous studies mainly focused on the development of highly efficient catalysts, while rare reports concerned the mechanistic understanding of metal valence change, associated with the formation of inactive Co(II)-Salen complex. Herein, we report the mechanistic aspects of catalyst deactivation regarding the transformation of Co(III) to Co(II) derivative in the HKR of racemic epoxides catalyzed by SalenCo(III)OAc complexes with an appended 1,5,7-triazabicyclo[4.4.0]dec-5-ene on the ligand framework by means of electrospray ionization mass spectrometry (ESI-MS). Continuous determination of transient cationic species in ESI-MS positive mode in conjunction with UV-vis spectroscopic studies at various time points provides evidence that a certain amount of SalenCo(III)OAc molecules were reduced to the corresponding Co(II) derivatives in the HKR of racemic propylene oxide or styrene oxide. To be accompanied by the reduction of Co(III) to Co(II), the resultant diols were oxidized to α-hydroxy ketones. These analyses along with some control experiments gave a mechanistic understanding of catalyst deactivation of SalenCo(III)OAc-catalyzed HKR of racemic epoxides regarding an unveiled redox reaction between Co(III)-Salen and diol, the hydrolyzed product.

  7. The in vitro metabolism of benzo[a]pyrene by polychlorinated and polybrominated biphenyl induced rat hepatic microsomal monooxygenases.

    PubMed

    Haake, J M; Merrill, J C; Safe, S

    1985-09-01

    The metabolism of benzo[a]pyrene by halogenated biphenyl-induced rat hepatic microsomal monooxygenases was determined using a high pressure liquid chromatographic assay system. Incubation of benzo[a]pyrene with microsomes from rats pretreated with phenobarbitone or phenobarbitone-type inducers (2,2',4,4',5,5'-hexachlorobiphenyl, 2,2',4,4',6,6'-hexachlorobiphenyl, 2,2',5,5'-tetrachlorobiphenyl, 2,2',4,4',5,5'-hexabromobiphenyl, and 2,2',5,5'-tetrabromobiphenyl) resulted in increased overall metabolism of the hydrocarbon (less than fourfold) into phenolic, quinone, and diol metabolites, with the most striking increase observed in the formation of 4,5-dihydro-4,5-dihydroxybenzo[a]pyrene. In contrast, the metabolism of benzo[a]pyrene by microsomes from rats induced with 3-methylcholanthrene or 3,3',4,4'-tetrachlorobiphenyl resulted in a greater than 10-fold increase in overall benzo[a]pyrene metabolism, with the largest increases observed in the formation of the trans-7,8- and -9,10-dihydrodiol metabolites of benzo[a]pyrene. However, in comparison to control and phenobarbitone-induced microsomes, the oxidative conversion of benzo[a]pyrene by microsomes induced with 3-methylcholanthrene and 3,3',4,4'-tetrachlorobiphenyl into the 6,12-quinone was substantially inhibited. Previous reports have shown that the commercial halogenated biphenyl mixtures, fireMaster BP-6, and Aroclor 1254 are mixed-type inducers and that microsomes from rats pretreated with these mixtures markedly enhance the overall metabolism of benzo[a]pyrene. Not surprisingly, the metabolism of benzo[a]pyrene by microsomes from rats pretreated with the mixed-type inducers, 2,3,3',4,4'-penta-,2,3,3',4,4',5-hexa-, and 2',3,3',4,4',5-hexa- chlorobiphenyl was also increased and the metabolic profile was similar to that observed with fireMaster BP-6 and Aroclor 1254 induced microsomes.

  8. Comparative metabolism of benzo[a]pyrene by liver microsomes of channel catfish and brown bullhead

    SciTech Connect

    Yuan, Z.X.; Kumar, S.; Sikka, H.C.

    1997-04-01

    The authors investigated the metabolism of the carcinogen benzo[a]pyrene (BaP) by liver microsomes of channel catfish (Ictalurus punctatus) and brown bullhead (Ameiurus nebulosus) pretreated with 3-methylcholanthrene. The catfish liver microsomes metabolized BaP at a considerably lower rate than did the brown bullhead liver microsomes. Although the BaP metabolites produced by the liver microsomes of the two species were qualitatively similar, there were considerable differences in the relative proportions of individual metabolites formed. The catfish liver microsomes produced a considerably lower proportion of benzo-ring diols of BaP including BaP-7,8-diol (the proximate carcinogenic metabolite of BaP) than did the bullhead liver microsomes. Compared to the bullhead liver microsomes, the catfish microsomes converted a higher proportion of BaP to phenolic metabolites.

  9. Benzo[a]pyrene and glycine N-methyltransferse Interactions: Gene expression profiles of the liver detoxification pathway

    SciTech Connect

    Lee, C.-M.; Chen, S.-Y.; Lee, Y.-C.G.; Huang, C.-Y.F.; Chen, Y.-M. Arthur . E-mail: arthur@ym.edu.tw

    2006-07-15

    Benzo[a]pyrene (BaP) is one of many polycyclic aromatic hydrocarbons that have been identified as major risk factors for developing various cancers. We previously demonstrated that the liver cancer susceptibility gene glycine N-methyltransferase (GNMT) is capable of binding with BaP and protecting cells from BaP-7,8-diol 9,10-epoxide-DNA adduct formation. In this study, we used a cytotoxicity assay to demonstrate that the higher expression level of GNMT, the lower cytotoxicity occurred in the cells treated with BaP. In addition, a cDNA microarray containing 7,597 human genes was used to examine gene expression patterns in BaP-treated HepG2 (a liver cancer cell line that expresses very low levels of GNMT) and SCG2-1-1 (a stable HepG2 clone that expresses high levels of GNMT) cells. The results showed that among 6,018 readable HepG2 genes, 359 (6.0%) were up-regulated more than 1.5-fold and 768 (12.8%) were down-regulated. Overexpression of GNMT in SCG2-1-1 cells resulted in the down-regulation of genes related to the detoxification, kinase/phosphatase pathways, and oncogenes. Furthermore, real-time PCR was used to validate microarray data from 21 genes belonging to the detoxification pathway. Combining both microarray and real-time PCR data, the results showed that among 89 detoxification pathway genes analyzed, 22 (24.7%) were up-regulated and 6 (6.7%) were down-regulated in BaP-treated HepG2 cells, while in the BaP-treated SCG2-1-1 cells, 12 (13.5%) were up-regulated and 26 (29.2%) were down-regulated (P < 0.001). Therefore, GNMT sequesters BaP, diminishes BaP's effects to the liver detoxification pathway and prevents subsequent cytotoxicity.

  10. Lycopene epoxides and apo-lycopenals formed by chemical reactions and autoxidation in model systems and processed foods.

    PubMed

    Rodriguez, Evelyn B; Rodriguez-Amaya, Delia B

    2009-01-01

    To gain a better understanding of the reactions and the underlying mechanisms of the oxidative degradation of lycopene, the products formed by epoxidation with m-chloroperbenzoic acid (MCPBA), oxidative cleavage with KMnO(4), and autoxidation in low-moisture and aqueous model systems, under light exposure, at ambient temperature were identified. The presence of oxidation products was also verified in processed products (tomato juice, tomato paste, tomato puree, guava juice, "goiabada"). A total of 8 lycopene epoxides and a cyclolycopene diol were formed by the reaction of lycopene with MCPBA and 6 apo-lycopenals were produced with KMnO(4). Some of these oxidation products were not detected in the model systems and in the foods analyzed, but the acid-catalyzed rearrangement product 2,6-cyclolycopene-1,5-diol and apo-12'-lycopenal were found in all model and food systems and lycopene-1,2-epoxide and 2,6-cyclolycopene-1,5-epoxide were found in the model systems and in all but 1 ("goiabada") of the 5 foods analyzed. Other epoxides and apo-lycopenals were found in some systems. The inability to detect an intermediate product could be due to a fast turn over. Increased Z-isomerization was also observed and Z-isomers of the oxidation products were detected.

  11. Evaluation of ovotoxicity induced by 7, 12-dimethylbenz[a]anthracene and its 3,4-diol metabolite utilizing a rat in vitro ovarian culture system

    SciTech Connect

    Igawa, Yoshiyuki; Keating, Aileen F. Rajapaksa, Kathila S.; Sipes, I. Glenn; Hoyer, Patricia B.

    2009-02-01

    The polycyclic aromatic hydrocarbon 7, 12-dimethylbenz[a]anthracene, (DMBA), targets and destroys all follicle types in rat and mouse ovaries. DMBA requires bioactivation to DMBA-3,4-diol-1,2-epoxide for ovotoxicity via formation of the intermediate, DMBA-3,4-diol (catalyzed by microsomal epoxide hydrolase; mEH). mEH was shown to be involved in DMBA bioactivation for ovotoxicity induction in B6C3F{sub 1} mouse ovaries. The current study compared DMBA and DMBA-3,4-diol mediated ovotoxicity, and investigated mEH involvement in DMBA-3,4-diol bioactivation in Fischer 344 (F344) rat ovary. F344 postnatal day (PND) 4 rat ovaries were cultured in vehicle control or media containing 1) DMBA or DMBA-3,4-diol (12.5 nM - 1 {mu}M; 15 days); 2) DMBA (1 {mu}M; 6 h - 15 days); and 3) DMBA (1 {mu}M) or DMBA-3,4-diol (75 nM) {+-} the mEH activity inhibitor cyclohexene oxide (CHO; 2 mM; 4 days). Ovaries were histologically evaluated and mEH mRNA and protein were measured by reverse transcriptase PCR or Western blotting, respectively. Ovotoxicity following 15 days of culture occurred (P < 0.05) at lower concentrations of DMBA-3,4-diol (12.5 nM - primordial; 75 nM - primary) than DMBA (75 nM - primordial; 375 nM - primary). The temporal pattern of mEH expression following DMBA exposure showed mRNA up-regulation (P < 0.05) on day 2, with increased protein (P < 0.05) on day 4, the earliest time of observed follicle loss (P < 0.05). mEH inhibition prevented DMBA-induced, but not DMBA-3,4-diol-induced ovotoxicity. These results demonstrate a conserved response in mice and rats for ovarian mEH involvement in DMBA bioactivation to its ovotoxic, 3,4-diol-1,2-epoxide form.

  12. BENZO[A]PYRENE-7,8-QUINONE FORMS COVALENT-DNA ADDUCTS IN VITRO BUT NONE WERE DETECTED IN THE LUNGS OR LIVERS OF STRAIN A/J MICE IN VIVO

    EPA Science Inventory

    Benzo[a]pyrene (B[a]P) is a potent human and rodent lung carcinogen. This activity has been ascribed in part to the formation of B[a]P-7,8-dio1-9,10-epoxide (BPDE)-DNA adducts. Other carcinogenic mechanisms have been proposed: 1.] The induction of apurinic sites from radical cati...

  13. Dysregulation of Soluble Epoxide Hydrolase and Lipidomic Profiles in Anorexia Nervosa

    PubMed Central

    Shih, Pei-an Betty; Yang, Jun; Morisseau, Christophe; German, J. Bruce; Van Zeeland, Ashley; Armando, Aaron M.; Quehenberger, Oswald; Bergen, Andrew W.; Magistretti, Pierre; Berrettini, Wade; Halmi, Katherine Ann; Schork, Nicholas; Hammock, Bruce D.; Kaye, Walter

    2015-01-01

    Individuals with anorexia nervosa (AN) restrict eating and become emaciated. AN tend to have an aversion to foods rich in fat. Because Epoxide Hydrolase 2 (EPHX2) was identified as a novel AN susceptibility gene, and because its protein product, soluble epoxide hydrolase (sEH), converts bioactive epoxides of polyunsaturated fatty acid (PUFA) to the corresponding diols, lipidomic and metabolomic targets of EPHX2 were assessed to evaluate the biological functions of EPHX2 and their role in AN. Epoxide substrates of sEH and associated oxylipins were measured in ill AN, recovered AN, and gender- and race-matched controls. PUFA and oxylipin markers were tested as potential biomarkers for AN. Oxylipin ratios were calculated as proxy markers of in vivo sEH activity. Several free- and total PUFAs were associated with AN diagnosis and with AN recovery. AN displayed elevated n-3 PUFAs and may differ from controls in PUFA elongation and desaturation processes. Cytochrome P450 pathway oxylipins from arachidonic acid, linoleic acid, alpha-linolenic acid, and docosahexaenoic acid PUFAs are associated with AN diagnosis. The diol:epoxide ratios suggest the sEH activity is higher in AN compared to controls. Multivariate analysis illustrates normalization of lipidomic profiles in recovered ANs. EPHX2 influences AN risk through in vivo interaction with dietary PUFAs. PUFA composition and concentrations as well as sEH activity may contribute to the pathogenesis and prognosis of AN. Our data support the involvement of EPHX2-associated lipidomic and oxylipin dysregulations in AN, and reveal their potential as biomarkers to assess responsiveness to future intervention or treatment. PMID:25824304

  14. Purification and characterisation of a novel enantioselective epoxide hydrolase from Aspergillus niger M200.

    PubMed

    Kotik, Michael; Kyslík, Pavel

    2006-02-01

    Purification of a novel enantioselective epoxide hydrolase from Aspergillus niger M200 has been achieved using ammonium sulphate precipitation, ionic exchange, hydrophobic interaction, and size-exclusion chromatography, in conjunction with two additional chromatographic steps employing hydroxylapatite, and Mimetic Green. The enzyme was purified 186-fold with a yield of 15%. The apparent molecular mass of the enzyme was determined to be 77 kDa under native conditions and 40 kDa under denaturing conditions, implying a dimeric structure of the native enzyme. The isoelectric point of the enzyme was estimated to be 4.0 by isoelectric focusing electrophoresis. The enzyme has a broad substrate specificity with highest specificities towards tert-butyl glycidyl ether, para-nitrostyrene oxide, benzyl glycidyl ether, and styrene oxide. Enantiomeric ratios of 30 to more than 100 were determined for the hydrolysis reactions of 4 epoxidic substrates using the purified enzyme at a reaction temperature of 10 degrees C. Product inhibition studies suggest that the enzyme is able to differentiate to a high degree between the (R)-diol and (S)-diol product of the hydrolysis reaction with tert-butyl glycidyl ether as the substrate. The highest activity of the enzyme was at 42 degrees C and a pH of 6.8. Six peptide sequences, which were obtained by cleavage of the purified enzyme with trypsin and mass spectrometry analysis of the tryptic peptides, show high similarity with corresponding sequences originated from the epoxide hydrolase from Aspergillus niger LCP 521.

  15. Comparison of the kinetics of various biomarkers of benzo[a]pyrene exposure following different routes of entry in rats.

    PubMed

    Moreau, Marjory; Bouchard, Michèle

    2015-07-01

    The effect of route of exposure on the kinetics of key biomarkers of exposure to benzo[a]pyrene (BaP), a known human carcinogen, was studied. Rats were exposed to an intravenous, intratracheal, oral and cutaneous dose of 40 µmol kg(-1) BaP. BaP and several metabolites were measured in blood, urine and feces collected at frequent intervals over 72 h post-treatment, using high-performance liquid chromatography/fluorescence. Only BaP and 3-hydroxyBaP (3-OHBaP) were detectable in blood at all time points. There were route-to-route differences in the excreted amounts (% dose) of metabolites but the observed time courses of the excretion rate were quite similar. In urine, total amounts of BaP metabolites excreted over the 0-72 h period followed the order: trans-4,5-dihydrodiolBaP (4,5-diolBaP) ≥ 3-OHBaP > 7-OHBaP ≥ 7,8-diolBaP after intravenous injection and intratracheal instillation; 3-OHBaP ≈ 7-OHBaP ≥ 4,5-diolBaP > 7,8-diolBaP after cutaneous application; 3-OHBaP ≥ 4,5-diolBaP ≈ 7-OHBaP > 7,8-diolBaP following oral administration. In feces, total amounts of BaP metabolites recovered were: 7-OHBaP ≈ 3-OHBaP > 4,5-diolBaP > 7,8-diolBaP > BaP-7,8,9,10-tetrol following all administration routes. For all exposure routes, excretion of 4,5- and 7,8-diolBaP was almost complete over the 0-24 h period in contrast with that of 3- and 7-OHBaP. This study confirms the interest of measuring multiple metabolites due to route-to-route differences in the relative excretion of the different biomarkers and in the time courses of diolBaPs versus OHBaPs. Concentration ratios of the different metabolites may help indicate time and main route of exposure.

  16. Epoxide hydrolase of Trichoderma reesei: Biochemical properties and conformational characterization.

    PubMed

    de Oliveira, Gabriel Stephani; Adriani, Patricia Pereira; Borges, Flavia Garcia; Lopes, Adriana Rios; Campana, Patricia T; Chambergo, Felipe S

    2016-08-01

    Epoxide hydrolases (EHs) are enzymes that are present in all living organisms and catalyze the hydrolysis of epoxides to the corresponding vicinal diols. EHs have biotechnological potential in chiral chemistry. We report the cloning, purification, enzymatic activity, and conformational analysis of the TrEH gene from Trichoderma reesei strain QM9414 using circular dichroism spectroscopy. The EH gene has an open reading frame encoding a protein of 343 amino acid residues, resulting in a molecular mass of 38.2kDa. The enzyme presents an optimum pH of 7.2, and it is highly active at temperatures ranging from 23 to 50°C and thermally inactivated at 70°C (t1/2=7.4min). The Michaelis constants (Km) were 4.6mM for racemic substrate, 21.7mM for (R)-(+)-styrene oxide and 3.0mM for (S)-(-)-styrene oxide. The kcat/Km analysis indicated that TrEH is enantioselective and preferentially hydrolyzes (S)-(-)-styrene oxide. The conformational stability studies suggested that, despite the extreme conditions (high temperatures and extremely acid and basic pHs), TrEH is able to maintain a considerable part of its regular structures, including the preservation of the native cores in some cases. The recombinant protein showed enantioselectivity that was distinct from other fungus EHs, making this protein a potential biotechnological tool.

  17. Copolymerization of CO2 and epoxides catalyzed by metal salen complexes.

    PubMed

    Darensbourg, Donald J; Mackiewicz, Ryan M; Phelps, Andrea L; Billodeaux, Damon R

    2004-11-01

    The design of efficient metal catalysts for the selective coupling of epoxides and carbon dioxide to afford completely alternating copolymers has made significant gains over the past decade. Hence, it is becoming increasingly clear that this "greener" route to polycarbonates has the potential to supplement or supplant current processes for the production of these important thermoplastics, which involve the condensation polymerization of diols and phosgene or organic carbonates. On the basis of the experiences in our laboratory, this Account summarizes our efforts at optimizing (salen)CrIIIX catalysts for the selective formation of polycarbonates from alicyclic and aliphatic epoxides with CO2. An iterative catalyst design process is employed in which the salen ligand, initiator, cocatalyst, and reaction conditions are systematically varied, with the reaction rates and product selectivity being monitored by in situ infrared spectroscopy.

  18. Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: role for omega-3 epoxides.

    PubMed

    López-Vicario, Cristina; Alcaraz-Quiles, José; García-Alonso, Verónica; Rius, Bibiana; Hwang, Sung H; Titos, Esther; Lopategi, Aritz; Hammock, Bruce D; Arroyo, Vicente; Clària, Joan

    2015-01-13

    Soluble epoxide hydrolase (sEH) is an emerging therapeutic target in a number of diseases that have inflammation as a common underlying cause. sEH limits tissue levels of cytochrome P450 (CYP) epoxides derived from omega-6 and omega-3 polyunsaturated fatty acids (PUFA) by converting these antiinflammatory mediators into their less active diols. Here, we explored the metabolic effects of a sEH inhibitor (t-TUCB) in fat-1 mice with transgenic expression of an omega-3 desaturase capable of enriching tissues with endogenous omega-3 PUFA. These mice exhibited increased CYP1A1, CYP2E1, and CYP2U1 expression and abundant levels of the omega-3-derived epoxides 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic (19,20-EDP) in insulin-sensitive tissues, especially liver, as determined by LC-ESI-MS/MS. In obese fat-1 mice, t-TUCB raised hepatic 17,18-EEQ and 19,20-EDP levels and reinforced the omega-3-dependent reduction observed in tissue inflammation and lipid peroxidation. t-TUCB also produced a more intense antisteatotic action in obese fat-1 mice, as revealed by magnetic resonance spectroscopy. Notably, t-TUCB skewed macrophage polarization toward an antiinflammatory M2 phenotype and expanded the interscapular brown adipose tissue volume. Moreover, t-TUCB restored hepatic levels of Atg12-Atg5 and LC3-II conjugates and reduced p62 expression, indicating up-regulation of hepatic autophagy. t-TUCB consistently reduced endoplasmic reticulum stress demonstrated by the attenuation of IRE-1α and eIF2α phosphorylation. These actions were recapitulated in vitro in palmitate-primed hepatocytes and adipocytes incubated with 19,20-EDP or 17,18-EEQ. Relatively similar but less pronounced actions were observed with the omega-6 epoxide, 14,15-EET, and nonoxidized DHA. Together, these findings identify omega-3 epoxides as important regulators of inflammation and autophagy in insulin-sensitive tissues and postulate sEH as a druggable target in metabolic

  19. Isolation and determination of benzo(a)pyrene glucuronide and sulfate conjugates in soybean leaves

    SciTech Connect

    Negishi, T.; Nakano, M.; Kobayashi, S.; Kim, C.H.

    1987-08-01

    BaP is metabolized in mammalian systems by the mixed function oxidase system of liver microsomes. This system catalyzes the oxidation of BaP via epoxide intermediate to phenol, diol and quinone metabolites. One of these 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-BaP is thought to act as the ultimate carcinogen by binding covalently to cellular DNA. It is also known that Cunninghamella elegans oxidized BaP to its phenol, diol and quinone metabolites. In addition, the alcohols were detected as glucuronide and sulfate conjugates. These metabolites are remarkably similar to those observed in higher organisms. On the other hand, some investigators have demonstrated that plants take up BaP and anthracene from soil or culture medium containing these compounds. This paper reports the finding that soybeans grown in BaP polluted soil take it up and metabolize to its phenol, diol and the glucuronide and sulfate conjugates of the alcohols.

  20. Surprising unreactivity of cholesterol-5,6-epoxides towards nucleophiles[S

    PubMed Central

    Paillasse, Michael R.; Saffon, Nathalie; Gornitzka, Heinz; Silvente-Poirot, Sandrine; Poirot, Marc; de Medina, Philippe

    2012-01-01

    We recently established that drugs used for the treatment and the prophylaxis of breast cancers, such as tamoxifen, were potent inhibitors of cholesterol-5,6-epoxide hydrolase (ChEH), which led to the accumulation of 5,6α-epoxy-cholesterol (5,6α-EC) and 5,6β-epoxy-cholesterol (5,6β-EC). This could be considered a paradox because epoxides are known as alkylating agents with putative carcinogenic properties. We report here that, as opposed to the carcinogen styrene-oxide, neither of the ECs reacted spontaneously with nucleophiles. Under catalytic conditions, 5,6β-EC remains unreactive whereas 5,6α-EC gives cholestan-3β,5α-diol-6β-substituted compounds. These data showed that 5,6-ECs are stable epoxides and unreactive toward nucleophiles in the absence of a catalyst, which contrasts with the well-known reactivity of aromatic and aliphatic epoxides. These data rule out 5,6-EC acting as spontaneous alkylating agents. In addition, these data support the existence of a stereoselective metabolism of 5,6α-EC. PMID:22285872

  1. Mechanism of Degradation of an α-Keto-Epoxide, a Model for the Warhead for Various Proteasome Inhibitor Anticancer Agents.

    PubMed

    Phizackerley, Kirsten M; Jumaa, Mouhannad; Lopalco, Antonio; Wolfe, Bradley H; Ablan, Christopher D; Stella, Valentino J

    2016-12-20

    The anticancer agent, carfilzomib, has a unique α-keto-epoxide warhead. The model α-keto-epoxide, N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)pivalamide (1), along with a few of its degradation products was synthesized and studied. The kinetics of hydrolysis and identification of some of the degradation products of 1 were performed at pH values 2, 4, 5, 7, and 8 at 25°C, 40°C, and 60°C and followed by HPLC and liquid chromatography-mass spectroscopy, respectively. 1 degraded independent of pH between pH values 4-7 but showed some acid catalysis at pH 2 and base catalysis at pH 8. Energy of activation, Ea, values progressed from 16.8 ± 0.1 at pH 2 to 20.3 ± 0.1 kcal/mole at pH 8. The major initial degradation products in the pH range 4-5 were the S,R diol (hydrolysis of the epoxide), and S,R chlorohydrin (in the presence of chloride ions). At pH 7-8, the major products were the R,R diastereomer and the S,R and R,R diols. At pH 2, additional unidentified products were seen with relative retention times of 0.28, 0.30, 0.33, and 0.35 and masses equivalent to the diols. The study of 1 provides insight into the degradation of future drugs that use an α-keto-epoxide functional group.

  2. Effects of dynamic exercise on plasma arachidonic acid epoxides and diols in human volunteers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Metabolites of the cytochrome P450 pathway may contribute to vasodilation of the vasculature of skeletal muscle during exercise. We determined effects of exercise intensity and duration on plasma concentrations of specific metabolites in the epoxyeicosatrienoic acid family. This allowed us to dete...

  3. Trigger factor assisted folding of the recombinant epoxide hydrolases identified from C. pelagibacter and S. nassauensis.

    PubMed

    Saini, Priya; Wani, Shadil Ibrahim; Kumar, Ranjai; Chhabra, Ravneet; Chimni, Swapandeep Singh; Sareen, Dipti

    2014-12-01

    Epoxide hydrolases (EHs), are enantioselective enzymes as they catalyze the kinetic resolution of racemic epoxides into the corresponding enantiopure vicinal diols, which are useful precursors in the synthesis of chiral pharmaceutical compounds. Here, we have identified and cloned two putative epoxide hydrolase genes (cpeh and sneh) from marine bacteria, Candidatus pelagibacter ubique and terrestrial bacteria, Stackebrandtia nassauensis, respectively and overexpressed them in pET28a vector in Escherichia coli BL21(DE3). The CPEH protein (42kDa) was found to be overexpressed as inactive inclusion bodies while SNEH protein (40kDa) was found to form soluble aggregates. In this study, the recombinant CPEH was successfully transformed from insoluble aggregates to the soluble and functionally active form, using pCold TF vector, though with low EH activity. To prevent the soluble aggregate formation of SNEH, it was co-expressed with GroEL/ES chaperone and was also fused with trigger factor (TF) chaperone at its N-terminus. The TF chaperone-assisted correct folding of SNEH led to a purified active EH with a specific activity of 3.85μmol/min/mg. The pure enzyme was further used to biocatalyze the hydrolysis of 10mM benzyl glycidyl ether (BGE) and α-methyl styrene oxide (MSO) with an enantiomeric excess of the product (eep) of 86% and 73% in 30 and 15min, respectively. In conclusion, this is the first report about the heterologous expression of epoxide hydrolases using TF as a molecular chaperone in pCold TF expression vector, resulting in remarkable increase in the solubility and activity of the otherwise improperly folded recombinant epoxide hydrolases.

  4. A novel and enantioselective epoxide hydrolase from Aspergillus brasiliensis CCT 1435: purification and characterization.

    PubMed

    Beloti, Lilian L; Costa, Bruna Z; Toledo, Marcelo A S; Santos, Clelton A; Crucello, Aline; Fávaro, Marianna T P; Santiago, André S; Mendes, Juliano S; Marsaioli, Anita J; Souza, Anete P

    2013-10-01

    A novel epoxide hydrolase from Aspergillus brasiliensis CCT1435 (AbEH) was cloned and overexpressed in Escherichia coli cells with a 6xHis-tag and purified by nickel affinity chromatography. Gel filtration analysis and circular dichroism measurements indicated that this novel AbEH is a homodimer in aqueous solution and contains the typical secondary structure of an α/β hydrolase fold. The activity of AbEH was initially assessed using the fluorogenic probe O-(3,4-epoxybutyl) umbelliferone and was active in a broad range of pH (6-9) and temperature (25-45°C); showing optimum performance at pH 6.0 and 30°C. The Michaelis constant (KM) and maximum rate (Vmax) values were 495μM and 0.24μM/s, respectively. Racemic styrene oxide (SO) was used as a substrate to assess the AbEH activity and enantioselectivity, and 66% of the SO was hydrolyzed after only 5min of reaction, with the remaining (S)-SO ee exceeding 99% in a typical kinetic resolution behavior. The AbEH-catalyzed hydrolysis of SO was also evaluated in a biphasic system of water:isooctane; (R)-diol in 84% ee and unreacted (S)-SO in 36% ee were produced, with 43% conversion in 24h, indicating a discrete enantioconvergent behavior for AbEH. This novel epoxide hydrolase has biotechnological potential for the preparation of enantiopure epoxides or vicinal diols.

  5. Multiphoton Spectral Analysis of Benzo[a]pyrene Uptake and Metabolism in a Rat Liver Cell Line

    PubMed Central

    Barhoumi, Rola; Mouneimne, Youssef; Ramos, Ernesto; Morisseau, Christophe; Hammock, Bruce D.; Safe, Stephen; Parrish, Alan R.; Burghardt, Robert C

    2011-01-01

    Dynamic analysis of the uptake and metabolism of polycyclic aromatic hydrocarbons (PAHs) and their metabolites within live cells in real time has the potential to provide novel insights into genotoxic and non-genotoxic mechanisms of cellular injury caused by PAHs. The present work, combining the use of metabolite spectra generated from metabolite standards using multiphoton spectral analysis and an “advanced unmixing process”, identifies and quantifies the uptake, partitioning, and metabolite formation of one of the most important PAHs (benzo[a]pyrene, BaP) in viable cultured rat liver cells over a period of 24 hr. The application of the advanced unmixing process resulted in the simultaneous identification of 8 metabolites in live cells at any single time. The accuracy of this unmixing process was verified using specific microsomal epoxide hydrolase inhibitors, glucuronidation and sulfation inhibitors as well as several mixtures of metabolite standards. Our findings prove that the two-photon microscopy imaging surpasses the conventional fluorescence imaging techniques and the unmixing process is a mathematical technique that seems applicable to analysis of BaP metabolites in living cells especially for analysis of changes of the ultimate carcinogen benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide. Therefore, the combination of the two-photon acquisition with the unmixing process should provide important insights into the cellular and molecular mechanisms by which BaP and other PAHs alter cellular homeostasis. PMID:21420996

  6. Multiphoton spectral analysis of benzo[a]pyrene uptake and metabolism in a rat liver cell line

    SciTech Connect

    Barhoumi, Rola; Mouneimne, Youssef; Ramos, Ernesto; Morisseau, Christophe; Hammock, Bruce D.; Safe, Stephen; Parrish, Alan R.; Burghardt, Robert C.

    2011-05-15

    Dynamic analysis of the uptake and metabolism of polycyclic aromatic hydrocarbons (PAHs) and their metabolites within live cells in real time has the potential to provide novel insights into genotoxic and non-genotoxic mechanisms of cellular injury caused by PAHs. The present work, combining the use of metabolite spectra generated from metabolite standards using multiphoton spectral analysis and an 'advanced unmixing process', identifies and quantifies the uptake, partitioning, and metabolite formation of one of the most important PAHs (benzo[a]pyrene, BaP) in viable cultured rat liver cells over a period of 24 h. The application of the advanced unmixing process resulted in the simultaneous identification of 8 metabolites in live cells at any single time. The accuracy of this unmixing process was verified using specific microsomal epoxide hydrolase inhibitors, glucuronidation and sulfation inhibitors as well as several mixtures of metabolite standards. Our findings prove that the two-photon microscopy imaging surpasses the conventional fluorescence imaging techniques and the unmixing process is a mathematical technique that seems applicable to the analysis of BaP metabolites in living cells especially for analysis of changes of the ultimate carcinogen benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide. Therefore, the combination of the two-photon acquisition with the unmixing process should provide important insights into the cellular and molecular mechanisms by which BaP and other PAHs alter cellular homeostasis.

  7. Cork suberin molecular structure: stereochemistry of the C18 epoxy and vic-diol ω-hydroxyacids and α,ω-diacids analyzed by NMR.

    PubMed

    Santos, Sara; Cabral, Vanessa; Graça, José

    2013-07-24

    Suberin is the biopolyester that protects the secondary tissues of plants against environmental variability and aggressions. Cork suberin is composed mostly of C18 ω-hydroxyacids and α,ω-diacids, 9,10-substituted with an unsaturation, an epoxide ring, or a vic-diol group. Although determinant for suberin macromolecular structure, the stereochemistry of these monomers is poorly studied, sometimes with contradictory results. An NMR technique was used here to assign the configuration of the 9,10-epoxy and 9,10-diol groups in C18 suberin acids, comparing the chemical shifts of diagnostic (1)H and (13)C signals with the ones of model compounds, before and after conversion of the vic-diol group into benzylidene acetal derivatives. The relative configuration was proved to be cis in the C18 9,10-epoxy and threo in the C18 9,10-diol suberin acids. These monomers were present in suberin probably as racemic mixtures, as shown by polarimetry. The revealed stereochemistry allows the suberin macromolecule to be built as an ordered array of midchain kinked C18 acids, reinforced by intramolecular hydrogen bonding.

  8. Similarities between catalase and cytosolic epoxide hydrolase.

    PubMed

    Guenthner, T M; Qato, M; Whalen, R; Glomb, S

    1989-01-01

    Cytosolic epoxide hydrolase, measured as trans-stilbene oxide hydrolase activity, was isolated and purified from human and guinea pig liver cytosol. Antiserum to the guinea pig liver preparation reacted strongly with bovine liver catalase. We determined that this lack of selectivity of the antiserum was due to catalase contamination of the epoxide hydrolase preparation. We also determined that several commercial catalase preparations are contaminated with cytosolic epoxide hydrolase. Our human epoxide hydrolase preparation contained no detectable catalase contamination, yet antiserum to this protein also cross-reacted slightly with catalase, indicating some intrinsic similarity between the two enzymes. We conclude that catalase and cytosolic epoxide hydrolase contain some similar immunogenic epitopes, and we surmise that similarities between the subunits of these two enzymes may lead to their partial copurification. Functional similarities between the two enzymes are also demonstrated, as several compounds that inhibit catalase are also shown to inhibit cytosolic epoxide hydrolase activity in the same concentration range and rank order.

  9. Organocatalyzed enantioselective desymmetrization of aziridines and epoxides

    PubMed Central

    2013-01-01

    Summary Enantioselective desymmetrization of meso-aziridines and meso-epoxides with various nucleophiles by organocatalysis has emerged as a cutting-edge approach in recent years. This review summarizes the origin and recent developments of enantioselective desymmetrization of meso-aziridines and meso-epoxides in the presence of organocatalysts. PMID:24062828

  10. The catalytic activity of the endoplasmic reticulum-resident protein microsomal epoxide hydrolase towards carcinogens is retained on inversion of its membrane topology.

    PubMed Central

    Friedberg, T; Holler, R; Löllmann, B; Arand, M; Oesch, F

    1996-01-01

    Diol epoxides formed by the sequential action of cytochrome P-450 and the microsomal epoxide hydrolase (mEH) in the endoplasmic reticulum (ER) represent an important class of ultimate carcinogenic metabolites of polycyclic aromatic hydrocarbons. The role of the membrane orientation of cytochrome P-450 and mEH relative to each other in this catalytic cascade is not known. Cytochrome P-450 is known to have a type I topology. According to the algorithm of Hartman, Rapoport and Lodish [(1989) Proc. Natl. Acad. Sci. U.S.A. 86, 5786-5790], which allows the prediction of the membrane topology of proteins, mEH should adopt a type II membrane topology. Experimentally, mEH membrane topology has been disputed. Here we demonstrate that, in contrast with the theoretical prediction, the rat mEH has exclusively a type I membrane topology. Moreover we show that this topology can be inverted without affecting the catalytic activity of mEH. Our conclusions are supported by the observation that two mEH constructs (mEHg1 and mEHg2), containing engineered potential glycosylation sites at two separate locations after the C-terminal site of the membrane anchor, were not glycosylated in fibroblasts. However, changing the net charge at the N-terminus of these engineered mEH proteins by +3 resulted in proteins (++mEHg1 and ++mEHg2) that became glycosylated and consequently had a type II topology. The sensitivity of these glycosylated proteins to endoglycosidase H indicated that, like the native mEH, they are still retained in the ER. The engineered mEH proteins were integrated into membranes as they were resistant to alkaline extraction. Interestingly, an insect mEH with a charge distribution in its N-terminus similar to ++mEHg1 has recently been isolated. This enzyme might well display a type II topology instead of the type I topology of the rat mEH. Importantly, mEHg1, having the natural cytosolic orientation, as well as ++mEHg1, having an artificial huminal orientation, displayed rather

  11. Iron-catalyzed olefin epoxidation in the presence of acetic acid: insights into the nature of the metal-based oxidant.

    PubMed

    Mas-Ballesté, Rubén; Que, Lawrence

    2007-12-26

    The iron complexes [(BPMEN)Fe(OTf)2] (1) and [(TPA)Fe(OTf)2] (2) [BPMEN = N,N'-bis-(2-pyridylmethyl)-N,N'-dimethyl-1,2-ethylenediamine; TPA = tris-(2-pyridylmethyl)amine] catalyze the oxidation of olefins by H2O2 to yield epoxides and cis-diols. The addition of acetic acid inhibits olefin cis-dihydroxylation and enhances epoxidation for both 1 and 2. Reactions carried out at 0 degrees C with 0.5 mol % catalyst and a 1:1.5 olefin/H2O2 ratio in a 1:2 CH3CN/CH3COOH solvent mixture result in nearly quantitative conversions of cyclooctene to epoxide within 1 min. The nature of the active species formed in the presence of acetic acid has been probed at low temperature. For 2, in the absence of substrate, [(TPA)FeIII(OOH)(CH3COOH)]2+ and [(TPA)FeIVO(NCCH3)]2+ intermediates can be observed. However, neither is the active epoxidizing species. In fact, [(TPA)FeIVO(NCCH3)]2+ is shown to form in competition with substrate oxidation. Consequently, it is proposed that epoxidation is mediated by [(TPA)FeV(O)(OOCCH3)]2+, generated from O-O bond heterolysis of the [(TPA)FeIII(OOH)(CH3COOH)]2+ intermediate, which is promoted by the protonation of the terminal oxygen atom of the hydroperoxide by the coordinated carboxylic acid.

  12. Metabolism of the environmental toxicant benzo(a)pyrene by subcellular fractions of human ovary.

    PubMed

    Rekhadevi, P V; Diggs, D L; Huderson, A C; Harris, K L; Archibong, A E; Ramesh, A

    2014-02-01

    Knowledge of the ability of the female reproductive system to metabolize environmental chemicals is critical not only from the standpoint of toxicity but also from infertility risk assessment. Benzo(a)pyrene (BaP) is a toxicant that is released into the environment from automobile exhausts, cigarette smoke, burning of refuse, industrial emissions, and hazardous waste sites. In exposed animals, BaP becomes activated to reactive metabolites that interfere with target organ function and as a consequence cause toxicity. Studies on animal models conducted in our laboratories and those of others have shown that BaP possess endocrine disrupting properties. Thus, this chemical has the potential to cause infertility and cancers in the female genital tract. An understanding of BaP metabolism in the female reproductive system will be of importance in the diagnosis and management of female fertility as well as cancers in the reproductive tissues. Therefore, the objective of our study was to examine the metabolism of BaP by human ovarian subcellular fractions. Human ovary samples (eight individuals) were obtained from postoperative tissue removed from subjects with uterine tumors. Subcellular fractions (nuclear, cytosolic, mitochondrial, and microsomal) were prepared by differential centrifugation. BaP (1 μM and 3 μM) was individually incubated with individual subcellular fractions for 15 min and the products were analyzed by high-performance liquid chromatography. Among the different fractions tested, microsomal BaP metabolism was higher than the rest of the fractions. The BaP metabolites identified were as follows: BaP-9,10-diol, BaP-4,5-diol, BaP-7,8-diol, 9(OH) BaP, 3(OH) BaP, BaP-1,6-dione, BaP-3,6-dione, and BaP-6,12-dione. Of interest was the presence of DNA-reactive metabolites such as BaP-3,6-dione, BaP-6,12-dione, and BaP 7,8-diol, which have been implicated in the causation of infertility and cancer. Our results indicate that women who are exposed to BaP via

  13. Metabolism of the environmental toxicant benzo(a)pyrene by subcellular fractions of human ovary

    PubMed Central

    Rekhadevi, PV; Diggs, DL; Huderson, AC; Harris, KL; Archibong, AE; Ramesh, A

    2014-01-01

    Knowledge of the ability of the female reproductive system to metabolize environmental chemicals is critical not only from the standpoint of toxicity but also from infertility risk assessment. Benzo(a)pyrene (BaP) is a toxicant that is released into the environment from automobile exhausts, cigarette smoke, burning of refuse, industrial emissions, and hazardous waste sites. In exposed animals, BaP becomes activated to reactive meta-bolites that interfere with target organ function and as a consequence cause toxicity. Studies on animal models conducted in our laboratories and those of others have shown that BaP possess endocrine disrupting properties. Thus, this chemical has the potential to cause infertility and cancers in the female genital tract. An understanding of BaP metabolism in the female reproductive system will be of importance in the diagnosis and management of female fertility as well as cancers in the reproductive tissues. Therefore, the objective of our study was to examine the metabolism of BaP by human ovarian subcellular fractions. Human ovary samples (eight individuals) were obtained from postoperative tissue removed from subjects with uterine tumors. Sub-cellular fractions (nuclear, cytosolic, mitochondrial, and microsomal) were prepared by differential centrifugation. BaP (1 μM and 3 μM) was individually incubated with individual subcellular fractions for 15 min and the products were analyzed by high-performance liquid chromatography. Among the different fractions tested, microsomal BaP metabolism was higher than the rest of the fractions. The BaP metabolites identified were as follows: BaP-9,10-diol, BaP-4,5-diol, BaP-7,8-diol, 9(OH) BaP, 3(OH) BaP, BaP-1,6-dione, BaP-3,6-dione, and BaP-6,12-dione. Of interest was the presence of DNA-reactive metabolites such as BaP-3,6-dione, BaP-6,12-dione, and BaP 7,8-diol, which have been implicated in the causation of infertility and cancer. Our results indicate that women who are exposed to BaP via

  14. Ruthenium-catalyzed selective monoamination of vicinal diols.

    PubMed

    Bähn, Sebastian; Tillack, Annegret; Imm, Sebastian; Mevius, Kathleen; Michalik, Dirk; Hollmann, Dirk; Neubert, Lorenz; Beller, Matthias

    2009-01-01

    The monoamination of vicinal diols in the presence of in situ generated ruthenium catalysts has been investigated. Among the various phosphines tested in combination with [Ru(3)(CO)(12)], N-phenyl-2-(dicyclohexyl-phosphanyl)pyrrole showed the best performance. After optimization of the reaction conditions this system was applied to different secondary amines and anilines as well as a number of vicinal diols. With the exception of ethylene glycol, monoamination of the vicinal diols occurred selectively and the corresponding amino alcohols were obtained in good yields, producing water as the only side product.

  15. CARBINOLAMINES AND GEMINAL DIOLS IN AQUEOUS ENVIRONMENTAL ORGANIC CHEMISTRY

    EPA Science Inventory

    Organic chemistry textbooks generally treat geminal diols as curiosities-exceptions to the stability of the C=O double bond. However, most aldehydes of environmental significance, to wit, trichloroethanal (chloral), methanala (formaldehyde), ethanal (acetaldehyde), and propanal ...

  16. Fluoride compounds of tungsten with bridging deprotonated diols

    SciTech Connect

    Kokunov, Yu.V.; Bochkareva, V.A.; Buslaev, Yu.A.

    1987-05-01

    The reactions of tungsten hexafluoride with ethylene glycol, 1,2- and 1,3-propanediol, and 2,3-butanediol have been studied by /sup 19/F NMR. As a result, dimeric, trimeric, and tetrameric compounds with four or five fluoride atoms in which the tungsten atoms are joined to one another by deprotonated moieties of the diols, and each metal atom is bonded to the other metal atoms by means of only one such group, were obtained. Dimeric compounds, in which the two tungsten atoms are joined by two bridging deprotonated moieties of the diols in a stabilized gauche conformation, are obtained at an appropriate concentration of the diols. When the diol:WF/sub 6/ ratio is increased, monomeric octahedral compounds of tungsten with three fluorine atoms form. The parameters of the /sup 19/F NMR spectra of the compounds obtained have been determined.

  17. Divergent Reactivity via Cobalt Catalysis: An Epoxide Olefination.

    PubMed

    Jamieson, Megan L; Hume, Paul A; Furkert, Daniel P; Brimble, Margaret A

    2016-02-05

    Cobalt salts exert an unexpected and profound influence on the reactivity of epoxides with dimethylsulfoxonium methylide. In the presence of a cobalt catalyst, conditions for epoxide to an oxetane ring expansion instead deliver homoallylic alcohol products, corresponding to a two-carbon epoxide homologation/ring-opening tandem process. The observed reactivity change appears to be specifically due to cobalt salts and is broadly applicable to a variety of epoxides, retaining the initial stereochemistry. This transformation also provides operationally simple access to enantiopure homoallylic alcohols from chiral epoxides without use of organometallic reagents. Tandem epoxidation-homologation of aldehydes in a single step is also demonstrated.

  18. IRIS Toxicological Review of Benzo[a]pyrene (Final Report)

    EPA Science Inventory

    EPA has finalized the Integrated Risk Information System (IRIS) assessment of benzo[a]pyrene. This assessment addresses the potential cancer and noncancer human health effects from long-term exposure to benzo[a]pyrene. Now final, this assessment will update the toxicological info...

  19. 40 CFR 721.2675 - Perfluoroalkyl epoxide (generic name).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Perfluoroalkyl epoxide (generic name... Substances § 721.2675 Perfluoroalkyl epoxide (generic name). (a) Chemical substances and significant new uses subject to reporting. (1) The chemical substance identified generically as perfluoroalkyl epoxide (PMN...

  20. 40 CFR 721.10233 - Linear alkyl epoxide (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Linear alkyl epoxide (generic). 721... Substances § 721.10233 Linear alkyl epoxide (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as linear alkyl epoxide (PMN...

  1. 40 CFR 721.10233 - Linear alkyl epoxide (generic).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Linear alkyl epoxide (generic). 721... Substances § 721.10233 Linear alkyl epoxide (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as linear alkyl epoxide (PMN...

  2. 40 CFR 721.10233 - Linear alkyl epoxide (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Linear alkyl epoxide (generic). 721... Substances § 721.10233 Linear alkyl epoxide (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as linear alkyl epoxide (PMN...

  3. 21 CFR 172.723 - Epoxidized soybean oil.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Epoxidized soybean oil. 172.723 Section 172.723... CONSUMPTION Other Specific Usage Additives § 172.723 Epoxidized soybean oil. Epoxidized soybean oil may be... reacting soybean oil in toluene with hydrogen peroxide and formic acid. (b) It meets the...

  4. 21 CFR 172.723 - Epoxidized soybean oil.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Epoxidized soybean oil. 172.723 Section 172.723....723 Epoxidized soybean oil. Epoxidized soybean oil may be safely used in accordance with the following prescribed conditions: (a) The additive is prepared by reacting soybean oil in toluene with hydrogen...

  5. 21 CFR 172.723 - Epoxidized soybean oil.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Epoxidized soybean oil. 172.723 Section 172.723... CONSUMPTION Other Specific Usage Additives § 172.723 Epoxidized soybean oil. Epoxidized soybean oil may be... reacting soybean oil in toluene with hydrogen peroxide and formic acid. (b) It meets the...

  6. 21 CFR 172.723 - Epoxidized soybean oil.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Epoxidized soybean oil. 172.723 Section 172.723... CONSUMPTION Other Specific Usage Additives § 172.723 Epoxidized soybean oil. Epoxidized soybean oil may be... reacting soybean oil in toluene with hydrogen peroxide and formic acid. (b) It meets the...

  7. 21 CFR 172.723 - Epoxidized soybean oil.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Epoxidized soybean oil. 172.723 Section 172.723... CONSUMPTION Other Specific Usage Additives § 172.723 Epoxidized soybean oil. Epoxidized soybean oil may be... reacting soybean oil in toluene with hydrogen peroxide and formic acid. (b) It meets the...

  8. Rhenium-catalyzed deoxydehydration of diols and polyols.

    PubMed

    Dethlefsen, Johannes R; Fristrup, Peter

    2015-03-01

    The substitution of platform chemicals of fossil origin by biomass-derived analogues requires the development of chemical transformations capable of reducing the very high oxygen content of biomass. One such reaction, which has received increasing attention within the past five years, is the rhenium-catalyzed deoxydehydration (DODH) of a vicinal diol into an alkene; this is a model system for abundant polyols like glycerol and sugar alcohols. The present contribution includes a review of early investigations of stoichiometric reactions involving rhenium, diols, and alkenes followed by a discussion of the various catalytic systems that have been developed with emphasis on the nature of the reductant, the substrate scope, and mechanistic investigations.

  9. Analysis of tetrahydroxylated benzo[a]pyrene isomers in hair as biomarkers of exposure to benzo[a]pyrene.

    PubMed

    Grova, Nathalie; Hardy, Emilie M; Meyer, Pauline; Appenzeller, Brice M R

    2016-03-01

    A first gas chromatography-tandem mass spectrometry (GC-MS/MS) method was designed for analysis of four tetrahydroxylated benzo[a]pyrene metabolites (benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydrotetrol, benzo[a]pyrene-r-7,t-8,t-9,t-10-tetrahydrotetrol, benzo[a]pyrene-r-7,t-8,c-9,c-10-tetrahydrotetrol, and benzo[a]pyrene-r-7,t-8,c-9,t-10-tetrahydrotetrol) in hair. Hair powder extract was submitted to liquid-solid extraction, followed by C18 solid-phase purification. The analytes were derivatized with use of N-methyl-N-(trimethylsilyl)trifluoroacetamide and then analyzed by GC-MS/MS in negative chemical ionization mode. The calibration curve was linear from the limit of quantification (LOQ) to 20 pg/mg in hair. The coefficient of determination of the calibration curve was more than 0.975 for all the analytes investigated. The LOQs ranged from 0.075 to 0.2 pg/mg in hair. The method was afterward applied to the analysis of hair of 16 rats randomly allocated to experimental groups receiving 16 polycyclic aromatic hydrocarbons solubilized in oil at 0 or 0.8 mg/kg body weight by oral administration three times per week for 90 days. The analysis of monohydroxylated and dihydroxylated benzo[a]pyrenes was conducted in parallel by GC-MS/MS on the same samples. All tetrahydroxylated benzo[a]pyrene isomers were detected in hair samples collected from rats exposed to polycyclic aromatic hydrocarbons. Benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydrotetrol, the most abundant isomer in hair of treated rats, was also the principal isomer released in DNA adduct hydrolysis in humans. Moreover, the benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydrotetrol concentrations in hair were significantly greater than those of 2-hydroxybenzo[a]pyrene, 1-hydroxybenzo[a]pyrene, 7-hydroxybenzo[a]pyrene, and 4-hydroxybenzo[a]pyrene and similar to those of 9-hydroxybenzo[a]pyrene and 3-hydroxybenzo[a]pyrene. The method was also sufficiently sensitive to monitor environmental levels of exposure because two hair

  10. Alkene epoxidation employing metal nitro complexes

    DOEpatents

    Andrews, M.A.; Cheng, C.W.; Kelley, K.P.

    1982-07-15

    Process for converting alkenes to form epoxides utilizes transition metal nitro complexes of the formula: M(RCN)/sub 2/XNO/sub 2/ wherein M is palladium or platinum, R is an alkyl or aryl group containing up to 12 carbon atoms, and X is a monoanionic, monodentate ligand such as chlorine, optionally in the presence of molecular oxygen.

  11. Polymerization of epoxidized triglycerides with fluorosulfonic acid

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of triglycerides as agri-based renewable raw materials for the development of new products is highly desirable in view of uncertain future petroleum prices. A new method of polymerizing epoxidized soybean oil has been devised with the use of fluorosulfonic acid. Depending on the reaction con...

  12. Free radicals of benzo(a)pyrene and derivatives.

    PubMed Central

    Sullivan, P D

    1985-01-01

    The evidence for biological involvement, the spectroscopic properties (especially EPR), and the reactions, of free radicals derived from benzo(a)pyrene and its methylated, hydroxylated, and fluorinated derivatives are reviewed. PMID:3007095

  13. IRIS Toxicological Review of Benzo[a]pyrene (Final Report) ...

    EPA Pesticide Factsheets

    EPA has finalized the Integrated Risk Information System (IRIS) assessment of benzo[a]pyrene. This assessment addresses the potential cancer and noncancer human health effects from long-term exposure to benzo[a]pyrene. Now final, this assessment will update the toxicological information on benzo[a]pyrene posted in 1987. EPA’s program and regional offices may use this assessment to inform decisions to protect human health. EPA is undertaking an update of the Integrated Risk Information System (IRIS) health assessment for benzo[a]pyrene (BaP). The outcome of this project is an updated Toxicological Review and IRIS Summary for BaP that will be entered into the IRIS database.

  14. Improved catalytic activity of homochiral dimeric cobalt-salen complex in hydrolytic kinetic resolution of terminal racemic epoxides.

    PubMed

    Kureshy, Rukhsana I; Singh, Surendra; Khan, Noor-Ul H; Abdi, Sayed H R; Ahmad, Irshad; Bhatt, Achyut; Jasra, Raksh V

    2005-11-01

    Enantiomerically pure epoxides (99%, ee) and diols (98%, ee) from racemic epichlorohydrin, 1,2-epoxypropane, 1,2-epoxyhexane, 1,2-epoxyoctane, and 1,2-epoxydodecane were obtained in 2-12 h by hydrolytic kinetic resolution (HKR) using the recyclable dimeric homochiral Co(III)-salen complex 1' (0.2 mol %) derived from 5,5-(2',2'-dimethylpropane)-di-[(R,R)-{N-(3-tert-butylsalicylidine)-N'-(3',5'-di-tert-butylsalicylidine)}-1,2-cyclohexanediamine] with cobalt(II) acetate. Unlike its monomeric version, the catalyst could be recycled several times without loss in performance. The use of BF(4) as counter ion in HKR reactions was also investigated.

  15. Analyses of procyanidins in foods using Diol phase HPLC

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Separation of procyanidins using silica-based HPLC suffered from poor resolution for higher oligomers and low sensitivity due to the fluorescence quenching effects of methylene chloride in the mobile phase. Optimization of a published Diol-phase HPLC method resulted in near baseline separation for p...

  16. Suppression of the Ethanol Withdrawal Syndrome by Aliphatic Diols

    DTIC Science & Technology

    1979-06-07

    Two halogenated hydrocarbons , alcohols exert their intoxicating properties through an interac- which are amphiphiles like alcohols and diols, were both...induce a virtually identical spectrum of phatic hydrocarbons could not. The data suggest that short- intoxication signs. Because of their pharmacological...their ability to induce to determine if partitioning into membrasps is an important intoxication since 1) alcohols and aliphatic hydrocarbons with

  17. Soluble epoxide hydrolase inhibitor 1-trifluoromethoxyphenyl-3- (1-propionylpiperidin-4-yl) urea attenuates bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Zhou, Yong; Yang, Jun; Sun, Guo-Ying; Liu, Tian; Duan, Jia-Xi; Zhou, Hui-Fang; Lee, Kin Sing; Hammock, Bruce D; Fang, Xiang; Jiang, Jian-Xin; Guan, Cha-Xiang

    2016-02-01

    Epoxyeicosatrienoic acids (EETs), the metabolites of arachidonic acid derived from the cytochrome P450 (CYP450) epoxygenases, are mainly metabolized by soluble epoxide hydrolase (sEH) to their corresponding diols. EETs but not their diols, have anti-inflammatory properties and inhibition of sEH might provide protective effects against inflammatory fibrosis. We test the effects of a selected sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), on bleomycin-induced pulmonary fibrosis (PF) in mice. A mouse model of PF was established by intratracheal injection of bleomycin and TPPU was administered for 21 days after bleomycin injection. We found TPPU treatment improved the body weight loss and survival rate of bleomycin-stimulated mice. Histological examination showed that TPPU treatment alleviated bleomycin-induced inflammation and maintained the alveolar structure of the pulmonary tissues. TPPU also decreased the bleomycin-induced deposition of collagen and the expression of procollagen I mRNA in lung tissues of mice. TPPU decreased the transforming growth factor-β1 (TGF-β1), interleukin-1β (IL-1β) and IL-6 levels in the serum of bleomycin-stimulated mice. Furthermore, TPPU inhibited the proliferation and collagen synthesis of mouse fibroblasts and partially reversed TGF-β1-induced α-smooth muscle actin expression. Our results indicate that the inhibition of sEH attenuates bleomycin-induced inflammation and collagen deposition and therefore prevents bleomycin-induced PF in a mouse model.

  18. Integrated chemical-biological treatment of benzo[a]pyrene

    SciTech Connect

    Zeng, Yu; Hong, P.K.A.; Wavrek, D.A.

    2000-03-01

    Benzo[a]pyrene of natural and anthropogenic sources is one of the toxic, mutagenic, polycyclic aromatic hydrocarbons (PAHs) listed as priority pollutants. This study focuses on an integrated treatment of benzo[a]pyrene involving sequential chemical oxidation and biological degradation. The objectives are to (1) provide mechanistic details in the ozone-mediated degradation of benzo[a]pyrene in the aqueous phase, (2) test the biodegradability of resultant intermediates, and (3) test the feasibility for the coupled chemical-biological treatment of the five-ring PAH. Batch and packed column reactors were used to examine the degradation pathways of benzo[a]pyrene subject to ozonation in the aqueous phase. After different ozonation times, samples containing reaction intermediates and byproducts from both reactors were collected, identified for organic contents, and further biologically inoculated to determine their biodegradability. The O{sub 3}-pretreated samples were incubated for 5, 10, 15, and 20 days; afterward biochemical oxygen demand (BOD), chemical oxygen demand (COD), and E. coli toxicity tests were conducted along with qualitative and quantitative determinations of benzo[a]pyrene, intermediates, and reaction products by GC/FID and GC/MS methods. Prevalent intermediates identified at different stages included ring-opened aldehydes, phthalic derivatives, and aliphatics. The degradation of benzo[a]pyrene is primarily initiated via O{sub 3}-mediated ring-opening, followed by O{sub 3} and hydroxyl radical fragmentation, and ultimately brought to complete mineralization primarily via hydroxyl radicals. Intermediates formed during chemical oxidation were biodegradable with a measured first-order rate constant (k{sub 0}) of 0.18 day{sup {minus}1}. The integrated chemical-biological system seems feasible for treating recalcitrant compounds, while pretreatment by chemical oxidation appears useful in promoting soluble intermediates from otherwise highly insoluble

  19. Soluble Epoxide Hydrolase Null Mice Exhibit Female and Male Differences In Regulation of Vascular Homeostasis

    PubMed Central

    Vanella, Luca; Canestraro, Martina; Lee, Craig R.; Cao, Jian; Zeldin, Darryl C.; Schwartzman, Michal L.; Abraham, Nader G.

    2015-01-01

    Increased CYP epoxygenase activity and consequently up regulation of epoxyeicosatrienoic acids (EETs) levels provides protection against metabolic syndrome and cardiovascular diseases. Conversion of arachidonic acid epoxides to diols by soluble epoxide hydrolase (sEH) diminishes the beneficial cardiovascular properties of these epoxyeicosanoids. We therefore examined the possible biochemical consequences of sEH deletion on vascular responses in male and female mice. Through the use of the sEH KO mouse, we provide evidence of differences in the compensatory response in the balance between nitric oxide (NO), carbon monoxide (CO), EETs and the vasoconstrictor 20-HETE in male and female KO mice. Serum levels of adiponectin, TNFα, IL-1b and MCP1 and protein expression in vascular tissue of p-AMPK, p-AKT and p-eNOS were measured. Deletion of sEH caused a significant (p<0,05) decrease in body weight, and an increase in adiponectin, pAMPK and pAKT levels in female KO mice compared to male KO mice. Gene deletion resulted in a higher production of renal EETs in female KO compared to male KO mice and, concomitantly, we observed an increase in renal 20-HETEs levels and superoxide anion production only in male KO mice. sEH deletion increased p-AKT and p-eNOS protein expression but decreased p-AMPK levels in female KO mice. Increased levels of p-eNOS at Thr-495 were observed only in KO male mice. While p-eNOS at 1177 were not significantly different between male and female. Nitric oxide production was unaltered in male KO mice. These results provide evidence of gender differences in the preservation of vascular homeostasis in response to sEH deletion which involves regulation of phosphorylation of eNOS at the 495 site. PMID:25908301

  20. Mechanics of Crack Growth in Epoxide Adhesives

    DTIC Science & Technology

    1978-05-01

    mind when considering the static G (arrest) values shown in Figure 3. Ic 9 First, Bascom et al 7 ’I 0 have elegantly demonstrated that for rubber ...in limited regions of the material. The diameter of the pores or channels in a craze is typically a few tens of nanometres and the void content is...about 40 to 60%. However, while there is definite proof for craze formation in rubber -modified epoxide 24 materials, the evidence for craze formation in

  1. Mutagenicity of chloroalkene epoxides in bacterial systems.

    PubMed

    Kline, S A; McCoy, E C; Rosenkranz, H S; Van Duuren, B L

    1982-04-01

    6 alpha-chloroepoxides have been tested for in vitro activity in a variety of systems. The epoxides were cis- and trans-1-chloropropene oxide, cis- and trans-1,3-dichloropropene oxide, trichloroethylene oxide and tetrachloroethylene oxide. The epoxides were assayed for mutagenicity in the absence of metabolic activation in S. typhimurium TA1535 and E. coli WP2 uvrA and for preferential inhibition of growth of DNA-repair-deficient E. coli. All 6 epoxides possessed DNA-modifying activity as evidenced by their ability to preferentially inhibit DNA polymerase-deficient E. coli. All of the test chemicals except trichloroethylene oxide were mutagenic for S. typhimurium and all except trichloroethylene oxide and tetrachloroethylene oxide were mutagenic for E. coli Wp2 uvrA. Cis- and trans-1,3-dichloropropene oxide were the most potent mutagens and DNA modifiers. For all cases, the cis isomers were more active than the corresponding trans isomers. alpha-Chloroepoxides are considered likely to be the active intermediates of the carcinogenic parent halo-olefins. These mutagenicity studies are considered relevant in assessing the carcinogenicity of the parent hydrocarbons.

  2. The juvenile hormone (JH) epoxide hydrolase gene in the honey bee (Apis mellifera) genome encodes a protein which has negligible participation in JH degradation.

    PubMed

    Mackert, Aline; Hartfelder, Klaus; Bitondi, Márcia Maria Gentile; Simões, Zilá Luz Paulino

    2010-09-01

    Epoxide hydrolases are multifunctional enzymes that are best known in insects for their role in juvenile hormone (JH) degradation. Enzymes involved in JH catabolism can play major roles during metamorphosis and reproduction, such as the JH epoxide hydrolase (JHEH), which degrades JH through hydration of the epoxide moiety to form JH diol, and JH esterase (JHE), which hydrolyzes the methyl ester to produce JH acid. In the honey bee, JH has been co-opted for additional functions, mainly in caste differentiation and in age-related behavioral development of workers, where the activity of both enzymes could be important for JH titer regulation. Similarity searches for jheh candidate genes in the honey bee genome revealed a single Amjheh gene. Sequence analysis, quantification of Amjheh transcript levels and Western blot assays using an AmJHEH-specific antibody generated during this study revealed that the AmJHEH found in the fat body shares features with the microsomal JHEHs from several insect species. Using a partition assay we demonstrated that AmJHEH has a negligible role in JH degradation, which, in the honey bee, is thus performed primarily by JHE. High AmJHEH levels in larvae and adults were related to the ingestion of high loads of lipids, suggesting that AmJHEH has a role in dietary lipid catabolism.

  3. The electron-impact promoted fragmentation of aurone epoxides.

    NASA Technical Reports Server (NTRS)

    Brady, B. A.; O'Sullivan, W. I.; Duffield, A. M.

    1972-01-01

    The mass spectra of six aurone epoxides have been rationalized with the aid of high resolution mass spectrometry and metastable ion evidence. These compounds fragment in a well defined manner and mechanisms are proposed for the formation of their characteristic ions. Some similarity was observed between the mass spectra of 6-methoxyaurone epoxide (II), 4-hydroxy-7-methoxy-3-phenylcoumarin (VII) and 7-methoxyflavonol (IX). The possibility that VII and IX are intermediates in the fragmentation of epoxide II is discussed. Thermal rearrangement of aurone epoxide II was shown to yield the corresponding flavonol IX and coumarin VII.

  4. Simple Epoxide Formation for the Organic Laboratory Using Oxone

    ERIC Educational Resources Information Center

    Broshears, Williams C.; Esteb, John J.; Richter, Jeremy; Wilson, Anne M.

    2004-01-01

    Epoxide chemistry is widely used in organic synthesis and regularly discussed in organic chemistry textbooks. An experiment to generate dimethyldioxirane in situ from acetone using Oxone is explained.

  5. Asymmetric Allylboration of Acyl Imines Catalyzed by Chiral Diols

    PubMed Central

    Lou, Sha; Moquist, Philip N.; Schaus, Scott E.

    2008-01-01

    Chiral BINOL-derived diols catalyze the enantioselective asymmetric allylboration of acyl imines. The reaction requires 15 mol% of (S)-3,3′-Ph2-BINOL as the catalyst and allyldiisopropoxyborane as the nucleophile. The reaction products are obtained in good yields (75 – 94%) and high enantiomeric ratios (95:5 – 99.5:0.5) for aromatic and aliphatic imines. High diastereoselectivities (dr > 98:2) and enantioselectivities (er > 98:2) are obtained in the reactions of acyl imines with crotyldiisopropoxyboranes. This asymmetric transformation is directly applied to the synthesis of maraviroc, the selective CCR5 antagonist with potent activity against HIV-1 infection. Mechanistic investigations of the allylboration reaction including IR, NMR, and mass spectrometry study indicate that acyclic boronates are activated by chiral diols via exchange of one of the boronate alkoxy groups with activation of the acyl imine via hydrogen bonding. PMID:18020334

  6. An epoxide hydrolase involved in the biosynthesis of an insect sex attractant and its use to localize the production site.

    PubMed

    Abdel-Latief, Mohatmed; Garbe, Leif A; Koch, Markus; Ruther, Joachim

    2008-07-01

    Epoxide hydrolases (EHs) are enzymes occurring in virtually any living organism. They catalyze the hydrolysis of epoxide containing lipids and are involved in crucial mechanisms, such as the detoxification of xenobiotics or the regulation of inflammation and blood pressure. Here, we describe a function of a putative EH gene in the biosynthesis of a sex attractant in the jewel wasp Nasonia vitripennis and use this gene to localize the site of pheromone production. Males of this parasitic wasp release a mixture of (4R,5R)-( threo-) and (4R,5S)-( erythro-)5-hydroxy-4-decanolide (HDL) to attract virgin females. Using a stable isotope labeled precursor, we demonstrated that vernolic acid ( erythro-12,13-epoxy-octadec-9Z-enoic acid) is converted by N. vitripennis males to threo-HDL. This suggested the involvement of an EH in hydrolyzing the fatty acid epoxide under inversion of the stereochemistry into the respective diol, which might be further processed by chain shortening and lactonization to HDL. We cloned a putative N. vitripennis EH gene (Nasvi-EH1) encoding 470 amino acids and localized its transcripts in the male rectal papillae by in situ RT-PCR. Chemical analyses and histological studies confirmed that males synthesize the sex attractant in the rectal vesicle and release it via the anal orifice. Involvement of Nasvi-EH1 in HDL biosynthesis was established by RNAi-mediated gene silencing. Injection of Nasvi-EH1 dsRNA into male abdomens inhibited pheromone biosynthesis by 55% and suppressed the targeted gene transcripts in the rectal vesicle by 95%.

  7. An epoxide hydrolase involved in the biosynthesis of an insect sex attractant and its use to localize the production site

    PubMed Central

    Abdel-latief, Mohatmed; Garbe, Leif A.; Koch, Markus; Ruther, Joachim

    2008-01-01

    Epoxide hydrolases (EHs) are enzymes occurring in virtually any living organism. They catalyze the hydrolysis of epoxide containing lipids and are involved in crucial mechanisms, such as the detoxification of xenobiotics or the regulation of inflammation and blood pressure. Here, we describe a function of a putative EH gene in the biosynthesis of a sex attractant in the jewel wasp Nasonia vitripennis and use this gene to localize the site of pheromone production. Males of this parasitic wasp release a mixture of (4R,5R)-(threo-) and (4R,5S)-(erythro-)5-hydroxy-4-decanolide (HDL) to attract virgin females. Using a stable isotope labeled precursor, we demonstrated that vernolic acid (erythro-12,13-epoxy-octadec-9Z-enoic acid) is converted by N. vitripennis males to threo-HDL. This suggested the involvement of an EH in hydrolyzing the fatty acid epoxide under inversion of the stereochemistry into the respective diol, which might be further processed by chain shortening and lactonization to HDL. We cloned a putative N. vitripennis EH gene (Nasvi-EH1) encoding 470 amino acids and localized its transcripts in the male rectal papillae by in situ RT-PCR. Chemical analyses and histological studies confirmed that males synthesize the sex attractant in the rectal vesicle and release it via the anal orifice. Involvement of Nasvi-EH1 in HDL biosynthesis was established by RNAi-mediated gene silencing. Injection of Nasvi-EH1 dsRNA into male abdomens inhibited pheromone biosynthesis by 55% and suppressed the targeted gene transcripts in the rectal vesicle by 95%. PMID:18579785

  8. Role of cyclic AMP in pulmonary xenobiotic metabolism with special emphasis on benzo(a)pyrene

    SciTech Connect

    Schaeffer, V.H.

    1986-01-01

    This thesis was intended to investigate the role of the intracellular regulator, cAMP, on pulmonary xenobiotic metabolism using the well-studied carcinogen, benzo(a)pyrene (BP) as a representative xenobiotic. Lung slices from rats administered N/sup 6/, O/sup 2/', dibutyryl cAMP (DcAMP), theophylline or forskolin, all of which elevated biologically reactive cAMP levels in the lung, showed an increased ability to metabolize (/sup 3/H)-BP. This effect occurred beyond 6 hr following treatment and reached a maximum at 12 hr, at a time when cAMP content had already peaked and returned to basal levels. The perfusion of BP through the isolated lungs of animals administered DcAMP in vivo indicated that the BP metabolites primarily responsible for the cyclic nucleotide-induced increase in metabolism were the 3-hydroxy BP, 9-hydroxy BP, BP 9, 10 diol, BP-glucuronides and BP-glutathione conjugates. Kinetic analysis indicated that the Km component of these reactions was altered without a corresponding change in Vmax, suggesting that elevated pulmonary cAMP content may be affecting the detoxication enzymes, UDP-glucuronyltransferase and sulfotransferase. Studies with pulmonary microsomes from DcAMP-treated animals indicated that the cyclic nucleotide not only enhanced the hydroxylation of BP but also the cytochrome P450-dependent hydroxylation of coumarin. This is supported by the fact that DcAMP administration in vivo also enhanced phosphorylation of two classes of nuclear proteins, histones and nuclear acidic proteins, believed to play a role in the transcription of RNA and DNA.

  9. IRIS Toxicological Review of Benzo[a]pyrene (External ...

    EPA Pesticide Factsheets

    The IRIS Toxicological Review of Benzo[a]pyrene was released for external peer review in September 2014. The EPA’s Science Advisory Board’s (SAB) Chemical Assessment Advisory Committee (CAAC) conducted a peer review of the scientific basis supporting the benzo[a]pyrene assessment and released a final report of their review in April 2016. Information regarding the peer review can be found at the SAB's website. EPA is undertaking an update of the Integrated Risk Information System (IRIS) health assessment for benzo[a]pyrene (BaP). The outcome of this project is an updated Toxicological Review and IRIS Summary for BaP that will be entered into the IRIS database.

  10. IRIS Toxicological Review of Benzo[a]pyrene (Interagency ...

    EPA Pesticide Factsheets

    In January 2017, EPA finalized the IRIS assessment of Benzo[a]pyrene. The Toxicological Review was reviewed internally by EPA and by other federal agencies and White House Offices before public release. Consistent with the May 2009 IRIS assessment development process, all written comments on IRIS assessments submitted by other federal agencies and White House Offices are made publicly available. Accordingly, interagency comments and the interagency science discussion materials provided to other agencies, including interagency review drafts of the IRIS Toxicological Review of Benzo[a]pyrene are posted on this site. EPA is undertaking an update of the Integrated Risk Information System (IRIS) health assessment for benzo[a]pyrene (BaP). The outcome of this project is an updated Toxicological Review and IRIS Summary for BaP that will be entered into the IRIS database.

  11. IRIS Toxicological Review of Benzo[a]pyrene (Public ...

    EPA Pesticide Factsheets

    EPA is developing an Integrated Risk Information System (IRIS) assessment of benzo[a]pyrene and has released the draft assessment for public comment and external peer review. When final, the assessment will appear on the IRIS database. EPA is undertaking an update of the Integrated Risk Information System (IRIS) health assessment for benzo[a]pyrene (BaP). The outcome of this project is an updated Toxicological Review and IRIS Summary for BaP that will be entered into the IRIS database.

  12. Ubiquitin Protein Ligase Ring2 Is Involved in S-phase Checkpoint and DNA Damage in Cells Exposed to Benzo[a]pyrene.

    PubMed

    Yang, Jin; Chen, Wentao; Fan, Yanfeng; Zhang, Huitao; Wang, Wubin; Zhang, Hongjie

    2016-10-01

    Previous studies in our laboratory demonstrated that Ring2 may affect DNA damage and repair through pathways other than through regulating the expression of the nucleotide excision repair protein. In a series of experiments using wild-type cell (16HBE and WI38) and small interfering RNA (siRNA) Ring2 cells exposed to benzo[a]pyrene (BaP), we evaluated the cell cycle and DNA damage. The benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE-DNA) adduct assay demonstrated that in vitro exposure to BaP increased DNA damage in a time- and dose-dependent manner in wild-type and siRNA Ring2 cells. Analysis of covariance showed that a decrease of Ring2 caused DNA hypersensitivity to BaP. Flow cytometry results and proliferating cell nuclear antigen levels indicated that inhibition of Ring2 attenuated the effect of BaP on S-phase arrest. Taken together, these data implied that the lower proportion of cells in the S phase induced by inhibition of Ring2 may play an important role in DNA hypersensitivity to BaP.

  13. Chiral Ketone and Iminium Catalysts for Olefin Epoxidation

    NASA Astrophysics Data System (ADS)

    Wong, O. Andrea; Shi, Yian

    Organo-catalyzed asymmetric epoxidation has received much attention in the past 30 years and significant progress has been made for various types of olefins. This review will cover the advancement made in the field of chiral ketone and chiral iminium salt-catalyzed epoxidations.

  14. Hypoxia diminishes the detoxification of the environmental mutagen benzo[a]pyrene.

    PubMed

    Schults, Marten A; Sanen, Kathleen; Godschalk, Roger W; Theys, Jan; van Schooten, Frederik J; Chiu, Roland K

    2014-11-01

    Hypoxia promotes genetic instability and is therefore an important factor in carcinogenesis. We have previously shown that activation of the hypoxia responsive transcription factor HIFα can enhance the mutagenic phenotype induced by the environmental mutagen benzo[a]pyrene (BaP). To further elucidate the mechanism behind the ability of hypoxia to increase mutagenicity of carcinogens, we examined the activation and detoxification of BaP under hypoxic conditions. To this end, the human lung carcinoma cell line A549 was treated with BaP under 20%, 5% or 0.2% oxygen for 18h and alterations in BaP metabolism were assayed. First, BaP-induced expression of key metabolic enzymes was analysed; expression levels of the activating CYP1A1 and CYP1B1 were increased, while the detoxifying enzymes UGT1A6 and UGT2B7 were significantly reduced by hypoxia. To evaluate whether these changes had an effect on metabolism, levels of BaP and several of its metabolites were determined. Cells under hypoxia have a reduced capacity to metabolise BaP leaving more of the parent molecule intact. Additionally, BaP-7,8-dihydrodiol, the pre-cursor metabolite of the reactive metabolite BaP-7,8-dihydroxy-9,10-epoxide (BPDE), was formed in higher concentrations. Finally, under hypoxia, DNA adducts accumulated over a period of 168 h, whereas adducts were efficiently removed in 20% oxygen conditions. The delayed detoxification kinetics resulted in a 1.5-fold increase in DNA adducts. These data indicate that the metabolism under hypoxic conditions has shifted towards increased activation of BaP instead of detoxification and support the idea that modulation of carcinogen metabolism is an important additional mechanism for the observed HIF1 mediated genetic instability.

  15. Loss of VHL in RCC Reduces Repair and Alters Cellular Response to Benzo[a]pyrene

    PubMed Central

    Schults, Marten A.; Oligschlaeger, Yvonne; Godschalk, Roger W.; Van Schooten, Frederik-Jan; Chiu, Roland K.

    2013-01-01

    Mutations of the von Hippel-Lindau (VHL) tumor suppressor gene occur in the majority of sporadic renal-cell carcinomas (RCC). Loss of VHL function is associated with stabilization of hypoxia-inducible factor α (HIFα). We and others demonstrated that there is a two-way interaction between the aryl hydrocarbon receptor, which is an important mediator in the metabolic activation and detoxification of carcinogens, and the HIF1-pathway leading to an increased genetic instability when both pathways are simultaneously activated. The aim of this study was to investigate how environmental carcinogens, such as benzo[a]pyrene (BaP), which can be metabolically activated to BaP-7,8-diOH-9,10-epoxide (BPDE) play a role in the etiology of RCC. We exposed VHL-deficient RCC4 cells, in which HIFα is stabilized regardless of oxygen tension, to 0.1 μM BaP for 18 h. The mutagenic BPDE-DNA adduct levels were increased in HIFα stabilized cells. Using qRT-PCR, we demonstrated that absence of VHL significantly induced the mRNA levels of AhR downstream target CYP1A1. Furthermore, HPLC analysis indicated that loss of VHL increased the concentration of BaP-7,8-dihydroxydiol, the pre-cursor metabolite of BPDE. Interestingly, the capacity to repair BPDE-DNA adducts in the HIFα stabilized RCC4 cells, was markedly reduced. Taken together, these data indicate that loss of VHL affects BaP-mediated genotoxic responses in RCC and decreases repair capacity. PMID:24195061

  16. Epoxides--is there a human health problem?

    PubMed Central

    Manson, M M

    1980-01-01

    The purpose of this review is to consider whether epoxides represent a hazard to human health. Possible means of occupational and non-occupational exposure are discussed with reference to the production and uses of industrially important compounds and other epoxides, such as naturally occurring plant and fungal products. In addition to epoxides themselves, unsaturated compounds that may be metabolised in vivo to epoxides are included, since this appears to be a further important means of exposure. The toxicology, in particular carcinogenicity and mutagenicity, is discussed, along with a brief outline of the biochemistry such as metabolism, binding to cell constituents, and DNA repair mechanisms. The question of interactions between different epoxides in vivo is also raised. PMID:7004476

  17. Alterations in the metabolism of benzo(a)pyrene in syrian hamster embryo (SHE) cells pretreated with phenolic antioxidants

    SciTech Connect

    Strniste, G.F.; Okinaka, R.T.; Chen, D.J.

    1983-01-01

    Inhibition of chemical- or raddiation-induced neoplasia has been observed in animals whose diets were supplemented with antioxidants commonly used as food additives. Inhibition of the carcinogenicity of benzo(a)pyrene (BaP) or of 7,12-dimenthylbenz(a)anthracene (DMBA) - in rats has been achieved by the addition of the phenolic antioxidants butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) to the diet. Our data suggest that in SHE cells antioxidants inhibit the overall metabolism of BaP to its various oxidized moieties including 7,8-diol- and 7,8,9,10-tetrol-BaP. A plausible explanation for our results with SHE cells is that the antioxidants interact directly with AHH, thus inhibiting AHH metabolic capacity. From analysis of nuclear material from SHE cells (+- antioxidants) incubated for 36 hours with BaP at 1 ..mu..g/ml, it is calculated that 4.6, 2.4 and 2.9 pmol BaP are bound to the DNA isolated from 10/sup 7/ nuclei of control, BHA-(20 ..mu..g/ml) and p-MP-(10 ..mu..g/ml) treated cultures, respectively.

  18. Brassinolide activities of 2alpha,3alpha-diols versus 3alpha,4alpha-diols in the bean second internode bioassay: explanation by molecular modeling methods.

    PubMed

    Sísa, Miroslav; Vilaplana-Polo, Marc; Ballesteros, Carme Brosa; Kohout, Ladislav

    2007-10-01

    In general, the structural requirements postulated for a high brassinolide activity are: 2alpha,3alpha-diol, 6-ketone or better 7-oxalactone in B-ring, A/B trans fused ring junction, a cis C-22,C-23-diol preferentially with RR configurations, and a C-24 methyl or ethyl substituent [Takatsuto S, Yazawa N, Ikekawa N, Takematsu T, Takeuchi Y, Koguchi M. Structure-activity relationship of brassinosteroids. Phytochemistry 1983;22:2437-41; Thompson MJ, Meudt WJ, Mandava NB, Dutky SR, Lusby WR, Spaulding DW. Synthesis of brassinosteroids and relationship of structure to plant growth-promoting effects. Steroids 1982;39:89-105]. We found that the 3alpha,4alpha-diols 4, 6 and 8 are more active than the 2alpha,3alpha-diols 3, 5 and 7 [Sísa M, Budesínský M, Kohout L. Synthesis of 7a-homo and 7a,7b-dihomo-5alpha-cholestane analogues of brassinolide. Collect Czech Chem Commun 2003;68:2171-89]. This fact is in strong contrast with the structure requirements mentioned above. Our hypothesis suggests that the lower activity of 2alpha,3alpha-diols and/or the higher activity of 3alpha,4alpha-diols could be explained by twisting and distortion of the molecule due to the seven- or eight-membered B-ring and also by the position of a carbonyl group relative to the A-ring diol. 3D-SAR computer methodologies as alignments and overlaps of GRID maps and 3D-QSAR analysis GRID-GOLPE (CoMFA-like) were used as an effort to explain the higher bioactivity of 3alpha,4alpha-diols 4, 6 and 8 in comparison with the 2alpha,3alpha-diols 3, 5 and 7 of B-ring enlarged brassinosteroids.

  19. Modulatory effects of catechin hydrate against genotoxicity, oxidative stress, inflammation and apoptosis induced by benzo(a)pyrene in mice.

    PubMed

    Shahid, Ayaz; Ali, Rashid; Ali, Nemat; Hasan, Syed Kazim; Bernwal, Preeti; Afzal, Shekh Mohammad; Vafa, Abul; Sultana, Sarwat

    2016-06-01

    Benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon (PAH) is a strong mutagen and potent carcinogen. The aim of the present study was to investigate the efficacy of catechin hydrate against B(a)P induced genotoxicity, oxidative stress, inflammation, apoptosis and to explore its underlying molecular mechanisms in the lungs of Swiss albino mice. Administration of B(a)P (125 mg/kg b. wt., p. o.) increased the activities of toxicity markers such as LPO, LDH and B(a)P metabolizing enzymes [NADPH-cytochrome P450 reductase (CYPOR) and microsomal epoxide hydrolase (mEH)] with subsequent decrease in the activities of tissue anti-oxidant armory (SOD, CAT, GPx, GR, GST, QR and GSH). It also caused DNA damage and activation of apoptotic and inflammatory pathway by upregulation of TNF-α, IL-6, NF-kB, COX-2, p53, bax, caspase-3 and down regulating Bcl-2. However, pre-treatment with catechin at a dose of 20 and 40 mg/kg significantly decreased LDH, LPO, B(a)P metabolizing enzymes and increased anti-oxidant armory as well as regulated apoptosis and inflammation in lungs. Histological results also supported the protective effects of catechin. The findings of the present studies suggested that catechin as an effective natural product attenuates B(a)P induced lung toxicity.

  20. Metabolites analysis, metabolic enzyme activities and bioaccumulation in the clam Ruditapes philippinarum exposed to benzo[a]pyrene.

    PubMed

    Liu, Dong; Pan, Luqing; Li, Zhen; Cai, Yuefeng; Miao, Jingjing

    2014-09-01

    A study was performed on clams (Ruditapes philippinarum) exposed to 0.03, 0.3 and 3μg/L benzo[a]pyrene (B[a]P) for 21 days. B[a]P metabolite contents, activities of aryl hydrocarbon hydroxylase (AHH), 7-ethoxyresorufin O-deethylase (EROD), epoxide hydrolase (EH), dihydrodiol dehydrogenase (DD), glutathione-S-transferase (GST), sulfotransferase (SULT) and uridinediphosphate glucuronyltransferase (UGT) and B[a]P bioaccumulation were assayed in gills and digestive glands. Results showed that the order of B[a]P phase I metabolite contents was 9-hydroxy-B[a]P>B[a]P-1,6-dione>B[a]P-7,8-dihydrodiol, and the concentration of B[a]P-7,8-dihydrodiol sulfate conjugates was higher than that of B[a]P-7,8-dihydrodiol glucuronide conjugates. B[a]P accumulation and the activities of AHH, EROD, EH, DD, SULT and UGT increased first and then reached equilibrium. GST activity was induced first and then depressed. The concentration of B[a]P was far higher than that of its metabolites. Besides, there were no significant differences between enzyme activities in gills and those in digestive glands. These results provided information on B[a]P metabolic mechanism in bivalve and scientific data for pollution monitoring and food security.

  1. Determination of 3-Monochloropropane-1,2-diol and 2-Monochloropropane-1,3-diol (MCPD) Esters and Glycidyl Esters by Microwave Extraction in Different Foodstuffs.

    PubMed

    Marc, Corinne; Drouard-Pascarel, Valérie; Rétho, Cécile; Janvion, Patrice; Saltron, Frédéric

    2016-06-01

    This paper describes a method for the determination of 3-monochloropropane-1,2-diol and 2-monochloropropane-1,3-diol (MCPD) esters and glycidyl esters in various foodstuffs, which are isolated using microwave extraction. The next step is based on alkaline-catalyzed ester cleavage. The released glycidol is transformed into monobromopropanediol (MBPD). All compounds are derivatized in free diols (MCPD and MBPD) with phenylboronic acid and analyzed by gas chromatography-mass spectrometry (GC-MS). The method was validated for oils with a limit of quantitation (LOQ) of 0.1 mg/kg, for chips and crisps with a LOQ of 0.02 mg/kg, and for infant formula with a LOQ of 0.0025 mg/L. Recoveries of each sample were controlled by standard addition on extracts before derivatization. Quantitation was performed by the addition of isotopically labeled glycidyl and 3-monochloropropane-1,2-diol (3-MCPD) esters.

  2. Prediction of drug-drug interactions with carbamazepine-10,11-epoxide using a new in vitro assay for epoxide hydrolase inhibition.

    PubMed

    Rosa, Maria; Bonnaillie, Pierre; Chanteux, Hugues

    2016-12-01

    1. Carbamazepine is an antiepileptic drug which is metabolized by CYP3A4 into carbamazepine-10,11-epoxide. This metabolite is then detoxified by epoxide hydrolase. As carbamazepine-10,11-epoxide has been associated with neurotoxicity, it is critical to identify whether a new antiepileptic drug has the potential to inhibit epoxide hydrolase and therefore increase carbamazepine-10,11-epoxide plasma levels. 2. In this study, an in vitro assay was developed to evaluate epoxide hydrolase activity by using carbamazepine-10,11-epoxide as probe substrate. The ability of this assay to predict drug-drug interactions (DDI) at the epoxide hydrolase level was also investigated. 3. To this aim, known inhibitors of epoxide hydrolase for which in vivo data are available were used. Firstly, carbamazepine-10,11-epoxide hydrolase activity was determined in liver microsomes, cytosol and hepatocytes. Thereafter, the IC50 of epoxide hydrolase inhibitors (progabide, valproic acid, valpromide and valnoctamide) was determined in liver microsomes and hepatocytes. Finally, prediction of AUC increase was performed using the in vitro data generated. 4. Interestingly, epoxide hydrolase activity was found to be much higher in human hepatocytes compared to liver microsomes/cytosol. Even though assessed on a limited number of compounds, this study demonstrated that the use of hepatocytes seems to be a more relevant model to assess and predict DDI at the epoxide hydrolase level.

  3. Monitoring benzo(a)pyrene exposure using laser-excited Shpol'skii spectroscopy of benzo(a)pyrene metabolites

    NASA Astrophysics Data System (ADS)

    Ariese, Freek; Kok, S. J.; Verkaik, M.; Hoornweg, Gerard P.; Gooijer, Cees; Velthorst, Nel H.; Hofstraat, Johannes W.

    1993-03-01

    Exposure to polycyclic aromatic hydrocarbons (PAHs) is considered a serious threat to the health of animals and humans and should be thoroughly monitored. Next to chemical analysis of PAHs in the various environmental compartments, PAH metabolites in body fluids (e.g., bile and urine) could be measured to determine the actual uptake. Although pyrene is not considered particularly toxic, its metabolite 1-hydroxy pyrene is often used as a biomarker because it is usually found at considerable concentrations and the analysis is relatively simple. As the result of differences in volatility and/or solubility, the uptake of more relevant carcinogens like benzo(a)pyrene may be some orders of magnitude lower and is far more difficult to measure. Determination of benzo(a)pyrene metabolites requires a very selective and sensitive method, and so far these compounds could only be detected after exposure to heavy pollution. In this paper it will be shown how several hydroxy benzo(a)pyrene metabolites are selectively determined using Shpol'skii spectroscopy. With this method, highly resolved fluorescence spectra are obtained upon cooling the sample in a suitable solvent to cryogenic temperatures. When a tunable laser system is employed as an excitation source, sub- femtomole amounts can be detected. Applications of the technique to marine monitoring (benzo(a)pyrene metabolites in fish bile) and to occupational hygienics (benzo(a)pyrene metabolites in workers' urine) are discussed. The data will be compared with 1-hydroxy pyrene concentrations to evaluate the routine use of the latter compound as a biomarker.

  4. 40 CFR 721.8085 - Reaction product of substituted aromatic diol, formaldehyde and alkanolamine, propoxylated...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Reaction product of substituted... Reaction product of substituted aromatic diol, formaldehyde and alkanolamine, propoxylated (generic). (a... generically as reaction product of substituted aromatic diol, formaldehyde and alkanolamine, propoxylated...

  5. 40 CFR 721.8085 - Reaction product of substituted aromatic diol, formaldehyde and alkanolamine, propoxylated...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Reaction product of substituted... Reaction product of substituted aromatic diol, formaldehyde and alkanolamine, propoxylated (generic). (a... generically as reaction product of substituted aromatic diol, formaldehyde and alkanolamine, propoxylated...

  6. 40 CFR 721.2625 - Reaction product of alkane-diol and epichlorohydrin.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Reaction product of alkane-diol and... Specific Chemical Substances § 721.2625 Reaction product of alkane-diol and epichlorohydrin. (a) Chemical... as reaction product of alkanediol and epichlorohydrin (PMN P-89-760) is subject to reporting...

  7. 40 CFR 721.8085 - Reaction product of substituted aromatic diol, formaldehyde and alkanolamine, propoxylated...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Reaction product of substituted... Reaction product of substituted aromatic diol, formaldehyde and alkanolamine, propoxylated (generic). (a... generically as reaction product of substituted aromatic diol, formaldehyde and alkanolamine, propoxylated...

  8. 40 CFR 721.8085 - Reaction product of substituted aromatic diol, formaldehyde and alkanolamine, propoxylated...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Reaction product of substituted... Reaction product of substituted aromatic diol, formaldehyde and alkanolamine, propoxylated (generic). (a... generically as reaction product of substituted aromatic diol, formaldehyde and alkanolamine, propoxylated...

  9. 40 CFR 721.8085 - Reaction product of substituted aromatic diol, formaldehyde and alkanolamine, propoxylated...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Reaction product of substituted... Reaction product of substituted aromatic diol, formaldehyde and alkanolamine, propoxylated (generic). (a... generically as reaction product of substituted aromatic diol, formaldehyde and alkanolamine, propoxylated...

  10. 40 CFR 721.2625 - Reaction product of alkane-diol and epichlorohydrin.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Reaction product of alkane-diol and... Specific Chemical Substances § 721.2625 Reaction product of alkane-diol and epichlorohydrin. (a) Chemical... as reaction product of alkanediol and epichlorohydrin (PMN P-89-760) is subject to reporting...

  11. 40 CFR 721.2625 - Reaction product of alkane-diol and epichlorohydrin.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Reaction product of alkane-diol and... Specific Chemical Substances § 721.2625 Reaction product of alkane-diol and epichlorohydrin. (a) Chemical... as reaction product of alkanediol and epichlorohydrin (PMN P-89-760) is subject to reporting...

  12. 40 CFR 721.10662 - Acetaldehyde, substituted-, reaction products with 2-butyne-1, 4-diol (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Acetaldehyde, substituted-, reaction...-, reaction products with 2-butyne-1, 4-diol (generic). (a) Chemical substance and significant new uses...-, reaction products with 2-butyne-1, 4-diol (PMN P-11-204) is subject to reporting under this section for...

  13. 40 CFR 721.2625 - Reaction product of alkane-diol and epichlorohydrin.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Reaction product of alkane-diol and... Specific Chemical Substances § 721.2625 Reaction product of alkane-diol and epichlorohydrin. (a) Chemical... as reaction product of alkanediol and epichlorohydrin (PMN P-89-760) is subject to reporting...

  14. 40 CFR 721.2625 - Reaction product of alkane-diol and epichlorohydrin.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Reaction product of alkane-diol and... Specific Chemical Substances § 721.2625 Reaction product of alkane-diol and epichlorohydrin. (a) Chemical... as reaction product of alkanediol and epichlorohydrin (PMN P-89-760) is subject to reporting...

  15. Carcinogenicity and mechanistic insights on the behavior of epoxides and epoxide-forming chemicals.

    PubMed

    Melnick, Ronald L

    2002-12-01

    Many epoxides and their precursors are high production volume chemicals that have major uses in the polymer industry and as intermediates in the manufacture of other chemicals. Several of these chemicals were demonstrated to be carcinogenic in laboratory animal studies conducted by the Ramazzini Foundation (e.g., vinyl chloride, acrylonitrile, styrene, styrene oxide, and benzene) and by the National Toxicology Program (e.g., ethylene oxide, 1,3-butadiene, isoprene, chloroprene, acrylonitrile, glycidol, and benzene). The most common sites of tumor induction were lung, liver, harderian gland, and circulatory system in mice; Zymbal's gland and brain in rats; and mammary gland and forestomach in both species. Differences in cancer outcome among studies of epoxide chemicals may be related to differences in study design (e.g., dose, duration, and route of exposure; observation period; animal strains), as well as biological factors affecting target organ dosimetry of the DNA-reactive epoxide (toxicokinetics) and tissue response (toxicodynamics). N7-Alkylguanine, N1-alkyladenine, and cyclic etheno adducts, as well as K-ras and p53 mutations, have been detected in animals and/or workers exposed to several of these chemicals. The classifications of these chemical carcinogens by IARC and NTP are based on animal and human data and results of mechanistic studies. Reducing occupational and environmental exposures to these chemicals will certainly reduce human cancer risks.

  16. Hydrolysis of the 2',3'-allylic epoxides of allylbenzene, estragole, eugenol, and safrole by both microsomal and cytosolic epoxide hydrolases.

    PubMed

    Luo, G; Qato, M K; Guenthner, T M

    1992-01-01

    2',3'-Allylic epoxide derivatives of allylbenzene and its analogs estragole, eugenol, and safrole were synthesized, and their enzymatic conversion to dihydrodiols by cytosolic and microsomal epoxide hydrolases was examined. All four epoxides were good substrates for both epoxide hydrolases, with Michaelis constants in the low micromolar range. Two putatively selective inhibitors of cytosolic and microsomal epoxide hydrolases, trichloropropylene oxide and nordihydroguaiaretic acid, were used to inhibit the hydrolysis of these allylic epoxides. Minimal selectivity toward either hydrolase was seen with either inhibitor, suggesting that the "selectivity" of these inhibitors is highly substrate-dependent. The susceptibilities of these epoxides to rapid hydrolysis by both epoxide hydrolases may explain their low genotoxic potencies in vivo.

  17. Benzo(a)pyrene uptake by lymph: a possible transport mode for immunosuppressive chemicals

    SciTech Connect

    Busbee, D.L.; Joe, C.O.; Rankin, P.W.; Ziprin, R.L.; Wilson, R.D.

    1984-01-01

    Benzo(a)pyrene, a lipophilic promutagen, reached maximal concentrations in the thoracic duct lymphatic circulation within 2 h after gastric instillation. Benzo(a)pyrene in lymph obtained by thoracic duct cannulation decreased to approximately control levels within 4 h after treatment. When lymph was not allowed to enter the blood vascular circulation, serum levels of benzo(a)pyrene increased very slowly, suggesting minimal mesenteric blood vascular absorption of the lipophilic hydrocarbon. Benzo(a)pyrene partitions into lymph lipoproteins as a function of the lipoprotein concentration. Data suggest that low-density lipoproteins may take up benzo(a)pyrene more efficiently than do very low-density or high-density lipoproteins, and that lymph components other than lipoproteins do not take up and transport benzo(a)pyrene. We propose that lipophilic xenobiotic compounds interact with cells of the immune system via lymphatic lipoprotein transport of potentially mutagenic, carcinogenic, or immuno-suppressive agents.

  18. Synthesis and reactivity of coumarin 3,4-epoxide.

    PubMed

    Born, S L; Rodriguez, P A; Eddy, C L; Lehman-McKeeman, L D

    1997-11-01

    Coumarin is used widely as a fragrance constituent and is administered clinically in the treatment of certain lymphedemas and malignancies. Although toxicity occurs only rarely in humans treated clinically with high-dose coumarin, it is well established that coumarin is hepatotoxic in the rat. This species difference in susceptibility to toxicity reflects the disparate metabolic processes occurring in humans and rodents. In humans, coumarin is converted extensively via cytochrome P450 2A6 to the nontoxic 7-hydroxycoumarin metabolite. In contrast, coumarin 3,4-epoxidation is thought to predominate in rodent species, resulting in the formation of several potentially toxic metabolites. Coumarin epoxide is thought to be highly unstable and has not been isolated synthetically or as a microsomal product. To address this issue, coumarin 3,4-epoxide was synthesized, and its stability and fate have been determined. Coumarin 3,4-epoxide was prepared by reacting coumarin with dimethyldioxirane. The epoxide was stable in organic solvents and survived conditions required for analysis by gas chromotography. Its structure was confirmed via 1H-NMR and gas chromatography-mass spectrometry-infrared spectroscopy (GC-MS-IR). In contrast, coumarin 3,4-epoxide was unstable in aqueous solution, converting within 20 sec to a ring-opened compound. Using GC-MS-IR analysis, the single coumarin 3,4-epoxide product was identified as o-hydroxyphenylacetaldehyde (o-HPA). Although other investigators have suggested that 3-hydroxycoumarin is an intermediate in o-HPA formation from coumarin 3,4-epoxide, we have demonstrated that 3-hydroxycoumarin, incubated in an aqueous system or with liver microsomal proteins, does not form o-HPA. Thus, the results of the present work establish that coumarin 3,4-epoxide can be synthesized and that o-HPA, which has previously been shown to be a prominent coumarin metabolite in rat liver microsomal incubations, is formed directly from coumarin 3,4-epoxide. These

  19. Metabolism of benzo(a)pyrene in cultured human bronchus

    SciTech Connect

    Stoner, G.D.; Daniel, F.B.

    1982-04-01

    Lung cancer is a major cause of cancer deaths in many countries. Based on clinical, experimental, epidemiologic and autopsy data, cigarette smoking has been identified as the major risk factor in the development of lung cancer. The majority of lung cancers in man are bronchiogenic carcinomas which are thought to arise from a metaplastic squamous differentiation of the large bronchi. Polycyclic aromatic hydrocarbons, such as benzo(a)pyrene (PB), found in cigarette smoke and environmental pollutants, were associated with lung cancer in man. Since most chemical carcinogens have to be metabolically activated in the body before exerting their carcinogenicity, it is important to study the metabolic fate of benzo(a)pyrene in the human bronchus. Recent developments in the maintenance and growth of viable human epithelial tissues and cells in vitro have made possible the study of chemical carcinogenesis directly in human tissue.

  20. Enhancing productivity for cascade biotransformation of styrene to (S)-vicinal diol with biphasic system in hollow fiber membrane bioreactor.

    PubMed

    Gao, Pengfei; Wu, Shuke; Praveen, Prashant; Loh, Kai-Chee; Li, Zhi

    2017-03-01

    Biotransformation is a green and useful tool for sustainable and selective chemical synthesis. However, it often suffers from the toxicity and inhibition from organic substrates or products. Here, we established a hollow fiber membrane bioreactor (HFMB)-based aqueous/organic biphasic system, for the first time, to enhance the productivity of a cascade biotransformation with strong substrate toxicity and inhibition. The enantioselective trans-dihydroxylation of styrene to (S)-1-phenyl-1,2-ethanediol, catalyzed by Escherichia coli (SSP1) coexpressing styrene monooxygenase and an epoxide hydrolase, was performed in HFMB with organic solvent in the shell side and aqueous cell suspension in the lumen side. Various organic solvents were investigated, and n-hexadecane was found as the best for the HFMB-based biphasic system. Comparing to other reported biphasic systems assisted by HFMB, our system not only shield much of the substrate toxicity but also deflate the product recovery burden in downstream processing as the majority of styrene stayed in organic phase while the diol product mostly remained in the aqueous phase. The established HFMB-based biphasic system enhanced the production titer to 143 mM, being 16-fold higher than the aqueous system and 1.6-fold higher than the traditional dispersive partitioning biphase system. Furthermore, the combination of biphasic system with HFMB prevents the foaming and emulsification, thus reducing the burden in downstream purification. HFMB-based biphasic system could serve as a suitable platform for enhancing the productivity of single-step or cascade biotransformation with toxic substrates to produce useful and valuable chemicals.

  1. IRIS Toxicological Review of Benzo[a]pyrene (Interagency ...

    EPA Pesticide Factsheets

    On August 21, 2013, the draft Toxicological Review of Benzo[a]pyrene and the draft charge to external peer reviewers were released for public review and comment. The Toxicological Review and charge were reviewed internally by EPA and by other federal agencies and White House Offices before public release. Consistent with the May 2009 IRIS assessment development process, all written comments on IRIS assessments submitted by other federal agencies and White House Offices are made publicly available. Accordingly, interagency comments and the interagency science consultation materials provided to other agencies, including interagency review drafts of the IRIS Toxicological Review of Benzo[a]pyrene and the charge to external peer reviewers, are posted on this site. EPA is undertaking an update of the Integrated Risk Information System (IRIS) health assessment for benzo[a]pyrene (BaP). The outcome of this project is an updated Toxicological Review and IRIS Summary for BaP that will be entered into the IRIS database.

  2. Utilization of a diol-stationary phase column in ion chromatographic separation of inorganic anions.

    PubMed

    Arai, Kaori; Mori, Masanobu; Kozaki, Daisuke; Nakatani, Nobutake; Itabashi, Hideyuki; Tanaka, Kazuhiko

    2012-12-28

    We describe the ion chromatographic separation of inorganic anions using a diol-stationary phase column (-CH(OH)CH(2)OH; diol-column) without charged functional groups. Anions were separated using acidic eluent as in typical anion-exchange chromatography. The retention volumes of anions on the diol-column increased with increasing H(+) concentration in the eluent. The anion-exchange capacities of diol-columns in the acidic eluent (pH 2.8) were larger than that of zwitterionic stationary phase column but smaller than that of an anion-exchange column. The separation of anions using the diol-column was strongly affected by the interaction of H(+) ions with the diol-functional groups and by the types of the eluents. In particular, the selection of the eluent was very important for controlling the retention time and resolution. Good separation was obtained using a diol-column (HILIC-10) with 5 mM phthalic acid as eluent. The limits of detection at a signal-to-noise ratio of 3 ranged from 1.2 to 2.7 μM with relative standard deviations (RSD, n=5) of 0.04-0.07% for the retention time and 0.4-2.0% for the peak areas. This method was successfully applied to the determination of H(2)PO(4)(-), Cl(-), and NO(3)(-) in a liquid fertilizer sample.

  3. Absolute Stereochemistry of 1,2-Diols from Lipids of Thermomicrobia.

    PubMed

    Lagutin, Kirill; Wong, Herbert; Vyssotski, Mikhail; MacKenzie, Andrew

    2016-03-01

    1,2-Diol based phospholipids are a well-known feature of bacteria from the class Thermomicrobia. Since these bacteria contain only lipids with an alkyldiol-1-phosphate backbone instead of sn-glycero-3-phosphate, it is important to elucidate the stereochemistry of the 1,2-diols. We have studied the absolute stereochemistry of long-chain 1,2-diols isolated from Thermorudis pharmacophila (formerly known as Thermomicrobia sp. WKT50.2) by nuclear magnetic resonance (NMR) using α-methoxyphenylacetic acid (MPA). Low-temperature (-60 °C) NMR of bis-(R)-MPA ester showed (R) stereochemistry of the 1,2-diols. This is the first report concerning the stereochemistry of natural 1,2-diols, which replace the glyceride moiety in phospholipids. The (R) stereochemistry of the diols is expected as it is the same configuration as for the common bacterial lipid backbone-sn-glycero-3-phosphate. This is the first application of low-temperature NMR of a single MPA derivative for assignment of stereochemistry of natural 1,2-diols. The results were confirmed by the comparison of NMR data with bis-(R)-MPA ester of (R) and rac-1,2-octanediol.

  4. Immunohistochemical study of epoxide hydrolase induced by trichloroethylene in rat liver

    SciTech Connect

    Kawamoto, T.; Hobara, T.; Ogino, K.; Takemoto, T.; Nakamura, K.; Imamura, A.; Koshiro, A.; Kobayashi, H.; Iwamoto, S.; Sakai, T.

    1987-10-01

    Epoxide hydrolase catalyzes the hydrolation of potentially toxic, electrophilic epoxides that are often generated during cytochrome P-450 catalyzed monooxigenation, forming the corresponding transdihydrodiols. It is well-known that trichloroethylene is metabolized by cytochrome P-450 containing mixed-function oxidase systems to trichloroethylene oxide, which decomposes to other metabolites. As trichloroethylene is an epoxide, epoxide hydrolase is suspected to catalyze the hydrolation of trichloroethylene oxide. No reports have appeared about the relationship between trichloroethylene and epoxide hydrolase. In this report, the authors studied the effect of trichloroethylene on epoxide hydrolase immunohistochemically.

  5. Preliminary physiologically based pharmacokinetic models for benzo[a]pyrene and dibenzo[def,p]chrysene in rodents

    SciTech Connect

    Crowell, Susan Ritger; Amin, Shantu G.; Anderson, Kim A.; Krishnegowda, Gowdahalli; Sharma, Arun K.; Soelberg, Jolen J.; Williams, David E.; Corley, Richard A.

    2011-12-15

    Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated as byproducts of natural and anthropogenic combustion processes. Despite significant public health concern, physiologically based pharmacokinetic (PBPK) modeling efforts for PAHs have so far been limited to naphthalene, plus simpler PK models for pyrene, nitropyrene, and benzo[a]pyrene (B[a]P). The dearth of published models is due in part to the high lipophilicity, low volatility, and myriad metabolic pathways for PAHs, all of which present analytical and experimental challenges. Our research efforts have focused upon experimental approaches and initial development of PBPK models for the prototypic PAH, B[a]P, and the more potent, albeit less studied transplacental carcinogen, dibenzo[def,p]chrysene (DBC). For both compounds, model compartments included arterial and venous blood, flow limited lung, liver, richly perfused and poorly perfused tissues, diffusion limited fat, and a two compartment theoretical gut (for oral exposures). Hepatic and pulmonary metabolism was described for both compounds, as were fractional binding in blood and fecal clearance. Partition coefficients for parent PAH along with their diol and tetraol metabolites were estimated using published algorithms and verified experimentally for the hydroxylated metabolites. The preliminary PBPK models were able to describe many, but not all, of the available data sets, comprising multiple routes of exposure (oral, intravenous) and nominal doses spanning several orders of magnitude. Supported by Award Number P42 ES016465 from the National Institute of Environmental Health Sciences. -- Highlights: Black-Right-Pointing-Pointer We present PBPK models for benzo[a]pyrene (B[a]P) and dibenzo[def,p]chrysene (DBC). Black-Right-Pointing-Pointer B[a]P model accurately predicts data from multiple sources over a wide dose range. Black-Right-Pointing-Pointer DBC model was based on the B[a]P model as less chemical specific

  6. Characterization of novel long-chain 1,2-diols in Thermus species and demonstration that Thermus strains contain both glycerol-linked and diol-linked glycolipids.

    PubMed Central

    Wait, R; Carreto, L; Nobre, M F; Ferreira, A M; da Costa, M S

    1997-01-01

    In this study, we purified and characterized tetra- and triglycosyl glycolipids (GL-1 and GL-2, respectively) from two different colonial forms of Thermus scotoductus X-1, from T. filiformis Tok4 A2, and from T. oshimai SPS-11. Acid hydrolysis of the purified glycolipids liberated, in addition to the expected long-chain fatty acids, two components which were identified by gas chromatography-mass spectrometry as 16-methylheptadecane-1,2-diol and 15-methylheptadecane-1,2-diol. Fast atom bombardment mass spectrometry of the intact glycolipids indicated that a major proportion consisted of components with glycan head groups linked to long-chain 1,2-diols rather than to glycerol, although in all cases glycerol-linked compounds containing similar glycan head groups were also present. As in other Thermus strains, the polar head group of GL-1 from T. filiformis Tok4 A2 and from T. scotoductus X-1 colony type t2 was a glucosylgalactosyl-(N-acyl)glucosaminylglucosyl moiety. However, GL-2 from T. scotoductus X-1 colony type t1 and from T. oshimai SPS-11 was a truncated analog which lacked the nonreducing terminal glucose. Long-chain 1,2-diols have been previously reported in the polar lipids of Thermomicrobium roseum and (possibly) Chloroflexus aurantiacus, but to our knowledge, this is the first report of their detection in other bacteria and the first account of the structural determination of long-chain diol-linked glycolipids. PMID:9324266

  7. Epoxygenase Eicosanoids: Synthesis of Tetrahydrofuran-Diol Metabolites and Their Vasoactivity

    PubMed Central

    Falck, J. R.; Reddy, L. Manmohan; Byun, Kihwan; Campbell, William B.; Yi, Xiu-Yu

    2007-01-01

    Eight members of a recently identified family of tetrahydrofuran-diols (THFDs), originating from epoxyeicosatrienoic acids (EETs), were prepared stereospecifically from D-(+)-glucose. The THFDs potently induced relaxation of pre-contracted bovine arteries. PMID:17293113

  8. Correlation between production of benzo(A)pyrene metabolites and BPDE I-DG adduct levels in human epithelial cells in vitro pretreated with cytochrome P450 inhibitors or inducer

    SciTech Connect

    Lehman, T.A.; Milo, G.E.

    1987-05-01

    Human epidermal keratinocytes were established from neonatal foreskins. Cultures were pretreated for 24 hr with either butylated hydroxyanisole (BHA), methyl butylated hydroxyanisole (MeBHA) or 7,8 benzoflavone (7,8BF). For metabolite detection studies, cultures were treated with radiolabeled benzo(a)pyrene (BP) for 24 hr. Ethyl acetate soluble metabolites were extracted for HPLC analysis. BHA and 7,8BF pretreatment both significantly decreased intracellular production of 7,8 diol BP compared to cultures treated only with radiolabeled BP. MeBHA pretreatment greatly increased intracellular 7,8 diol BP formation compared to BP treated controls. For DNA adduct analysis, cultures were pretreated as described above, and then treated for 24 hr with non-radiolabeled BP. Cellular DNA was isolated and /sup 32/P-postlabeled for adduct analysis. Cultures pretreated with either BHA or 7,8BF formed significantly fewer BPDE I-dG adducts than nonpretreated cultures, while cultures pretreated with MeBHa formed more BPDE I-dG adducts. Thus, BHA and 7,8BF act similarly in reducing BP activation and adduct formation while MeBHa, a structural analog of BHA, increases BP activation and adduct formation in human keratinocyte cultures in vitro.

  9. IRIS Toxicological Review of Benzo[a]pyrene (External Review Draft)

    EPA Science Inventory

    The IRIS Toxicological Review of Benzo[a]pyrene was released for external peer review in September 2014. The EPA’s Science Advisory Board’s (SAB) Chemical Assessment Advisory Committee (CAAC) conducted a peer review of the scientific basis supporting the benzo[a]pyrene assessmen...

  10. Asymmetric catalysis of epoxide ring-opening reactions.

    PubMed

    Jacobsen, E N

    2000-06-01

    The discovery of the metal salen-catalyzed asymmetric ring-opening (ARO) of epoxides is chronicled. A screening approach was adopted for the identification of catalysts for the addition of TMSN(3) to meso-epoxides, and the chiral (salen)CrN(3) complex was identified as optimal. Kinetic and structural studies served to elucidate the mechanism of catalysis, which involves cooperative activation of both epoxide and azide by two different metal centers. Covalently linked bimetallic complexes were constructed on the basis of this insight, and shown to catalyze the ARO with identical enantioselectivity but 1-2 orders of magnitude greater reactivity than the monomeric analogues. Extraordinarily high selectivity is observed in the kinetic resolution of terminal epoxides using the (salen)CrN(3)/TMSN(3) system. A search for a practical method for the kinetic resolution reaction led to the discovery of highly enantiomer-selective hydrolytic ring-opening using the corresponding (salen)Co(III) catalyst. This system displays extraordinary substrate generality, and allows practical access to enantiopure terminal epoxides on both laboratory and industrial scales.

  11. Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance.

    PubMed

    Luria, Ayala; Bettaieb, Ahmed; Xi, Yannan; Shieh, Guang-Jong; Liu, Hsin-Chen; Inoue, Hiromi; Tsai, Hsing-Ju; Imig, John D; Haj, Fawaz G; Hammock, Bruce D

    2011-05-31

    Visceral obesity has been defined as an important element of the metabolic syndrome and contributes to the development of insulin resistance and cardiovascular disease. Increasing endogenous levels of epoxyeicosatrienoic acids (EETs) are known for their analgesic, antihypertensive, and antiinflammatory effects. The availability of EETs is limited primarily by the soluble epoxide hydrolase (sEH, EPHX2), which metabolizes EETs to their less active diols. In this study, we tested the hypothesis that EETs are involved in glucose regulation and in retarding the development of insulin resistance. To address the role of EETs in regulating glucose homeostasis and insulin signaling, we used mice with targeted gene deletion of sEH (Ephx2-null mice) and a subsequent study with a selective sEH inhibitor. When wild-type mice are fed a high fat diet, insulin resistance develops. However, knockout or inhibition of sEH activity resulted in a significant decrease in plasma glucose. These findings are characterized by enhancement of tyrosyl phosphorylation of the insulin receptor, insulin receptor substrate 1, and their downstream cascade. In addition, pancreatic islets were larger when sEH was disrupted. This effect was associated with an increase in vasculature. These observations were supported by pharmacological inhibition of sEH. These data suggest that an increase in EETs due to sEH-gene knockout leads to an increase in the size of islets and improved insulin signaling and sensitivity.

  12. Soluble epoxide hydrolase inhibition does not prevent cardiac remodeling and dysfunction after aortic constriction in rats and mice.

    PubMed

    Morgan, Lisa A; Olzinski, Alan R; Upson, John J; Zhao, Shufang; Wang, Tao; Eisennagel, Stephen H; Hoang, Bao; Tunstead, James R; Marino, Joseph P; Willette, Robert N; Jucker, Beat M; Behm, David J

    2013-04-01

    Epoxyeicosatrienoic acids, substrates for soluble epoxide hydrolase (sEH), exhibit vasodilatory and antihypertrophic activities. Inhibitors of sEH might therefore hold promise as heart failure therapeutics. We examined the ability of sEH inhibitors GSK2188931 and GSK2256294 to modulate cardiac hypertrophy, fibrosis, and function after transverse aortic constriction (TAC) in rats and mice. GSK2188931 administration was initiated in rats 1 day before TAC, whereas GSK2256294 treatment was initiated in mice 2 weeks after TAC. Four weeks later, cardiovascular function was assessed, plasma was collected for drug and sEH biomarker concentrations, and left ventricle was isolated for messenger RNA and histological analyses. In rats, although GSK2188931 prevented TAC-mediated increases in certain genes associated with hypertrophy and fibrosis (α-skeletal actin and connective tissue growth factor), the compound failed to attenuate TAC-induced increases in left ventricle mass, posterior wall thickness, end-diastolic volume and pressure, and perivascular fibrosis. Similarly, in mice, GSK2256294 did not reverse cardiac remodeling or systolic dysfunction induced by TAC. Both compounds increased the sEH substrate/product (leukotoxin/leukotoxin diol) ratio, indicating sEH inhibition. In summary, sEH inhibition does not prevent cardiac remodeling or dysfunction after TAC. Thus, targeting sEH seems to be insufficient for reducing pressure overload hypertrophy.

  13. Lithium BINOL Phosphate Catalyzed Desymmetrization of meso-Epoxides with Aromatic Thiols

    PubMed Central

    2015-01-01

    A highly enantioselective method for desymmetrization of meso-epoxides using thiols is reported. This is the first example of epoxide activation achieved using metal BINOL phosphates. The reaction has a broad scope in terms of epoxide substrates and aromatic thiol nucleophiles. The resulting β-hydroxyl sulfides are obtained in excellent yield and enantioselectivity. PMID:25317934

  14. 40 CFR 721.10210 - Soybean oil, epoxidized, reaction products with diethanolamine.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Soybean oil, epoxidized, reaction... Significant New Uses for Specific Chemical Substances § 721.10210 Soybean oil, epoxidized, reaction products... chemical substance identified as soybean oil, epoxidized, reaction products with diethanolamine (PMN...

  15. 40 CFR 721.10210 - Soybean oil, epoxidized, reaction products with diethanolamine.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Soybean oil, epoxidized, reaction... Significant New Uses for Specific Chemical Substances § 721.10210 Soybean oil, epoxidized, reaction products... chemical substance identified as soybean oil, epoxidized, reaction products with diethanolamine (PMN...

  16. 40 CFR 721.10210 - Soybean oil, epoxidized, reaction products with diethanolamine.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Soybean oil, epoxidized, reaction... Significant New Uses for Specific Chemical Substances § 721.10210 Soybean oil, epoxidized, reaction products... chemical substance identified as soybean oil, epoxidized, reaction products with diethanolamine (PMN...

  17. 40 CFR 721.10210 - Soybean oil, epoxidized, reaction products with diethanolamine.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Soybean oil, epoxidized, reaction... Significant New Uses for Specific Chemical Substances § 721.10210 Soybean oil, epoxidized, reaction products... chemical substance identified as soybean oil, epoxidized, reaction products with diethanolamine (PMN...

  18. Formation of furan fatty alkyl esters from their bis-epoxide fatty esters

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Epoxidation of vegetable oils and consecutive epoxide ring-opening reaction is a widely investigated path for producing biobased lubricants and polymers. The reaction mechanism and products are considered well-studied and known. In the current study, the reactions of epoxidized alkyl soyate with fou...

  19. Sulfuric acid as a catalyst for ring-opening of biobased bis-epoxides

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vegetable oils can be relatively and easily transformed into bio-based epoxides. Because of this, the acid-catalyzed epoxide ring-opening has been explored for the preparation of bio-based lubricants and polymers. Detailed model studies are carried out only with mono-epoxide made from methyl oleate,...

  20. Carbinolamines and Geminal Diols in Aqueous Environmental Organic Chemistry

    NASA Astrophysics Data System (ADS)

    Urbansky, Edward T.

    2000-12-01

    Organic chemistry textbooks generally treat geminal diols as curiosities--exceptions to the stability of the C=O double bond. However, most aldehydes of environmental significance, to wit, trichloroethanal (chloral), methanal (formaldehyde), ethanal (acetaldehyde), and propanal (propionaldehyde), exhibit this behavior. Carbinolamines (hemiaminals) are usually considered to be unstable reaction intermediates of very short lifetime, despite a considerable volume of literature that suggests otherwise. In aqueous solution, carbinolamines can build up to substantial concentrations and play important roles in kinetics of aldehyde reactions, subsequent to formation of aldehydes as ozonation by-products during drinking water disinfection. A few carbinolamines are isolable, although these are not encountered in environmental systems. In general, the minimal conceptual treatment of these chemical species results from the central theme of synthetic utility that quite reasonably dominates organic chemistry courses and textbooks. Nonetheless, a pedagogical consequence is that students may be left with an incorrect perception that these species are unlikely to be encountered in common situations. Accordingly, it is important for teachers and students of environmental chemistry to remember that aqueous chemistry can be quite different from that observed in less polar and sometimes aprotic organic solvents.

  1. Epoxidation of propylene dimers and isomerization of mixtures obtained

    SciTech Connect

    Dobrev, D.M.; Kurtev, K.S.

    1988-05-10

    Mixtures of hexenes are obtained in the dimerization of propylene on a Ziegler catalyst. By the epoxidation of this mixture by organic peroxides, followed by isomerization of the oxides, C/sub 6/ ketones, which are used as solvents, can be obtained. The hexenes were obtained by dimerization of propylene in the presence of a Ni(C/sub 5/H/sub 7/O/sub 2/)/sub 2/-P(C/sub 6/H/sub 5/)/sub 3/-(C/sub 3/H/sub 5/)/sub 2/AlCl catalytic system. The epoxidation was carried with technical grade isopropylbenzyl hydroperoxide (IPBHP). MoO/sub 2/(C/sub 5/H/sub 7/O/sub 2/)/sub 2/ was used as the catalyst. The relative rates of epoxidation of different isomers contained in the dimeric fraction, with respect to 2-methyl-1-pentene, was determined by means of competing reactions.

  2. Reinforcing polymer composites with epoxide-grafted carbon nanotubes.

    PubMed

    Wang, Shiren; Liang, Richard; Wang, Ben; Zhang, Chuck

    2008-02-27

    An in situ functionalization method was used to graft epoxide onto single-walled carbon nanotubes (SWNTs) and improve the integration of SWNTs into epoxy polymer. The characterization results of Raman, FT-IR and transmission electron microscopy (TEM) validated the successful functionalization with epoxide. These functionalized SWNTs were used to fabricate nanocomposites, resulting in uniform dispersion and strong interfacial bonding. The mechanical test demonstrated that, with only 1 wt% loading of functionalized SWNTs, the tensile strength of nanocomposites was improved by 40%, and Young's modulus by 60%.These results suggested that efficient load transfer has been achieved through epoxide-grafting. This investigation provided an efficient way to improve the interfacial bonding of multifunctional high-performance nanocomposites for lightweight structure material applications.

  3. The impact of individual cytochrome P450 enzymes on oxidative metabolism of benzo[a]pyrene in human livers.

    PubMed

    Šulc, Miroslav; Indra, Radek; Moserová, Michaela; Schmeiser, Heinz H; Frei, Eva; Arlt, Volker M; Stiborová, Marie

    2016-04-01

    Benzo[a]pyrene (BaP) is a human carcinogen that covalently binds to DNA after metabolic activation by cytochrome P450 (CYP) enzymes. In this study human recombinant CYPs (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 3A4, and 3A5) were expressed in Supersomes™ together with their reductases, NADPH:CYP oxidoreductase, epoxide hydrolase and cytochrome b5 , to investigate BaP metabolism. Human CYPs produced up to eight BaP metabolites. Among these, BaP-7,8-dihydrodiol and BaP-9-ol, which are intermediates in BaP-derived DNA adduct formation, were mainly formed by CYP1A1 and 1B1, and to a lesser extent by CYP2C19 and 3A4. BaP-3-ol, a metabolite that is a 'detoxified' product of BaP, was formed by most human CYPs tested, although CYP1A1 and 1B1 produced it the most efficiently. Based on the amounts of the individual BaP metabolites formed by these CYPs and their expression levels in human liver, we determined their contributions to BaP metabolite formation in this organ. Our results indicate that hepatic CYP1A1 and CYP2C19 are most important in the activation of BaP to BaP-7,8-dihydrodiol, whereas CYP2C19, 3A4, and 1A1 are the major enzymes contributing to the formation of BaP-9-ol. BaP-3-ol is predominantly formed by hepatic CYP3A4, while CYP1A1 and 2C19 are less active.

  4. Multicomponent linchpin couplings. Reaction of dithiane anions with terminal epoxides, epichlorohydrin, and vinyl epoxides: efficient, rapid, and stereocontrolled assembly of advanced fragments for complex molecule synthesis.

    PubMed

    Smith, Amos B; Pitram, Suresh M; Boldi, Armen M; Gaunt, Matthew J; Sfouggatakis, Chris; Moser, William H

    2003-11-26

    The development, application, and advantages of a one-flask multicomponent dithiane linchpin coupling protocol, over the more conventional stepwise addition of dithiane anions to electrophiles leading to the rapid, efficient, and stereocontrolled assembly of highly functionalized intermediates for complex molecule synthesis, are described. Competent electrophiles include terminal epoxides, epichlorohydrin, and vinyl epoxides. High chemoselectivity can be achieved with epichlorohydrin and vinyl epoxides. For vinyl epoxides, the steric nature of the dithiane anion is critical; sterically unencumbered dithiane anions afford S(N)2 adducts, whereas encumbered anions lead primarily to SN2' adducts. Mechanistic studies demonstrate that the SN2' process occurs via syn addition to the vinyl epoxide. Integration of the multicomponent tactic with epichlorohydrin and vinyl epoxides permits the higher-order union of four and five components.

  5. Interaction of model aryl- and alkyl-boronic acids and 1,2-diols in aqueous solution.

    PubMed

    Marinaro, William A; Prankerd, Richard; Kinnari, Kaisa; Stella, Valentino J

    2015-04-01

    The goal of this work was to quantitate ester formation between alkyl and aryl boronic acids and vicinal-diols or 1,2-diols in aqueous solution. As used here, 1,2-diols includes polyols with one or more 1,2-diol pairs. Multiple techniques were used including apparent pKa shifts of the boronic acids using UV spectrophotometry (for aryl acids) and titration (for aryl and alkyl acids). Isothermal microcalorimetry was also used, with all reactions being enthalpically favored. For all the acids and 1,2-diols and the conditions studied, evidence only supported 1:1 ester formation. All the esters formed were found to be significantly more acidic, as Lewis acids, by 3-3.5 pKa units than the corresponding nonesterified boronic acid. The equilibrium constants for ester formation increased with increasing number of 1,2-diol pairs but stereochemistry may also play a role as sorbitol with five possible 1,2-diol pairs and five isomers (taking into account the stereochemistry of the alcohol groups) was twice as efficient at ester formation compared with mannitol, also with five possible 1,2-diol pairs but only three isomers. Alkyl boronic acids formed esters to a greater extent than aryl acids. Although some quantitative differences were seen between the various techniques used, rank ordering of the structure/reactivity was consistent. Formulation implications of ester formation between boronic acids and 1,2-diols are discussed.

  6. Effects of inhaled ammonium sulfate on benzo(a)pyrene carcinogenesis. [Hamster

    SciTech Connect

    Godleski, J.J.; Melnicoff, M.J.; Sadri, S.; Garbeil, P.

    1984-01-01

    The effect of inhaled ammonium sulfate on benzo(a)pyrene carcinogenesis in the lungs of Syrian golden hamsters was studied. Exposure to ammonium sulfate at an airborne concentration 20 times average United States ambient levels resulted in a significant depression of benzo(a)pyrene carcinogenesis in the first 6 mo of the study. However, at 2 yr, the termination of the study, there were no differences in cancer incidence between groups receiving benzo(a)pyrene and benzo(a)pyrene plus ammonium sulfate. In addition, at the concentration studied, inhaled ammonium sulfate did not significantly increase the incidence or severity of pneumonitis or pulmonary fibrosis in the hamster. However, this inhalation did increase the incidence of emphysema but not the severity. The decreased incidence of cancer during the first 6 mo of this study in animals receiving both benzo(a)pyrene and ammonium sulfate suggests that interaction between sulfate and benzo(a)pyrene does occur, but is insufficient to afford long-term protection against the development of cancer. No enhancement of carcinogenesis by benzo(a)pyrene occurs in the presence of inhaled sulfate. 31 references, 5 tables, 2 figures.

  7. Toxicological effects of benzo[a]pyrene on DNA methylation of whole genome in ICR mice.

    PubMed

    Zhao, L; Zhang, S; An, X; Tan, W; Pang, D; Ouyang, H

    2015-10-30

    It has been well known that alterations in DNA methylation - an important regulator of gene transcription - lead to cancer. Therefore a change in the level of DNA methylation of whole genome has been considered as a biomarker of carcinogenesis. Previously, a large number of experimental results in genetic toxicology have showed that benzo[a]pyrene could cause DNA mutation and fragmentation. However, there was little to no studies on alterations in DNA methylation of genome directly result from exposure to benzo[a]pyrene. In this paper, possible mechanisms of alterations in whole genomic DNA methylation by benzo[a]pyrene were investigated using ICR mice after benzo[a]pyrene exposure. The blood, liver, pancreas, skin, lung and bladder of ICR mice were removed and checked after a fixed time interval (6 hours) of benzo[a]pyrene exposure, and whole genomic DNA methylation level was determined by high performance liquid chromatography (HPLC). The results exhibited tissue specificity, that is, the level of whole genomic DNA methylation decreases significantly in blood and liver, rather than pancreas, lung, skin and bladder of ICR mice. This study investigated the direct relationship between aberrant DNA methylation level and benzo[a]pyrene exposure, which might be helpful to clarify the toxicological mechanism of benzo[a]pyrene in epigenetic perspectives.

  8. Biodegradation of benzo[a]pyrene by bacterial consortium isolated from mangrove sediment.

    PubMed

    Aziz, A; Agamuthu, P; Alaribe, F O; Fauziah, S H

    2017-03-27

    Benzo[a]pyrene is a high-molecular-weight polycyclic aromatic hydrocarbon highly recalcitrant in nature and thus harms the ecosystem and/or human health. Therefore, its removal from the marine environment is crucial. This research focuses on benzo[a]pyrene degradation by using enriched bacterial isolates in consortium under saline conditions. Bacterial isolates capable of using benzo[a]pyrene as sole source of carbon and energy were isolated from enriched mangrove sediment. These isolates were identified as Ochrobactrum anthropi, Stenotrophomonas acidaminiphila, and Aeromonas salmonicida ss salmonicida. Isolated O. anthropi and S. acidaminiphila degraded 26% and 20%, respectively, of an initial benzo[a]pyrene concentration of 20 mg/L after 8 days of incubation in seawater (28 ppm of NaCl). Meanwhile, the bacterial consortium decomposed 41% of an initial 50 mg/L benzo[a]pyrene concentration after 8 days of incubation in seawater (28 ppm of NaCl). The degradation efficiency of benzo[a]pyrene increased to 54%, when phenanthrene was supplemented as a co-metabolic substrate. The order of biodegradation rate by temperature was 30°C > 25°C > 35°C. Our results suggest that co-metabolism by the consortium could be a promising biodegradation strategy for benzo[a]pyrene in seawater.

  9. Lutein epoxide cycle, more than just a forest tale

    PubMed Central

    Becerril, José María; García-Plazaola, José Ignacio

    2009-01-01

    Two xanthophyll cycles have been described in higher plants: the ubiquitous violaxanthin (V) cycle and the taxonomically restricted lutein epoxide (Lx) cycle. Both involve the light induced de-epoxidation of an epoxidated xanthophyll (V or Lx) and the epoxidation back in the dark. Evolutionary trends and function of the Lx cycle are still not clear. Up to nowadays, significant amounts of Lx have been found in several unrelated taxa, but it is a character almost exclusive from woody plants (except in the case of the parasitic plant Cuscuta reflexa). We have found an exception to this pattern in Cucumis sativus L., which showed high concentrations of Lx. Since Lx cycle was operative in leaves and cotyledons of this species and Lx concentration were much higher in cotyledons than in leaves, we speculate a role for the early stages of development. To date, this species is the first herbaceous non-parasitic species with operative Lx cycle. Since this species can be much more easily and rapidly grown and investigated than woody plants, these data can open new horizons and new lines of investigation for Lx cycle. PMID:19794858

  10. ULTRASOUND-ASSISTED ORGANIC SYNTHESIS: ALCOHOL OXIDATION AND OLEFIN EPOXIDATION

    EPA Science Inventory

    Ultrasound-assisted Organic Synthesis: Alcohol Oxidation and Olefin Epoxidation

    Unnikrishnan R Pillai, Endalkachew Sahle-Demessie , Vasudevan Namboodiri, Quiming Zhao, Juluis Enriquez
    U.S. EPA , 26 W. Martin Luther King Dr. , Cincinnati, OH 45268
    Phone: 513-569-773...

  11. Novel microbial epoxide hydrolases for biohydrolysis of glycidyl derivatives.

    PubMed

    Kotik, Michael; Brichac, Jiri; Kyslík, Pavel

    2005-12-06

    Microbial isolates from biofilters and petroleum-polluted bioremediation sites were screened for the presence of enantioselective epoxide hydrolases active towards tert-butyl glycidyl ether, benzyl glycidyl ether, and allyl glycidyl ether. Out of 270 isolated strains, which comprised bacteria, yeasts, and filamentous fungi, four were selected based on the enantioselectivities of their epoxide hydrolases determined in biotransformation reactions. The enzyme of Aspergillus niger M200 preferentially hydrolyses (S)-tert-butyl glycidyl ether to (S)-3-tert-butoxy-1,2-propanediol with a relatively high enantioselectivity (the enantiomeric ratio E is about 30 at a reaction temperature of 28 degrees C). Epoxide hydrolases of Rhodotorula mucilaginosa M002 and Rhodococcus fascians M022 hydrolyse benzyl glycidyl ether with relatively low enantioselectivities, the former reacting predominantly with the (S)-enantiomer, the latter preferring the (R)-enantiomer. Enzymatic hydrolysis of allyl glycidyl ether by Cryptococcus laurentii M001 proceeds with low enantioselectivity (E=3). (R)-tert-Butyl glycidyl ether with an enantiomeric excess (ee) of over 99%, and (S)-3-tert-butoxy-1,2-propanediol with an ee-value of 86% have been prepared on a gram-scale using whole cells of A. niger M200. An enantiomeric ratio of approximately 100 has been determined under optimised biotransformation conditions with the partially purified epoxide hydrolase from A. niger M200. The regioselectivity of this enzyme was determined to be total for both (S)-tert-butyl glycidyl ether and (R)-tert-butyl glycidyl ether.

  12. DEVELOPMENT OF METABOLICALLY STABLE INHIBITORS OF MAMMALIAN MICROSOMAL EPOXIDE HYDROLASE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The microsomal epoxide hydrolase (mEH) plays a significant role in the metabolism of xenobiotics such as polyaromatic toxicants. Additionally, polymorphism studies have underlined a potential role of this enzyme in relation to a number of diseases, such as emphysema, spontaneous abortion, eclampsia ...

  13. Ring-opening Polymerization of Epoxidized Soybean Oil

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ring opening polymerization of epoxidized soybean oil (ESO) initiated by boron trifluoride diethyl etherate, (BF3•OEt2), in methylene chloride was conducted in an effort to develop useful biodegradable polymers. The resulting polymers (PESO) were characterized using Infrared (IR), differential scan...

  14. Diastereoselective Synthesis of Diketopiperazine Bis-α,β-Epoxides

    PubMed Central

    Ando, Shin; Grote, Amy L.; Koide, Kazunori

    2011-01-01

    Functionalized diketopiperazines (a.k.a. dioxopiperazines) are an important class of molecules in medicinal chemistry and material science. Herein we report a diastereoselective synthesis of diketopiperazine bis-α,β-epoxides via the oxidation of exocyclic olefins. Although six diastereomers may be formed by this approach, only one or two of them were observed. PMID:21250704

  15. Evaluation of the potential carcinogenicity of benzo(a)pyrene. Final report

    SciTech Connect

    Not Available

    1988-06-01

    Benzo(a)pyrene is a probable human carcinogen, classified as weight-of-evidence Group B2 under the EPA Guidelines for Carcinogen Risk Assessment (US EPA, 1986a). Evidence on potential carcinogenicity from animal studies is Sufficient, and the evidence from human studies is Inadequate. The potency factor (F) for benzo(a)pyrene is estimated to be 248/(mg/kg/day)(-1), placing it in potency group 1 according to the CAG's methodology for evaluating potential carcinogens (US EPA, 1986b). Combining the weight-of-evidence group and the potency group, benzo(a)pyrene is assigned a HIGH hazard ranking for the purposes of RQ adjustment.

  16. Experimental and DFT study of cyclodehydration and acetylation of ferrocenyl diols

    NASA Astrophysics Data System (ADS)

    Lapić, Jasmina; Višnjevac, Aleksandar; Cetina, Mario; Djaković, Senka; Vrček, Valerije; Rapić, Vladimir

    2012-07-01

    Racemic ferrocenyl diols, i.e. ferrocenyl(2-hydroxymethylphenyl)methanol (2), ferrocenyl-2-(2-hydroxymethylphenyl)ethanol (7), and ferrocenyl(2-(2-hydroxyethyl)phenyl)methanol (9) have been prepared by reduction of corresponding ketoesters using NaBH4 in a mixture EtOH and Et2O. In the course of these reactions new cyclic ethers 1-ferrocenyl-2-oxaindane (3), 3-ferrocenylisochromane (8), and 1-ferrocenylisochromane (10) have been isolated as side-products. Intramolecular cyclizations of ferrocenyl diols occur in both acidic and neutral medium. Density functional theory (BP86) calculations were used to explain the mechanism of these cyclodehydrations. Acid catalyzed reaction follows the classical SN1 mechanism, whereas the cyclodehydration in neutral medium is described as an SN2 reaction. X-ray diffraction analysis of new cyclic ether products has been performed. Monoacetates 11, 13 and 15 have been obtained in the reaction of ferrocenyl diols 2, 7, and 9, respectively, and acetic anhydride. Stereoselective acylation of racemic diols by vinyl acetate have been catalyzed by various lipases, and the best stereoselectivity has been observed for the diol 2 in the presence of Penicillium camembertii lipase.

  17. The C32 alkane-1,15-diol as a tracer for riverine input in coastal seas

    NASA Astrophysics Data System (ADS)

    Lattaud, Julie; Kim, Jung-Hyun; De Jonge, Cindy; Zell, Claudia; Sinninghe Damsté, Jaap S.; Schouten, Stefan

    2017-04-01

    Long chain alkyl diols are lipids that occur ubiquitously in marine sediments and are used as a proxy for sea surface temperature (SST), using the Long chain Diol Index (LDI), and for upwelling intensity/high nutrient conditions. The distribution of 1,13- and 1,15-diols has been documented in open marine and lacustrine sediments and suspended particulate matter, but rarely in coastal seas receiving a significant riverine, and thus continental organic matter, input. Here we studied the distribution of diols in four shelf seas with major river outflows: the Gulf of Lion, the Kara Sea, the Amazon shelf and the Berau delta, covering a wide range of climate conditions. The relative abundance of the C32 1,15-diol is consistently higher close to the river mouth and particularly in the suspended particulate matter of the rivers suggesting a terrigenous source. This is supported by statistical analysis which points out a significant positive correlation between the C32 1,15-diol and the Branched and Isoprenoid Tetraether index, a proxy reflecting soil and riverine input in marine environments. However, the C32 1,15-diol was not detected in soils and is unlikely to be derived from vegetation, suggesting that the C32 1,15-diol is mainly produced in rivers. This agrees with the observation that it is a dominant diol in most cultivated freshwater eustigmatophyte algae. We, therefore, suggest that the relative abundance of the C32 1,15-diol can potentially be used as a proxy for riverine organic matter input in shelf seas. Our results also show that long chain alkyl diols delivered by rivers can substantially affect LDI-reconstructed SSTs in coastal regions close to river mouths.

  18. Effect of epoxidation level on thermal properties and ionic conductivity of epoxidized natural rubber solid polymer nanocomposite electrolytes

    NASA Astrophysics Data System (ADS)

    Harun, Fatin; Chan, Chin Han; Sim, Lai Har; Winie, Tan; Zainal, Nurul Fatahah Asyqin

    2015-08-01

    Effect of epoxide content on the thermal and conductivity properties of epoxidized natural rubber (ENR) solid polymer nanocomposite electrolytes was investigated. Commercial available epoxidized natural rubber having 25 (ENR25) and 50 mole% (ENR50) epoxide, respectively were incorporated with lithium perchlorate (LiClO4) salt and titanium dioxide (TiO2) nanofiller via solution casting method. The solid polymer nanocomposite electrolytes were characterized by differential scanning calorimetry (DSC) and impedance spectroscopy (IS) for their thermal properties and conductivity, respectively. It was evident that introduction of LiClO4 causes a greater increase in glass transition temperature (Tg) and ionic conductivity of ENR50 as compared to ENR25. Upon addition of TiO2 in ENR/LiClO4 system, a remarkable Tg elevation was observed for both ENRs where ENR50 reveals a more pronounced changes. It is interesting to note that they exhibit different phenomenon in ionic conductivity with TiO2 loading where ENR25 shows enhancement of conductivity while ENR50 shows declination.

  19. Effect of epoxidation level on thermal properties and ionic conductivity of epoxidized natural rubber solid polymer nanocomposite electrolytes

    SciTech Connect

    Harun, Fatin; Chan, Chin Han; Winie, Tan; Sim, Lai Har; Zainal, Nurul Fatahah Asyqin

    2015-08-28

    Effect of epoxide content on the thermal and conductivity properties of epoxidized natural rubber (ENR) solid polymer nanocomposite electrolytes was investigated. Commercial available epoxidized natural rubber having 25 (ENR25) and 50 mole% (ENR50) epoxide, respectively were incorporated with lithium perchlorate (LiClO{sub 4}) salt and titanium dioxide (TiO{sub 2}) nanofiller via solution casting method. The solid polymer nanocomposite electrolytes were characterized by differential scanning calorimetry (DSC) and impedance spectroscopy (IS) for their thermal properties and conductivity, respectively. It was evident that introduction of LiClO{sub 4} causes a greater increase in glass transition temperature (T{sub g}) and ionic conductivity of ENR50 as compared to ENR25. Upon addition of TiO{sub 2} in ENR/LiClO{sub 4} system, a remarkable T{sub g} elevation was observed for both ENRs where ENR50 reveals a more pronounced changes. It is interesting to note that they exhibit different phenomenon in ionic conductivity with TiO{sub 2} loading where ENR25 shows enhancement of conductivity while ENR50 shows declination.

  20. NADPH-, NADH- and cumene hydroperoxide-dependent metabolism of benzo[a]pyrene by pyloric caeca microsomes of the sea star Asterias rubens L. (Echinodermata: Asteroidea).

    PubMed

    den Besten, P J; Lemaire, P; Livingstone, D R

    1994-10-01

    1. Benzo[a]pyrene (BaP) metabolism was studied in microsomes of the pyloric caeca (main digestive tissue and site of P450) of the echinoderm sea star (starfish) Asterias rubens. 2. NADPH-dependent metabolism of BaP produced phenols (36% of total metabolism), quinones (19%), dihydrodiols (25%) and putative protein adducts (20%). 3. NADH-dependent rates of BaP metabolism were approximately twice those found for NADPH-dependent metabolism, and metabolite formation was shifted towards dihydrodiols and quinones. 4. Cumene hydroperoxide (CHP)-dependent rates of BaP metabolism were also higher than NADPH-dependent rates by a factor of six for quinone and putative protein adduct production, and by a factor of four for phenol and dihydrodiol production. 5. Microsomal rates of BaP metabolism in BaP-exposed sea stars appeared to be elevated more in the case of NADPH-dependent than for CHP-dependent metabolism (respectively, increases of 130 and 41%), indicating the induction of forms of P450 preferentially catalysing NADPH-dependent metabolism. 6. 1,1,1-Trichloropropene-2,3-oxide (TCPO) inhibited dihydrodiol formation from both NADPH- and CHP-dependent BaP metabolism, indicating the involvement of epoxide hydratase in BaP metabolism. 7. Incubations of pyloric caeca microsomes with BaP and a superoxide anion radical-generating system (xanthine/xanthine oxidase) produced putative protein adducts but no free metabolites.

  1. Extraction of anthracene and benzo(a)pyrene from soil

    SciTech Connect

    Fowlie, P.J.A.; Bulman, T.L.

    1986-04-01

    Extraction of /sup 14/C labeled benzo(a)pyrene and anthracene from contaminated soil samples by Soxhlet and Polytron techniques was studied in a replicated 2/sup 4/ factorial experiment. Soxhlet extraction gave higher recoveries than Polytron extraction. Percent recoveries from both techniques were greater at a 50 /sup +/g/g contamination level than at 5/sup +/g/g. Pyrolysis of the extracted residue followed by trapping of /sup 14/CO/sub 2/ corroborated the extraction results. In addition, analysis of the residue showed a significant increase in /sup 14/C due to soil sterilization with HgCl/sub 2/ and an interaction effect between PAH and concentration. The effects of PAH, concentration, and HgCl/sub 2/ treatment on extraction and sorption were the same with both extraction methods. 6 references, 3 tables.

  2. Energy and chemicals from the selective electrooxidation of renewable diols by organometallic fuel cells.

    PubMed

    Bellini, Marco; Bevilacqua, Manuela; Filippi, Jonathan; Lavacchi, Alessandro; Marchionni, Andrea; Miller, Hamish A; Oberhauser, Werner; Vizza, Francesco; Annen, Samuel P; Grützmacher, H

    2014-09-01

    Organometallic fuel cells catalyze the selective electrooxidation of renewable diols, simultaneously providing high power densities and chemicals of industrial importance. It is shown that the unique organometallic complex [Rh(OTf)(trop2NH)(PPh3)] employed as molecular active site in an anode of an OMFC selectively oxidizes a number of renewable diols, such as ethylene glycol , 1,2-propanediol (1,2-P), 1,3-propanediol (1,3-P), and 1,4-butanediol (1,4-B) to their corresponding mono-carboxylates. The electrochemical performance of this molecular catalyst is discussed, with the aim to achieve cogeneration of electricity and valuable chemicals in a highly selective electrooxidation from diol precursors.

  3. Base damage, local sequence context and TP53 mutation hotspots: a molecular dynamics study of benzo[a]pyrene induced DNA distortion and mutability

    PubMed Central

    Menzies, Georgina E.; Reed, Simon H.; Brancale, Andrea; Lewis, Paul D.

    2015-01-01

    The mutational pattern for the TP53 tumour suppressor gene in lung tumours differs to other cancer types by having a higher frequency of G:C>T:A transversions. The aetiology of this differing mutation pattern is still unknown. Benzo[a]pyrene,diol epoxide (BPDE) is a potent cigarette smoke carcinogen that forms guanine adducts at TP53 CpG mutation hotspot sites including codons 157, 158, 245, 248 and 273. We performed molecular modelling of BPDE-adducted TP53 duplex sequences to determine the degree of local distortion caused by adducts which could influence the ability of nucleotide excision repair. We show that BPDE adducted codon 157 has greater structural distortion than other TP53 G:C>T:A hotspot sites and that sequence context more distal to adjacent bases must influence local distortion. Using TP53 trinucleotide mutation signatures for lung cancer in smokers and non-smokers we further show that codons 157 and 273 have the highest mutation probability in smokers. Combining this information with adduct structural data we predict that G:C>T:A mutations at codon 157 in lung tumours of smokers are predominantly caused by BPDE. Our results provide insight into how different DNA sequence contexts show variability in DNA distortion at mutagen adduct sites that could compromise DNA repair at well characterized cancer related mutation hotspots. PMID:26400171

  4. IRIS Toxicological Review of Benzo[a]pyrene (Public Comment Draft)

    EPA Science Inventory

    EPA is developing an Integrated Risk Information System (IRIS) assessment of benzo[a]pyrene and has released the draft assessment for public comment and external peer review. When final, the assessment will appear on the IRIS database.

  5. Modeling Epoxidation of Drug-like Molecules with a Deep Machine Learning Network

    PubMed Central

    2015-01-01

    Drug toxicity is frequently caused by electrophilic reactive metabolites that covalently bind to proteins. Epoxides comprise a large class of three-membered cyclic ethers. These molecules are electrophilic and typically highly reactive due to ring tension and polarized carbon–oxygen bonds. Epoxides are metabolites often formed by cytochromes P450 acting on aromatic or double bonds. The specific location on a molecule that undergoes epoxidation is its site of epoxidation (SOE). Identifying a molecule’s SOE can aid in interpreting adverse events related to reactive metabolites and direct modification to prevent epoxidation for safer drugs. This study utilized a database of 702 epoxidation reactions to build a model that accurately predicted sites of epoxidation. The foundation for this model was an algorithm originally designed to model sites of cytochromes P450 metabolism (called XenoSite) that was recently applied to model the intrinsic reactivity of diverse molecules with glutathione. This modeling algorithm systematically and quantitatively summarizes the knowledge from hundreds of epoxidation reactions with a deep convolution network. This network makes predictions at both an atom and molecule level. The final epoxidation model constructed with this approach identified SOEs with 94.9% area under the curve (AUC) performance and separated epoxidized and non-epoxidized molecules with 79.3% AUC. Moreover, within epoxidized molecules, the model separated aromatic or double bond SOEs from all other aromatic or double bonds with AUCs of 92.5% and 95.1%, respectively. Finally, the model separated SOEs from sites of sp2 hydroxylation with 83.2% AUC. Our model is the first of its kind and may be useful for the development of safer drugs. The epoxidation model is available at http://swami.wustl.edu/xenosite. PMID:27162970

  6. Leukotoxin Diols from Ground Corncob Bedding Disrupt Estrous Cyclicity in Rats and Stimulate MCF-7 Breast Cancer Cell Proliferation

    PubMed Central

    Markaverich, Barry M.; Crowley, Jan R.; Alejandro, Mary A.; Shoulars, Kevin; Casajuna, Nancy; Mani, Shaila; Reyna, Andrea; Sharp, John

    2005-01-01

    Previous studies in our laboratory demonstrated that high-performance liquid chromatography (HPLC) analysis of ground corncob bedding extracts characterized two components (peak I and peak II) that disrupted endocrine function in male and female rats and stimulated breast and prostate cancer cell proliferation in vitro and in vivo. The active substances in peak I were identified as an isomeric mixture of 9,12-oxy-10,13-dihydroxyoctadecanoic acid and 10,13-oxy-9,12-dihydroxyoctadecanoic acid, collectively designated tetrahydrofurandiols (THF-diols). Studies presented here describe the purification and identification of the HPLC peak II component as 9,10-dihydroxy-12-octadecenoic acid (leukotoxin diol; LTX-diol), a well-known leukotoxin. A synthetic mixture of LTX-diol and 12,13-dihydroxy-9-octadecenoic acid (isoleukotoxin diol; i-LTX-diol) isomers was separated by HPLC, and each isomer stimulated (p < 0.001) MCF-7 cell proliferation in an equivalent fashion. The LTX-diol isomers failed to compete for [3H]estradiol binding to the estrogen receptor or nuclear type II sites, even though oral administration of very low doses of these compounds (>> 0.8 mg/kg body weight/day) disrupted estrous cyclicity in female rats. The LTX-diols did not disrupt male sexual behavior, suggesting that sex differences exist in response to these endocrine-disruptive agents. PMID:16330350

  7. Crystallization and glass transition of the diols and aminoalcohols, according to DSC data

    NASA Astrophysics Data System (ADS)

    Solonina, I. A.; Rodnikova, M. N.; Kiselev, M. P.; Khoroshilov, A. V.

    2015-05-01

    Overcooling, crystallization, and glass transition of the diol series and aminoalcohols which are the liquids with spatial hydrogen-bond networks, which are the along with the overcooling of dioxane, dimethylsulfoxide, and acetonitrile, which do not have such networks were studied by DSC. The observed phenomena are explained by the stability of H-bond networks. It was concluded that changes in the stability of the networks in and between series of diols and aminoalcohols are due to differences between their molecular structures, the energies of their hydrogen bonds, and their network topologies.

  8. On the origins of kinetic resolution of cyclohexane-1,2-diols through stereoselective acylation by chiral tetrapeptides.

    PubMed

    Shinisha, C B; Sunoj, Raghavan B

    2009-08-06

    The relative energies of cyclohexane-1,2-diols and chiral tetrapeptide (2 (Boc) or 3 (Moc)) complexes calculated using DFT indicate a thermodynamic preference for chiral recognition toward (1R,2R)(e,e)-alpha isomer. The barrier for stereoselective acyl transfer is identified as lower for trans-(1R,2R)-cyclohexane-1,2-diol, leading to the kinetic resolution (KR) of trans-(1S,2S)-cyclohexane-1,2-diol. The prediction is in concert with the reported experiments for trans-diols, while that for hitherto unknown cis-diol demands experimental verification. It is proposed that desymmetrization would enable the resolution of cis-(1R,2S)-2-hydroxycyclohexyl acetate.

  9. Soluble Epoxide Hydrolase Deficiency Inhibits Dextran Sulfate Sodium-induced Colitis and Carcinogenesis in Mice

    PubMed Central

    DONG, HUA; LIAO, JIE; HAMMOCK, BRUCE D.; YANG, GUANG-YU

    2014-01-01

    Soluble epoxide hydrolase (sEH) hydrolyses/inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs) to their corresponding diols, and targeting sEH leads to strong anti-inflammatory effects. In the present study, using a tissue microarray and immunohistochemical approach, a significant increase of sEH expression was identified in ulcerative colitis (UC)-associated dysplasia and adenocarcinoma. The effects of deficiency in the sEH gene were determined on dextran sulfate sodium (DSS) colitis-induced carcinogenesis. The effects of EETs on lipopolysaccharide (LPS)-activated macrophages were analyzed in vitro. With extensive histopathological and immunohistochemical analyses, compared to wild-type mice, sEH−/− mice exhibited a significant decrease in tumor incidence (13/20 vs. 6/19, p<0.05) and a markedly reduced average tumor size (59.62±20.91 mm3 vs. 22.42±11.22 mm3), and a significant number of pre-cancerous dysplasia (3±1.18 vs. 2±0.83, p<0.01). The inflammatory activity, as measured by the extent/proportion of erosion/ulceration/dense lymphoplasmacytosis (called active colitis index) in the colon, was significantly lower in sEH−/− mice (44.7%±24.9% vs. 20.2%±16.2%, p<0.01). The quantitative polymerase chain reaction (qPCR) assays demonstrated significantly low levels of cytokines/chemokines including monocyte chemoattractant protein (MCP-1), inducible nitric oxide synthase (iNOS), vasopressin-activated calcium-mobilizing (VCAM-1), interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). In vitro, LPS-activated macrophages treated with 14,15-EET showed a significant reduction of LPS-triggered IL-1β and TNF-α expression. Eicosanoic acid metabolic profiling revealed a significant increase of the ratios of EETs/dihydroeicosatrienoic acids (DHETs) and epoxyoctadecennoic acid/dihydroxyoctadecenoic acid (EpOMEs/DiHOMEs). These results indicate that sEH plays an important role in the development of colitis and in inducing carcinogenesis

  10. Ovarian expressed microsomal epoxide hydrolase: Role in detoxification of 4-vinylcyclohexene diepoxide and regulation by phosphatidylinositol-3 kinase signaling

    SciTech Connect

    Bhattacharya, Poulomi; Sen, Nivedita; Hoyer, Patricia B.; Keating, Aileen F.

    2012-01-01

    4-vinylcyclohexene diepoxide (VCD) is a metabolite of 4-vinylcyclohexene (VCH) which has the potential to be formed in the ovary through CYP2E1 activity. VCD specifically destroys primordial and small primary follicles in the rodent ovary. Mouse ovaries exposed to VCD demonstrate increased mRNA and protein expression of microsomal epoxide hydrolase (mEH), and an inactive tetrol metabolite (4-(1,2-dihydroxy)ethyl-1,2-dihydroxycyclohexane) can be formed in mouse ovarian follicles, potentially through detoxification action of mEH. In contrast, mEH can bioactivate another ovotoxic chemical, 7,12-dimethylbenz[a]anthracene (DMBA) to a more toxic compound, DMBA-3,4-diol-1,2-epoxide. Thus, the present study evaluated a functional role for mEH during detoxification of VCD. Additionally, because inhibition of the phosphatidyinositol-3 kinase (PI3K) signaling pathway in a previous study protected primordial follicles from VCD-induced destruction, but accelerated DMBA-induced ovotoxicity, a role for PI3K in ovarian mEH regulation was evaluated. Using a post-natal day (PND) 4 Fischer 344 rat whole ovary culture system inhibition of mEH using cyclohexene oxide during VCD exposure resulted in a greater (P < 0.05) loss of primordial and small primary follicles relative to VCD-treated ovaries. Also, relative to controls, meh mRNA was increased (P < 0.05) on day 4 of VCD (30 μM) exposure, followed by increased (P < 0.05) mEH protein after 6 days. Furthermore, inhibition of PI3K signaling increased mEH mRNA and protein expression. Thus, these results support a functional role for mEH in the rat ovary, and demonstrate the involvement of PI3K signaling in regulation of ovarian xenobiotic metabolism by mEH. -- Highlights: ► Ovarian mEH functions to metabolize VCD to a less toxic compound. ► mEH expression is increased in a temporal pattern in response to VCD exposure. ► PI3K signaling is involved in regulation of ovarian mEH expression.

  11. Acute and chronic toxicity toward the bacteria Vibrio fischeri of organic narcotics and epoxides: structural alerts for epoxide excess toxicity.

    PubMed

    Blaschke, Ulrike; Paschke, Albrecht; Rensch, Ines; Schüürmann, Gerrit

    2010-12-20

    The acute and chronic bacterial toxicity of 34 organic compounds comprising 19 baseline narcotics and 15 epoxides has been determined with regard to 30-min bioluminescence and 24-h growth inhibition in terms of EC50 (effective concentration 50%) values employing Vibrio fischeri. For the narcotics, linear regression of log EC50 on log Kow (octanol/water partition coefficient) yields r2 (squared correlation coefficient) and rms (root-mean-square error) values of 0.95 and 0.44 (30-min), and 0.94 and 0.34 (24-h), respectively. Employing the resultant baseline narcosis models, toxicity enhancement (Te) values were derived as a ratio of narcosis-predicted over experimental EC50 for the epoxides. For seven aliphatic epoxides, log Te was below 1 in both assays, indicating narcosis-range toxicity with regard to 30-min bioluminescence and 24-h growth inhibition. Concerning eight nonaliphatic epoxides, log Te values up to 2.4 were observed, reflecting excess toxicity through an enhanced electrophilic reactivity of the compounds. Here, however, the intercorrelation between both assays was very low (r2 = 0.09). The results are discussed in terms of electronic substituent effects activating an SN2-type epoxide reaction with nucleophilic protein sites and side-chain activation offering alternative electrophile-nucleophile reaction routes at side-chain sites, leading to respective structural alerts as indicators of excess toxicity. Surprisingly, 30-min bioluminescence appears to be slightly more sensitive to chemical stress than 24-h growth, which holds both for baseline narcotics and for most of the epoxides. This is also reflected by effective narcosis doses 50%, ED50, of 7.1 mmol/kg (30-min) and 7.7 mmol/kg (24-h) estimated from narcosis theory. Keeping in mind the different end points (bioluminescence vs growth) involved, this finding demonstrates that chronic toxicity is not always more sensitive than acute toxicity, calling for analyses with regard to further respective

  12. Styrene-butadiene rubber/halloysite nanotubes composites modified by epoxidized natural rubber.

    PubMed

    Jia, Zhixin; Luo, Yuanfang; Yang, Shuyan; Du, Mingliang; Guo, Baochun; Jia, Demin

    2011-12-01

    The reinforcement effects of halloysite nanotubes on styrene-butadiene rubber and the modification effect of epoxidized natural rubber on styrene-butadiene rubber/halloysite nanotubes composites were studied. The structure, morphology and properties of styrene-butadiene rubber/halloysite nanotubes composites before and after the incorporation of epoxidized natural rubber were investigated. The results indicated that epoxidized natural rubber can promote the dispersion and orientation of halloysite nanotubes in styrene-butadiene rubber matrix at nanoscale and strengthen interfacial combination between halloysite nanotubes and styrene-butadiene rubber by the formation of covalent bonds and hydrogen bonds between epoxidized natural rubber and halloysite nanotubes. Consequently epoxidized natural rubber can improve the mechanical properties of the vulcanizates of styrene-butadiene rubber/halloysite nanotubes composites. Besides epoxidized natural rubber can decrease the rolling resistance of the vulcanizates and increase the wet grip property of the vulcanizates.

  13. The generation of oxidation products of benzo(a)pyrene by lipid peroxidation: a study using gamma-irradiation

    SciTech Connect

    Gower, J.D.; Wills, E.D.

    1984-09-01

    The role which active oxygen and radicals generated by the peroxidation of unsaturated fatty acids could play in the oxidation of benzo(a)pyrene has been studied using gamma-irradiation. Irradiation of benzo(a)pyrene resulted in the formation of benzo(a)pyrene 1,6-, 3,6- and 6,12-quinones and other more polar products which were analysed by h.p.l.c. OH. radicals are believed to be involved in this oxidation. The presence of polyunsaturated fatty acids and polyunsaturated lipids stimulated the formation of benzo(a)pyrene products following gamma-irradiation. Oxidation of benzo(a)pyrene also occurred over a period of days in the presence of autoxidising mackerel oil. The rate of benzo(a)pyrene oxidation was related to the extent of lipid peroxidation as determined by malonaldehyde formation. Malonaldehyde production as a result of peroxidising lipids was inhibited by benzo(a)pyrene which suggested that benzo(a)pyrene reacted directly with lipid peroxy radicals or hydroperoxides generated in the process of lipid peroxidation. These results demonstrate that oxidation products of the peroxidation of lipids and fatty acids are able to react directly with benzo(a)pyrene to form products including benzo(a)pyrene quinones without the presence of enzymes such as the cytochrome P-450 mixed function oxidase system and prostaglandin synthetase. It is possible that benzo(a)pyrene may be activated by these types of reactions in vivo or in vitro when benzo(a)pyrene is in contact with polyunsaturated lipids in foodstuffs or the intestinal lumen and peroxidation of unsaturated fats may play an important role in human carcinogenesis.

  14. Direct Epoxidation of Propylene over Stabilized Cu+ Surface Sites on Ti Modified Cu2O

    DOE PAGES

    Yang, X.; Kattel, S.; Xiong, K.; ...

    2015-07-17

    Direct propylene epoxidation by O2 is a challenging reaction because of the strong tendency for complete combustion. Results from the current study demonstrate the feasibility to tune the epoxidation selectivity by generating highly dispersed and stabilized Cu+ active sites in a TiCuOx mixed oxide. The TiCuOx surface anchors the key surface intermediate, oxametallacycle, leading to higher selectivity for epoxidation of propylene.

  15. Isolation and characterization of Xenopus soluble epoxide hydrolase.

    PubMed

    Purba, Endang R; Oguro, Ami; Imaoka, Susumu

    2014-07-01

    Soluble epoxide hydrolase (sEH) contributes to cell growth, but the contribution of sEH to embryonic development is not well understood. In this study, Xenopus sEH cDNA was isolated from embryos of Xenopus laevis. The Xenopus sEH was expressed in Escherichia coli and was purified. The epoxide hydrolase and phosphatase activities of purified sEH were investigated. The Xenopus sEH did not show phosphatase activity toward 4-methylumbelliferyl phosphate or several lysophosphatidic acids although it had EH activity. The amino acid sequence of Xenopus sEH was compared with that reported previously. We found amino acid substitutions of the 29th Thr to Asn and the 146th Arg to His and prepared a sEH mutant (N29T/H146R), designed as mutant 1. Neither wild-type sEH nor mutant 1 had phosphatase activity. Additional substitution of the 11th Gly with Asp was found by comparison with human sEH which has phosphatase activity, but the Xenopus sEH mutant G11D prepared as mutant 2 did not have phosphatase activity. The epoxide hydrolase activity of sEH seemed to be similar to that of human sEH, while Xenopus sEH did not have phosphatase activity toward several substrates that human sEH metabolizes.

  16. Probing the interactions between boronic acids and cis-diol-containing biomolecules by affinity capillary electrophoresis.

    PubMed

    Lü, Chenchen; Li, Hengye; Wang, Heye; Liu, Zhen

    2013-02-19

    The affinity of boronic acids to cis-diol-containing biomolecules has found wide applications in many fields, such as sensing, separation, drug delivery, and functional materials. A sound understanding of the binding interactions will greatly facilitate exquisite applications of this chemistry. Although a few analytical tools have been available for the characterization of the interactions, these techniques are associated with some apparent drawbacks, so they are only applicable to a limited range of boronic acids and cis-diol-containing biomolecules. Therefore, a widely applicable method is still greatly needed. In this work, an affinity capillary electrophoresis (ACE) method was established and validated to probe the interactions between boronic acids and cis-diol-containing biomolecules. The method was proven to be applicable to almost all types of cis-diol-containing biomolecules and boronic acids. Based on this method, a quantitative, comparative study on the interactions between 14 boronic acids that have important potentials for application with 5 typical monosaccharides of biological importance was carried out. The findings provided new insights into boronate affinity interactions, particularly the relationship between the binding strength with the molecular structures of the binding species. Besides, effects of pH and temperature on the binding strength were also investigated. This method exhibited several significant advantages, including (1) possibility of simultaneous study of multiple interactions, (2) low requirement on the purity of the binding species, (3) wide applicability, and (4) high accuracy and precision.

  17. 40 CFR 721.10662 - Acetaldehyde, substituted-, reaction products with 2-butyne-1, 4-diol (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT SIGNIFICANT NEW USES OF CHEMICAL SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10662 Acetaldehyde, substituted-, reaction products with 2-butyne-1, 4-diol (generic). (a) Chemical substance and significant new...

  18. Efficient hydrogenation of biomass-derived cyclic di-esters to 1,2-diols.

    PubMed

    Balaraman, Ekambaram; Fogler, Eran; Milstein, David

    2012-01-28

    The unprecedented homogeneous hydrogenation of cyclic di-esters, in particular biomass-derived glycolide and lactide, to the corresponding 1,2-diols is catalyzed by Ru(II) PNN (1) and Ru(II) CNN (2) pincer complexes under mild hydrogen pressure and (in the case of 1) neutral conditions. No racemization was observed when a chiral di-ester was used.

  19. Nickel-Catalyzed Regiodivergent Opening of Epoxides with Aryl Halides: Co-Catalysis Controls Regioselectivity

    PubMed Central

    Zhao, Yang; Weix, Daniel J.

    2014-01-01

    Epoxides are versatile intermediates in organic synthesis, but have rarely been employed in cross-coupling reactions. We report that bipyridine-ligated nickel can mediate the addition of functionalized aryl halides, a vinyl halide, and a vinyl triflate to epoxides under reducing conditions. For terminal epoxides, the regioselectivity of the reaction depends upon the co-catalyst employed. Iodide co-catalysis results in opening at the less hindered position via an iodohydrin intermediate. Titanocene co-catalysis results in opening at the more hindered position, presumably via TiIII-mediated radical generation. 1,2-Disubstituted epoxides are opened under both conditions to form predominantly the trans product. PMID:24341892

  20. Direct observation of enantiomer discrimination of epoxides by chiral salen complexes using ENDOR.

    PubMed

    Fallis, Ian A; Murphy, Damien M; Willock, David J; Tucker, Richard J; Farley, Robert D; Jenkins, Robert; Strevens, Robert R

    2004-12-08

    Electron nuclear double resonance (ENDOR) spectroscopy was used to investigate the weak enantioselective binding between chiral salen complexes [VO(1)] ((R,R)- and (S,S)-vanadyl N,N'-bis(3,5-di-tert-butylsalcylidene)-1,2-cyclohexanediamine) and chiral epoxides (e.g., (R)-/(S)-propylene epoxide, 5) in frozen (10 K) solution. Differences in epoxide binding by enatiomers of [VO(1)] was evidenced by changes to the 1H epoxide derived peaks in the ENDOR spectra, such that (R,R)-[VO(1)] + (R)-5 and (R,R)-[VO(1)] + (S)-5 yield noticeably different spectra. These changes were assigned to the small structural differences between the diastereomeric metal-epoxide adducts. Simulation of the spectra revealed differences in the VO...1Hepoxide distances for the diastereomeric pairs, which was confirmed by a complementary set of density functional theory (DFT) calculations. While the epoxide molecule is very weakly coordinated, ENDOR measurements of the racemic complex in racemic epoxide nevertheless indicated the preferential coordination of the (R)-5 to (R,R)-[VO(1)] (likewise (S)-(5) to (S,S)-[VO(1)]), which is favored over the binding of (S)-5 epoxide to (R,R)-[VO(1)] (and likewise (R)-5 epoxide to (S,S)-[VO(1)]). This demonstrates the unique power of the ENDOR technique to resolve weak chiral interactions for which EPR spectroscopy alone lacks sufficient resolution.

  1. Species differences in biliary excretion of benzo(a)pyrene

    SciTech Connect

    Weyand, E.H.; Bevan, D.R.

    1986-05-01

    Biliary excretion of benzo(a)pyrene (B(a)P) was investigated in rats, hamsters, and guinea pigs following intratracheal administration. (/sup 3/H)-B(a)P, in amounts of approximately 150 ng or 350 ..mu..g, was instilled into lungs and amounts of radioactivity excreted in bile were monitored for six hrs following administration. Differences in biliary excretion of (/sup 3/H)-B(a)P and/or metabolites among species were observed at low doses but not at high doses. Six hours after instillation of a low dose of B(a)P, 70, 54, and 62% of the dose was excreted in bile of rats, hamsters, and guinea pigs, respectively. Upon administration of the higher dose of B(a)P, approximately 50% of the dose was excreted in bile in six hrs by all species. Thus, rats and guinea pigs exhibit differences in biliary excretion of low and high doses of B(a)P whereas hamsters do not. Profiles of phase II metabolites in rats and hamsters were similar at both low and high doses, with the majority of metabolites being glucuronides and thioether conjugates. However, differences in relative amounts of these conjugates were observed between the two doses, with a shift towards a greater proportion of glucuronides at the higher dose. Metabolites in bile from guinea pigs were primarily thioether conjugates, which accounted for 88% of metabolites at the low dose and 95% at the high dose.

  2. Persistence of urinary excretion products of benzo(a)pyrene

    SciTech Connect

    Uziel, M.; Haglund, R.; White, D.A.

    1988-01-01

    Persistence of DNA-adducts has been observed in a variety of experimental circumstances and has been suggested as one potential mechanism for explaining the long-term delay before expression of proliferative disease. In this concept, a stable DNA-adduct, which is a remnant of a prior exposure in a nondividing cell, would not express the genotoxic effect until the cells were stimulated to divide, and thus explain the long-term delay in expression of cancer. An alternative view of the observation of persistent DNA-adducts, described in this communication, is the continuing replenishment of DNA adducts by formation and turnover of these adducts from exposure to a constant supply of the ultimate carcinogenic species derived from a prior exposure. It is of interest to note that virtually all experiments where ''persistent'' adducts have been observed have been high dose exposures. During the course of experiments designed to develop improved methods for detection of DNA adducts and related derivatives derived from polynuclear aromatic hydrocarbons (PAH), we observed that there was a continuous excretion of urinary derivatives of the injected benzo(a)pyrene (BaP) beyond the initial burst of detoxification. This report describes the time dependent distribution of those derivatives in blood, urine, feces, and at the site of injection. 11 refs., 5 figs., 4 tabs.

  3. Biosynthesis, isolation, and NMR analysis of leukotriene A epoxides: substrate chirality as a determinant of the cis or trans epoxide configuration[S

    PubMed Central

    Jin, Jing; Zheng, Yuxiang; Boeglin, William E.; Brash, Alan R.

    2013-01-01

    Leukotriene (LT)A4 and closely related allylic epoxides are pivotal intermediates in lipoxygenase (LOX) pathways to bioactive lipid mediators that include the leukotrienes, lipoxins, eoxins, resolvins, and protectins. Although the structure and stereochemistry of the 5-LOX product LTA4 is established through comparison to synthetic standards, this is the exception, and none of these highly unstable epoxides has been analyzed in detail from enzymatic synthesis. Understanding of the mechanistic basis of the cis or trans epoxide configuration is also limited. To address these issues, we developed methods involving biphasic reaction conditions for the LOX-catalyzed synthesis of LTA epoxides in quantities sufficient for NMR analysis. As proof of concept, human 15-LOX-1 was shown to convert 15S-hydroperoxy-eicosatetraenoic acid (15S-HPETE) to the LTA analog 14S,15S-trans-epoxy-eicosa-5Z,8Z,10E,12E-tetraenoate, confirming the proposed structure of eoxin A4. Using this methodology we then showed that recombinant Arabidopsis AtLOX1, an arachidonate 5-LOX, converts 5S-HPETE to the trans epoxide LTA4 and converts 5R-HPETE to the cis epoxide 5-epi-LTA4, establishing substrate chirality as a determinant of the cis or trans epoxide configuration. The results are reconciled with a mechanism based on a dual role of the LOX nonheme iron in LTA epoxide biosynthesis, providing a rational basis for understanding the stereochemistry of LTA epoxide intermediates in LOX-catalyzed transformations. PMID:23242647

  4. Effect of CYP2E1 gene deletion in mice on expression of microsomal epoxide hydrolase in response to VCD exposure.

    PubMed

    Keating, Aileen F; Rajapaksa, Kathila S; Sipes, I Glenn; Hoyer, Patricia B

    2008-10-01

    Females are born with a finite number of primordial follicles. 4-Vinylcyclohexene diepoxide (VCD) is a metabolite formed by epoxidation of 4-vinylcyclohexene (VCH) via its two monoepoxides 1,2- and 7,8-4-vinylcyclohexene monoepoxide (VCM). VCD specifically destroys small preantral (primordial and small primary) follicles in the rodent ovary. The phase I enzyme, cytochrome P450 isoform 2E1 (CYP2E1) is involved in ovarian metabolism of VCM to VCD. Further, microsomal epoxide hydrolase (mEH) can detoxify VCD to an inactive tetrol (4-(1,2-dihydroxy)ethyl-1,2-dihydroxycyclohexane). This study evaluated the effects of VCD-induced ovotoxicity on mEH in CYP2E1+/+ and -/- mice (129S(1)/SvImJ background strain) using a postnatal day 4 mouse whole ovary culture system. The hypothesis of our study is that there is a relationship between CYP2E1 and mEH gene expression in the mouse ovary. Relative to control, VCD exposure caused follicle loss (p < 0.05) in ovaries from both genotypes; however, after 15 days, this loss was greater (p < 0.05) in CYP2E1+/+ ovaries. In a time course (2-15 days), relative to control, VCD (5 microM) caused an increase (p < 0.05) in mEH mRNA by 0.5-fold (day 10) and 1.84-fold (day 15) in CYP2E1-/- but not +/+ ovaries. 7,12-Dimethylbenz[a]anthracene (DMBA) also destroys ovarian follicles but, unlike VCD, is bioactivated by mEH to an ovotoxic 3,4-diol-1,2-epoxide metabolite. Incubation of ovaries in increasing concentrations of DMBA (0.5-1 microM, 15 days) resulted in greater (p < 0.05) follicle loss in CYP2E1-/-, relative to +/+ ovaries. With greater mEH (CYP2E1-/-), increased follicle loss with DMBA (bioactivation) and decreased follicle loss with VCD (detoxification) support that ovarian expression of CYP2E1 and mEH may be linked.

  5. Topological, functional, and dynamic properties of the protein interaction networks rewired by benzo(a)pyrene.

    PubMed

    Ba, Qian; Li, Junyang; Huang, Chao; Li, Jingquan; Chu, Ruiai; Wu, Yongning; Wang, Hui

    2015-03-01

    Benzo(a)pyrene is a common environmental and foodborne pollutant that has been identified as a human carcinogen. Although the carcinogenicity of benzo(a)pyrene has been extensively reported, its precise molecular mechanisms and the influence on system-level protein networks are not well understood. To investigate the system-level influence of benzo(a)pyrene on protein interactions and regulatory networks, a benzo(a)pyrene-rewired protein interaction network was constructed based on 769 key proteins derived from more than 500 literature reports. The protein interaction network rewired by benzo(a)pyrene was a scale-free, highly-connected biological system. Ten modules were identified, and 25 signaling pathways were enriched, most of which belong to the human diseases category, especially cancer and infectious disease. In addition, two lung-specific and two liver-specific pathways were identified. Three pathways were specific in short and medium-term networks (<48h), and five pathways were enriched only in the medium-term network (6h-48h). Finally, the expression of linker genes in the network was validated by Western blotting. These findings establish the overall, tissue- and time-specific benzo(a)pyrene-rewired protein interaction networks and provide insights into the biological effects and molecular mechanisms of action of benzo(a)pyrene.

  6. The impact of individual cytochrome P450 enzymes on oxidative metabolism of benzo[a]pyrene in human livers

    PubMed Central

    Šulc, Miroslav; Indra, Radek; Moserová, Michaela; Schmeiser, Heinz H.; Frei, Eva; Arlt, Volker M.; White, P.

    2016-01-01

    Benzo[a]pyrene (BaP) is a human carcinogen that covalently binds to DNA after metabolic activation by cytochrome P450 (CYP) enzymes. In this study human recombinant CYPs (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 3A4, and 3A5) were expressed in Supersomes™ together with their reductases, NADPH:CYP oxidoreductase, epoxide hydrolase and cytochrome b5, to investigate BaP metabolism. Human CYPs produced up to eight BaP metabolites. Among these, BaP‐7,8‐dihydrodiol and BaP‐9‐ol, which are intermediates in BaP‐derived DNA adduct formation, were mainly formed by CYP1A1 and 1B1, and to a lesser extent by CYP2C19 and 3A4. BaP‐3‐ol, a metabolite that is a ‘detoxified’ product of BaP, was formed by most human CYPs tested, although CYP1A1 and 1B1 produced it the most efficiently. Based on the amounts of the individual BaP metabolites formed by these CYPs and their expression levels in human liver, we determined their contributions to BaP metabolite formation in this organ. Our results indicate that hepatic CYP1A1 and CYP2C19 are most important in the activation of BaP to BaP‐7,8‐dihydrodiol, whereas CYP2C19, 3A4, and 1A1 are the major enzymes contributing to the formation of BaP‐9‐ol. BaP‐3‐ol is predominantly formed by hepatic CYP3A4, while CYP1A1 and 2C19 are less active. Environ. Mol. Mutagen. 57:229–235, 2016. © 2016 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc. PMID:26919089

  7. DNA adduct formation in precision-cut rat liver and lung slices exposed to benzo[a]pyrene.

    PubMed

    Harrigan, Jeanine A; Vezina, Chad M; McGarrigle, Barbara P; Ersing, Noreen; Box, Harold C; Maccubbin, Alexander E; Olson, James R

    2004-02-01

    Chemical-DNA adducts provide an integrated measure of exposure, absorption, bioactivation, detoxification, and DNA repair following exposure to a genotoxic agent. Benzo[a]pyrene (BaP), a prototypical polycyclic aromatic hydrocarbon (PAH), can be bioactivated by cytochrome P-450s (CYPs) and epoxide hydrolase to genotoxic metabolites which form covalent adducts with DNA. In this study, we utilized precision-cut rat liver and lung slices exposed to BaP to investigate tissue-specific differences in chemical absorption and formation of DNA adducts. To investigate the contribution of bioactivating CYPs (such as CYP1A1 and CYP1B1) on the formation of BaP-DNA adducts, animals were also pretreated in vivo with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) prior to in vitro incubation of tissue slices with BaP. Furthermore, the tissue distribution of BaP and BaP-DNA adduct levels from in vivo studies were compared with those from the in vitro tissue slice experiments. The results indicate a time- and concentration-dependent increase in tissue-associated BaP following exposure of rat liver and lung tissue slices to BaP in vitro, with generally higher levels of BaP retained in lung tissue. Furthermore, rat liver and lung slices metabolized BaP to reactive intermediates that formed covalent adducts with DNA. Total BaP-DNA adducts increased with concentration and incubation time. Adduct levels (fmol adduct/microg DNA) in lung slices were greater than liver at all doses. Liver slices contained one major and two minor adducts, while lung slices contained two major and 3 minor adducts. The tissue-specific qualitative profile of these adducts in tissue slices was similar to that observed from in vivo studies, further validating the use of this model. Pretreatment of animals with TCDD prior to in vitro incubation with BaP potentiated the levels of DNA adduct formation. TCDD pretreatment altered the adduct distribution in lung but not in liver slices. Together, the results

  8. Screening for DNA adducts in ovarian follicles exposed to benzo[a]pyrene and cigarette smoke condensate using liquid chromatography-tandem mass spectrometry.

    PubMed

    Yao, Chunhe; Foster, Warren G; Sadeu, Jean C; Siddique, Shabana; Zhu, Jiping; Feng, Yong-Lai

    2017-01-01

    A rapid mass spectrometric method was applied to non-targeted screening of DNA adducts in follicular cells (granulosa cells and theca cells) from isolated ovarian follicles that were exposed in-vitro to benzo[a]pyrene (B[a]P) and cigarette smoke condensate (CSC) for 13days of culture. The method employed a constant neutral loss (CNL) scan to identify chromatographic peaks associated to a neutral loss of deoxyribose moiety of DNA nucleosides. These peaks were subsequently analyzed by a product ion scan in tandem mass spectrometry to elucidate structures of DNA adducts. The identification was further confirmed through synthesis of proposed DNA adducts where possible. Three DNA adducts, benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide-dG (BPDE-dG), phenanthrene 1,2-quinone-dG (PheQ-dG) and B[a]P-7,8-quinone-dG (BPQ-dG) were identified in the follicular cells from isolated ovarian follicles exposed to B[a]P. Along with these three, an additional DNA adduct, 4-aminobiphenyl-dG, was identified in the follicular cells from isolated ovarian follicles exposed to CSC. The amounts of the identified DNA adducts in follicular cells increased in a dose-dependent manner for both B[a]P (0, 1.5, 5, 15 and 45ng/mL) and CSC (0, 30, 60, 90 and 130μg/mL). The results revealed that B[a]P-related DNA adducts were the major adducts in the ovarian follicular cells exposed to CSC. The results also revealed that two oxidative biomarkers, 8-hydroxy-2-deoxy guanosine (8-OH-dG) and 8-isoprostane (8-IsoP), in both B[a]P-exposed and CSC-exposed ovarian follicles had strong correlations with the three DNA adducts, BPDE-dG, BPQ-dG and PheQ-dG. A pathway to describe formation of DNA adducts was proposed based on the DNA adducts observed.

  9. Carcinogenicity of airborne fine particulate benzo(a)pyrene: an appraisal of the evidence and the need for control.

    PubMed Central

    Perera, F

    1981-01-01

    Benzo(a)pyrene(BaP) originating from fossil fuel and other organic combustion processes is largely adsorbed on fine particulate and hence is a widespread atmospheric pollutant. Available emissions and air quality data are based on the total weight of particulate matter without reference to size and give little information on trends and concentrations of fine particulate BaP. Greater reliance on coal, synfuels and diesel fuel for energy production and transportation will significantly increase ambient levels of BaP. Because of the particulate size, BaP is substantially deposited in the lower lung and readily eluted into surrounding tissue. After elution in the lung, BaP is metabolically activated to its electrophilic, carcinogenic from by a complex enzyme system whose activity is increased by prior exposure to air pollutants, cigarette smoke and certain drugs. The resultant diol epoxide metabolite has been shown to bind covalently with the DNA of the lung. In experimental animals, BaP is a potent initiating carcinogen whose action is enhanced by sulfur dioxide, promoting agents and carrier fine particles. The effect of small, divided doses of BaP has been shown to be greater than that of a single high dose; no threshold has been established. Epidemiological studies show that mixtures containing BaP (such as urban air, industrial emissions and cigarette smoke) are carcinogenic and may interact synergistically. Occupational studies indicate that the action of BaP-containing mixtures is enhanced in the presence of SO2. However, quantitative risk assessment for BaP is precluded by problems in extrapolating to the general population from small-scale animal studies; uncertainties in findings of epidemiology; and imprecise exposure data. Existing stationary and mobile controls preferentially remove coarse particulate matter and are inefficient collectors of the particulate BaP. In the current absence of health and environmental standards for BaP, there is little incentive

  10. Formation of Epoxide Derived SOA and Gas-Phase Acids through Aqueous Aerosol Processing in the Southeastern United States during SOAS

    NASA Astrophysics Data System (ADS)

    Skog, K.; Teng, A.; Nguyen, T. B.; Nguyen, K.; Suda, S. R.; Xu, L.; Isaacman-VanWertz, G. A.; Feiner, P. A.; Zhang, L.; Olson, K. F.; Koss, A.; Wild, R. J.; St Clair, J.; Crounse, J.; Baumann, K.; Wennberg, P. O.; Petters, M.; Carlton, A. M. G.; Ng, N. L.; Brune, W. H.; De Gouw, J. A.; Goldstein, A. H.; Brown, S. S.; Edgerton, E. S.; McNeill, V. F.; Keutsch, F. N.

    2015-12-01

    Secondary organic aerosol (SOA) contributes to climate and adversely affects human health, but the formation of SOA is poorly understood. Recent studies have proposed that aqueous processing of water-soluble compounds like glyoxal and IEPOX can help explain the abundance of organosulfates, higher oxygen to carbon ratios, and SOA abundance. A comprehensive set of ambient gas- and aerosol-phase data was collected during June and July of 2013 as part of the Southern Oxidant and Aerosol Study (SOAS) at the Centreville, AL ground site. Both gas-phase photochemistry and aqueous-phase aerosol chemistry were modeled using a zero-dimensional box model. While it has been suggested that glyoxal can contribute to aqueous aerosol through the formation of acids and higher-molecular-weight compounds, it did not produce enhanced aqSOA concentrations. Instead, processing of aqueous glyoxal resulted in the production of gas-phase acids. AqSOA consisted almost entirely of epoxide processing products, mainly from the processing of IEPOX to methyl tetrol, and the organosulfate. In addition, the pinene oxides contributed to the formation of aqSOA, through the formation of organosulfates, diols, and organonitrates. These data are consistent with the abundance of IEPOX and pinene oxide organonitrate derived SOA seen at this site.

  11. Sources and proxy potential of long chain alkyl diols in lacustrine environments

    NASA Astrophysics Data System (ADS)

    Rampen, Sebastiaan W.; Datema, Mariska; Rodrigo-Gámiz, Marta; Schouten, Stefan; Reichart, Gert-Jan; Sinninghe Damsté, Jaap S.

    2014-11-01

    Long chain 1,13- and 1,15-alkyl diols form the base of a number of recently proposed proxies used for climate reconstruction. However, the sources of these lipids and environmental controls on their distribution are still poorly constrained. We have analyzed the long chain alkyl diol (LCD) composition of cultures of ten eustigmatophyte species, with three species from different families grown at various temperatures, to identify the effect of species composition and growth temperature on the LCD distribution. The results were compared with the LCD distribution of sixty-two lake surface sediments, and with previously reported LCD distributions from marine environments. The different families within the Eustigmatophyceae show distinct LCD patterns, with the freshwater family Eustigmataceae most closely resembling LCD distributions in both marine and lake environments. Unlike the other two eustigmatophyte families analyzed (Monodopsidaceae and Goniochloridaceae), C28 and C30 1,13-alkyl diols and C30 and C32 1,15-alkyl diols are all relatively abundant in the family Eustigmataceae, while the mono-unsaturated C32 1,15-alkyl diol was below detection limit. In contrast to the marine environment, LCD distributions in lakes did not show a clear relationship with temperature. The Long chain Diol Index (LDI), a proxy previously proposed for sea surface temperature reconstruction, showed a relatively weak correlation (R2 = 0.33) with mean annual air temperature used as an approximation for annual mean surface temperature of the lakes. A much-improved correlation (R2 = 0.74, p-value <0.001) was observed applying a multiple linear regression analysis between LCD distributions and lake temperatures reconstructed using branched tetraether lipid distributions. The obtained regression model provides good estimates of temperatures for cultures of the family Eustigmataceae, suggesting that algae belonging to this family have an important role as a source for LCDs in lacustrine

  12. Towards a General Understanding of Carbonyl‐Stabilised Ammonium Ylide‐Mediated Epoxidation Reactions

    PubMed Central

    Novacek, Johanna; Roiser, Lukas; Zielke, Katharina

    2016-01-01

    Abstract The key factors for carbonyl‐stabilised ammonium ylide‐mediated epoxidation reactions were systematically investigated by experimental and computational means and the hereby obtained energy profiles provide explanations for the observed experimental results. In addition, we were able to identify the first tertiary amine‐based chiral auxiliary that allows for high enantioselectivities and high yields for such epoxidation reactions. PMID:27381752

  13. 40 CFR 721.7210 - Epoxidized copolymer of phenol and substituted phenol.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Epoxidized copolymer of phenol and substituted phenol. 721.7210 Section 721.7210 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.7210 Epoxidized copolymer of phenol and substituted phenol. (a)...

  14. Inversion of product selectivity in an enzyme-inspired metallosupramolecular tweezer catalyzed epoxidation reaction†

    PubMed Central

    Ulmann, Pirmin A.; Braunschweig, Adam B.; Lee, One-Sun; Wiester, Michael J.

    2014-01-01

    This study describes a heteroligated, hemilabile PtII–P,S tweezer coordination complex that combines a chiral Jacobsen–Katsuki MnIII-salen epoxidation catalyst with an amidopyridine receptor, which leads to an inversion of the major epoxide product compared to catalysts without a recognition group. PMID:20448966

  15. Asymmetric Epoxidation: A Twinned Laboratory and Molecular Modeling Experiment for Upper-Level Organic Chemistry Students

    ERIC Educational Resources Information Center

    Hii, King Kuok; Rzepa, Henry S.; Smith, Edward H.

    2015-01-01

    The coupling of a student experiment involving the preparation and use of a catalyst for the asymmetric epoxidation of an alkene with computational simulations of various properties of the resulting epoxide is set out in the form of a software toolbox from which students select appropriate components. At the core of these are the computational…

  16. Evaluation of Benzo[a]pyrene in Food from China by High-Performance Liquid Chromatography-Fluorescence Detection

    PubMed Central

    Chen, Yong-Hong; Xia, En-Qin; Xu, Xiang-Rong; Li, Sha; Ling, Wen-Hua; Wu, Shan; Deng, Gui-Fang; Zou, Zhi-Fei; Zhou, Jing; Li, Hua-Bin

    2012-01-01

    The occurrence and levels of benzo[a]pyrene in various heat-treated foods from China were evaluated by high-performance liquid chromatography-fluorescence detection. In a total of 119 samples, 105 were found to contain benzo[a]pyrene at levels of 0.03 to 19.75 µg/kg. The benzo[a]pyrene contents in 12 animal source foods were higher than the Chinese maximum permissible level in food (5 µg/kg) and the highest level was 19.75 µg/kg, nearly four times the maximum permissible level. The results revealed a widespread carinogenic public health risk from benzo[a]pyrene in heat-treated foods. The highest benzo[a]pyrene levels were found in animal source samples such as charcoal-grilled and smoked meats, especially pork, beef and sausage, while trace levels of benzo[a]pyrene were present in grain food. Charcoal-grilled vegetables were found to also contain certain levels of benzo[a]pyrene. This study provided new information on benzo[a]pyrene content of a variety of heat-treated foods from China. PMID:23202838

  17. Evaluation of benzo[a]pyrene in food from China by high-performance liquid chromatography-fluorescence detection.

    PubMed

    Chen, Yong-Hong; Xia, En-Qin; Xu, Xiang-Rong; Li, Sha; Ling, Wen-Hua; Wu, Shan; Deng, Gui-Fang; Zou, Zhi-Fei; Zhou, Jing; Li, Hua-Bin

    2012-11-14

    The occurrence and levels of benzo[a]pyrene in various heat-treated foods from China were evaluated by high-performance liquid chromatography-fluorescence detection. In a total of 119 samples, 105 were found to contain benzo[a]pyrene at levels of 0.03 to 19.75 μg/kg. The benzo[a]pyrene contents in 12 animal source foods were higher than the Chinese maximum permissible level in food (5 μg/kg) and the highest level was 19.75 μg/kg, nearly four times the maximum permissible level. The results revealed a widespread carinogenic public health risk from benzo[a]pyrene in heat-treated foods. The highest benzo[a]pyrene levels were found in animal source samples such as charcoal-grilled and smoked meats, especially pork, beef and sausage, while trace levels of benzo[a]pyrene were present in grain food. Charcoal-grilled vegetables were found to also contain certain levels of benzo[a]pyrene. This study provided new information on benzo[a]pyrene content of a variety of heat-treated foods from China.

  18. Structure-Potency Relationships for Epoxides in Allergic Contact Dermatitis.

    PubMed

    Roberts, David W; Aptula, Aynur; Api, Anne Marie

    2017-02-20

    Epoxides are known or proposed to be involved in skin sensitization in various ways. Some are encountered directly, and others have been shown to be formed abiotically and metabolically from various unsaturated chemicals. They can react as SN2 electrophiles. To date no quantitative mechanistic models (QMMs) are known for skin sensitization potency of this subcategory of SN2 electrophiles. Here we have considered the reaction mechanistic chemistry of epoxides and combined published experimental kinetic data (rate constants k for reaction with a cysteine-based peptide) together with calculated hydrophobicity data (logP) to derive a QMM correlating potency in the local lymph node assay (LLNA), expressed as EC3, with a relative alkylation index (RAI, calculated as logk + 0.4 logP). The QMM equation, pEC3 = 2.42(±0.26) RAI + 4.04 (±0.25), n = 9, R(2) = 0.928, R(2)(adj) = 0.917, F = 90, s = 0.18, fits the data well, with one positive outlier. The outlier can be rationalized by its exhibiting an alert for oxidation of an amine moiety to give, in this case, the highly reactive glycidaldehyde. The epoxide QMM predicts the potency of a nonepoxide SN2 electrophile (predicted EC3, 0.48%; observed EC3, 0.5%), which suggests that it could form the basis for a more general H-polar SN2 QMM that could be a valuable tool in skin sensitization risk assessment for this quite extensive and structurally diverse reaction mechanistic domain.

  19. Fluorescence line-narrowing spectrometry: Application to the study of benzo(a)pyrene metabolic pathways

    SciTech Connect

    Zamzow, D.S.

    1988-07-01

    The application of fluorescence line-narrowing spectrometry (FLNS) to the study of the pathways involved in the metabolic activation of the environmental contaminant and carcinogen benzo(a)pyrene is described. Fluorescence line-narrowed (FLN) spectra of benzo(a)pyrene, 6-methyl-benzo(a)pyrene, and a number of benzo(a)pyrene-nucleoside adducts are presented. The activation of benzo(a)pyrene (BP) to metabolites capable of binding to DNA in the in vitro horseradish peroxidase-catalyzed binding of BP to DNA, the DNA from mice exposed (in vivo) to BP, and the DNA from fish exposed (in vivo) to a number of polycyclic aromatic hydrocarbons, including BP, is investigated by the analysis of the FLN spectra obtained from these samples. 65 refs., 22 figs., 4 tabs.

  20. Inhibition of aryl hydrocarbon receptor transactivation and DNA adduct formation by CYP1 isoform-selective metabolic deactivation of benzo[a]pyrene

    SciTech Connect

    Endo, Kaori; Uno, Shigeyuki; Seki, Taiichiro; Ariga, Toyohiko; Kusumi, Yoshiaki; Mitsumata, Masako; Yamada, Sachiko; Makishima, Makoto

    2008-07-15

    Benzo[a]pyrene (BaP), a polyaromatic hydrocarbon produced by the combustion of cigarettes and coke ovens, is a known procarcinogen. BaP activates the aryl hydrocarbon receptor (AhR) and induces the expression of a battery of genes, including CYP1A1, which metabolize BaP to toxic compounds. The possible role of CYP1 enzymes in mediating BaP detoxification or metabolic activation remains to be elucidated. In this study, we assessed the effects of CYP1 enzymes (CYP1A1, CYP1A2 and CYP1B1) on BaP-induced AhR transactivation and DNA adduct formation in HEK293 cells and HepG2 cells. Transfection of CYP1A1 and CYP1B1, but not CYP1A2, suppressed BaP-induced activation of AhR. Expression of CYP1A1 and CYP1A2, but not CYP1B1, inhibited DNA adduct formation in BaP-treated HepG2 cells. These results indicate that CYP1A1 and CYP1B1 play a role in deactivation of BaP on AhR and that CYP1A1 and CYP1A2 are involved in BaP detoxification by suppressing DNA adduct formation. BaP treatment did not induce DNA adduct formation in HEK293 cells, even after transfection of CYP1 enzymes, suggesting that expression of CYP1 enzymes is not sufficient for DNA adduct formation. Lower expression of epoxide hydrolase and higher expression of glutathione S-transferase P1 (GSTP1) and GSTM1/M2 were observed in HEK293 cells compared with HepG2 cells. Dynamic expression of CYP1A1, CYP1A2 and CYP1B1 along with expression of other enzymes such as epoxide hydrolase and phase II enzymes may determine the detoxification or metabolic activation of BaP.

  1. Characterization of the binding strengths between boronic acids and cis-diol-containing biomolecules by affinity capillary electrophoresis.

    PubMed

    Lü, Chenchen; Liu, Zhen

    2015-01-01

    The affinity of boronic acids toward cis-diol-containing biomolecules has found wide applications in many fields, such as sensing, separation, drug delivery, and functional materials. A sound understanding of the binding interactions will greatly facilitate exquisite applications of this chemistry. Traditional techniques are associated with some apparent drawbacks, so they are only applicable to a limited range of boronic acids and cis-diol-containing biomolecules. This chapter describes an affinity capillary electrophoresis (ACE) method for the characterization of the binding strengths between boronic acids and cis-diol-containing biomolecules. As compared with existing approaches, such as (11)B NMR, the ACE method exhibits several significant advantages: (1) possibility of simultaneous study of multiple interactions, (2) low requirement on the purity of the binding species, (3) widely applicable to almost all types of cis-diol-containing compounds and boronic acids, and (4) high accuracy and precision.

  2. Detoxication of the 2',3'-epoxide metabolites of allylbenzene and estragole. Conjugation with glutathione.

    PubMed

    Luo, G; Guenthner, T M

    1994-01-01

    The enzymatic detoxication in vitro of the 2',3'-epoxide derivatives of allylbenzene and estragole was examined, and the relative rates of enzymatic glutathione conjugation and epoxide hydrolysis were compared with those for styrene 1',2'-oxide. HPLC was used to determine the amounts of dihydrodiol and glutathione conjugate metabolites formed by cell extracts from several sources. Although some differences among species were observed, in general, the rates of epoxide inactivation by both pathways are similar. We conclude that one explanation for the apparent lack of genotoxicity of these allylic epoxides in vivo may be their rapid metabolic inactivation by both glutathione S-transferases and epoxide hydrolases, which occur to approximately equal degrees in vitro.

  3. Direct epoxidation in Candida antarctica lipase B studied by experiment and theory.

    PubMed

    Svedendahl, Maria; Carlqvist, Peter; Branneby, Cecilia; Allnér, Olof; Frise, Anton; Hult, Karl; Berglund, Per; Brinck, Tore

    2008-10-13

    Candida antarctica lipase B (CALB) is a promiscuous serine hydrolase that, besides its native function, catalyzes different side reactions, such as direct epoxidation. A single-point mutant of CALB demonstrated a direct epoxidation reaction mechanism for the epoxidation of alpha,beta-unsaturated aldehydes by hydrogen peroxide in aqueous and organic solution. Mutation of the catalytically active Ser105 to alanine made the previously assumed indirect epoxidation reaction mechanism impossible. Gibbs free energies, activation parameters, and substrate selectivities were determined both computationally and experimentally. The energetics and mechanism for the direct epoxidation in CALB Ser105Ala were investigated by density functional theory calculations, and it was demonstrated that the reaction proceeds through a two step-mechanism with formation of an oxyanionic intermediate. The active-site residue His224 functions as a general acid-base catalyst with support from Asp187. Oxyanion stabilization is facilitated by two hydrogen bonds from Thr40.

  4. Photoaffinity labeling of opioid receptor with morphine-7,8-oxide (morphine epoxide)

    SciTech Connect

    Takayanagi, I.; Shibata, R.; Miyata, N.; Hirobe, M.

    1982-05-01

    The opioid receptor mediating inhibitory action of morphine in the electrically stimulated guinea pig ileum was irreversibly photoinactivated by morphine epoxide (3 X 10(-6) M). Morphine epoxide (up to 3 X 10(-5) M) did not influence the responses of rat vas deferens (epsilon-receptor) or rabbit vas deferens (kappa-receptor) to electrical stimulation. Effective concentrations of morphine epoxide were much lower in the guinea pig ileum (mu-receptor) than in the mouse vas deference (delta-receptor). The inhibitory action of (Met)-enkephalin on the twitch responses of the rat vas deferens and mouse vas deferens to electrical stimulation were not influenced after irradiation in the presence of morphine epoxide (3 X 10(-6) M). Therefore, morphine epoxide is probably a useful probe for photoaffinity labeling of the mu-receptor in vitro.

  5. Catalysts for CO2/epoxide ring-opening copolymerization

    PubMed Central

    Trott, G.; Saini, P. K.; Williams, C. K.

    2016-01-01

    This article summarizes and reviews recent progress in the development of catalysts for the ring-opening copolymerization of carbon dioxide and epoxides. The copolymerization is an interesting method to add value to carbon dioxide, including from waste sources, and to reduce pollution associated with commodity polymer manufacture. The selection of the catalyst is of critical importance to control the composition, properties and applications of the resultant polymers. This review highlights and exemplifies some key recent findings and hypotheses, in particular using examples drawn from our own research. PMID:26755758

  6. Topological, functional, and dynamic properties of the protein interaction networks rewired by benzo(a)pyrene

    SciTech Connect

    Ba, Qian; Li, Junyang; Huang, Chao; Li, Jingquan; Chu, Ruiai; Wu, Yongning; Wang, Hui

    2015-03-01

    Benzo(a)pyrene is a common environmental and foodborne pollutant that has been identified as a human carcinogen. Although the carcinogenicity of benzo(a)pyrene has been extensively reported, its precise molecular mechanisms and the influence on system-level protein networks are not well understood. To investigate the system-level influence of benzo(a)pyrene on protein interactions and regulatory networks, a benzo(a)pyrene-rewired protein interaction network was constructed based on 769 key proteins derived from more than 500 literature reports. The protein interaction network rewired by benzo(a)pyrene was a scale-free, highly-connected biological system. Ten modules were identified, and 25 signaling pathways were enriched, most of which belong to the human diseases category, especially cancer and infectious disease. In addition, two lung-specific and two liver-specific pathways were identified. Three pathways were specific in short and medium-term networks (< 48 h), and five pathways were enriched only in the medium-term network (6 h–48 h). Finally, the expression of linker genes in the network was validated by Western blotting. These findings establish the overall, tissue- and time-specific benzo(a)pyrene-rewired protein interaction networks and provide insights into the biological effects and molecular mechanisms of action of benzo(a)pyrene. - Highlights: • Benzo(a)pyrene induced scale-free, highly-connected protein interaction networks. • 25 signaling pathways were enriched through modular analysis. • Tissue- and time-specific pathways were identified.

  7. Dietary cadmium and benzo(a)pyrene increased intestinal metallothionein expression in the fish Fundulus heteroclitus

    SciTech Connect

    Roesijadi, Guritno; Rezvankhah, Saeid; Perez-Matus, Alejandro; Mitelberg, A.; Torruellas, K.; Van Veld, P. A.

    2008-10-17

    To test the effect of dietary exposure to cadmium and benzo(a)pyrene on induction of metallothionein mRNA in the Fundulus heteroclitus, fish were individually fed a pelletized gel food containing cadmium, benzo(a)pyrene, or a combination of the two over a period of seven days, then analyzed for relative levels of metallothionein mRNA in the intestine, liver, and gill using real-time RT-qPCR. An initial experiment with only cadmium exposure showed an apparent 10-fold induction in the intestine, but no induction in liver or gill. Ingestion of contaminated pellets varied in individual fish, and because it was possible to monitor individual ingestion rates with our method, individual cadmium doses were estimated from the amount of ingested cadmium. When the levels of metallothionein mRNA were related to the dose to each fish, a linear dose-response relationship was observed for the intestine, but not the other organs, which showed no induction. In a second experiment, dose was controlled by placing the entire daily cadmium dose into a single contaminated pellet that was fed first (thereby, effectively controlling the effect of variable ingestion rates), and the interaction between cadmium and benzo(a)pyrene was also investigated. The intestine was again the primary organ for metallothionein induction by cadmium, with a 20-fold increase in metallothionein mRNA over control levels. When benzo(a)pyrene was administered together with cadmium, induction of metallothionein was potentiated by the presence of benzo(a)pyrene, with the main effect seen in the intestine, where already high levels of induction by cadmium alone increased by 1.74-fold when benzo(a)pyrene was present.

  8. On the existence of a scattering pre-peak in the mono-ols and diols

    NASA Astrophysics Data System (ADS)

    Poz̆ar, Martina; Perera, Aurélien

    2017-03-01

    We report a computer simulation study of four 1,n-diols (1,2-ethanediol to 1,5-pentanediol). It is found that increasing the alkyl chain length increases chain-like clusters, and correspondingly the structure factor pre-peak, just like for mono-ols. However, our calculated X-ray intensities show that the pre-peak tends to diminish to a shoulder, in contrast with mono-ols where the pre-peak becomes more apparent with increasing alkyl chain. We attribute this contrasting finding to the fact that the alkyl chain is constrained between the two hydroxyl groups in linear diols, while they are free in linear mono-ols.

  9. Analysis of benzo(a)pyrene in airborne particulates by gas chromatography

    NASA Technical Reports Server (NTRS)

    Luedecke, E.

    1976-01-01

    A routine method was developed to measure benzo(a)pyrene in airborne particulates. Samples were collected on a filter and the organic portion was extracted with cyclohexane. The polynuclear hydrocarbon (PNHC) fraction was separated from the aliphatics by column chromatography. An internal standard was added to the extract and a portion of it was injected into a gas chromatograph. Although the gas chromatographic method has often been reported in the literature, satisfactory separation of benzo(a)pyrene and benzo(e)pyrene has not been achieved. With the introduction of a nematic liquid crystal as the stationary phase good separation is now possible.

  10. Studies on the mechanism of activation of microsomal benzo(a)pyrene hydroxylation by flavonoids

    SciTech Connect

    Huang, M.T.; Chang, R.L.; Fortner, J.G.; Conney, A.H.

    1981-07-10

    7,8-benzoflavone or flavone stimulates the hydroxylation of benzo(a)pyrene by liver microsomes from rabbit, hamster, and man severalfold. Little or no activation by the flavonoid occurs in liver microsomes from rat or guinea pig. Intact liver microsomal membranes are not required for the activation. Although 7,8-benzoflavone does not stimulate the NADPH-dependent reduction of cytochrome c by rabbit liver microsomes, the NADPH-dependent reduction of cytochrome P-450 is stimulated by 7,8-benzoflavone either in the presence or absence of benzo(a)pyrene. Purified cytochrome P-450 reductase causes an increase in the rate of benzo(a)pyrene hydroxylation in cholate-solubilized liver microsomes from all of the species studied. In cholate-solubilized microsomes from all of the species susceptible for flavonoid activation, 7,8-benzoflavone decreases the K/sub m/ for cytochrome P-450 reductase and increases the V/sub max/ for benzo(a)pyrene hydroxylation. With cholate-solubilized human liver microsomes, the K/sub m/ for cytochrome P-450 reductase in the absence of flavonoids was about 3-fold higher than in the presence of 100 ..mu..M 7,8-benzoflavone or 500 ..mu..M flavone. 7,8-benzoflavone and flavone stimulate the hydroxylation of benzo(a)pyrene in liver microsomes at least in part by enhancing the interaction between cytochrome P-450 and cytochrome P-450 reductase. 7,8-benzoflavone does not influence the K/sub m/ for benzo(a)pyrene or NADPH, but the V/sub max/ values for benzo(a)pyrene are increased from 2.5- to 4-fold in rabbit liver microsomes. 7,8-benzoflavone does not stimulate the cumene hydroperoxide-dependent hydroxylation of benzo(a)pyrene by rabbit liver microsomes. In two partially purified cytochrome P-450 fractions from rabbit liver microsomes, flavone has a specific stimulatory effect on one of the reconstituted partially purified cytochrome P-450 systems, but an inhibitory effect on the other.

  11. Evaluation of the genotoxic potential of 3-monochloropropane-1,2-diol (3-MCPD) and its metabolites, glycidol and beta-chlorolactic acid, using the single cell gel/comet assay.

    PubMed

    El Ramy, R; Ould Elhkim, M; Lezmi, S; Poul, J M

    2007-01-01

    3-monochloropropane-1,2-diol (3-MCPD) is a member of a group of chemicals known as chloropropanols. It is found in many foods and food ingredients as a result of food processing. 3-MCPD is regarded as a rat carcinogen known to induce Leydig-cell and mammary gland tumours in males and kidney tumours in both genders. The aim of our study was to clarify the possible involvement of genotoxic mechanisms in 3-MCPD induced carcinogenicity at the target organ level. For that purpose, we evaluated DNA damages in selected target (kidneys and testes) and non-target (blood leukocytes, liver and bone marrow) male rat organs by the in vivo alkaline single cell gel electrophoresis (comet) assay, 3 and 24 h after 3-MCPD oral administration to Sprague-Dawley and Fisher 344 adult rats. 3-MCPD may be metabolised to a genotoxic intermediate, glycidol, whereas the predominant urinary metabolite in rats following 3-MCPD administration is beta-chlorolactic acid. Therefore, we also studied the DNA damaging effects of 3-MCPD and its metabolites, glycidol and beta-chlorolactic acid, in the in vitro comet assay on CHO cells. Our results show the absence of genotoxic potential of 3-MCPD in vivo in the target as well as in the non-target organs. Glycidol, the epoxide metabolite, induced DNA damages in CHO cells. beta-Chlorolactic acid, the main metabolite of 3-MCPD in rats, was shown to be devoid of DNA-damaging effects in vitro in mammalian cells.

  12. Pyrolytic transformations of the vinyl monoethers of diols in the presence of alkalis

    SciTech Connect

    Trofimov, B.A.; Oparina, L.A.; Parshina, L.N.; Lavrov, V.I.; Grigorenko, V.I.; Zhumabekov, M.K.

    1987-01-10

    The alkaline pyrolysis of the vinyl monoethers of diols takes place at 170-250/sup 0/C and is accompanied by cycloacetalization (ethylene glycol, 1,3-propanediol), by processes involving cleavage of the C-O bonds (diethylene glycol, 1,4-butanediol), and also by the release of hydrogen, carbon dioxide, methane, ethane, acetylene, potassium hydroxide, sodium hydroxide, and lithium hydroxide can result in explosion as a result of the vigorous and exothermic release of gas.

  13. Long chain 1,13- and 1,15-diols as a potential proxy for palaeotemperature reconstruction

    NASA Astrophysics Data System (ADS)

    Rampen, Sebastiaan W.; Willmott, Verónica; Kim, Jung-Hyun; Uliana, Eleonora; Mollenhauer, Gesine; Schefuß, Enno; Sinninghe Damsté, Jaap S.; Schouten, Stefan

    2012-05-01

    Although commonly reported in marine and freshwater environments, little is known about the biological sources of long chain alkyl 1,13- and 1,15-diols, and factors controlling their distributions. Here we analyzed the occurrence and distribution of these lipids in a comprehensive set of marine surface sediments and compare their distributions with environmental conditions like sea surface temperature (SST), salinity and nutrient concentrations. Fractional abundances of the C28 1,13-, C30 1,13- and C30 1,15-diols show a strong correlation with SST and based on these results, we propose the Long chain Diol Index (LDI), which expresses the C30 1,15-diol abundance relative to those of C28 1,13-, C30 1,13- and C30 1,15-diols. The LDI shows a strong linear correlation with SST (LDI = 0.033 × SST + 0.095; R2 = 0.969, n = 162) over a temperature range of -3 to 27 °C. Long chain diol distributions in sediments from the South Atlantic close to the Congo River outflow (West Africa) provided a 43 kyr LDI SST record. This record reflects several known climatic events and shows similarities with an alkenone-derived SST record obtained using the same suite of sediments, both in trend and in terms of absolute SST. This confirms the potential of the LDI as a proxy for palaeo-SST reconstruction.

  14. Functional thermoplastics from linear diols and diisocyanates produced entirely from renewable lipid sources.

    PubMed

    Hojabri, Leila; Kong, Xiaohua; Narine, Suresh S

    2010-04-12

    An unsaturated terminal diol, 1,18-octadec-9-endiol (ODEDO), and a saturated terminal diol, 1,9-nonanediol (NDO), were synthesized from oleic acid. The feasibility of utilizing these new diols for the production of thermoplastic polyurethanes (TPUs) was demonstrated by reacting them with a fatty acid-derived diisocyanate, 1,7-heptamethylene diisocyanate (HPMDI), and a commercially available petroleum-derived diisocyanate, 1,6-hexamethylene diisocyanate (HDI). One type of phase structure was obtained for both TPUs in this study, owing to the similarity between the ODEDO and NDO molecular structure. In addition, double yielding behavior (observed for the first time in polyurethanes) was observed in the stress-strain curves for both TPU systems. Compared to the TPUs prepared from HDI, the totally biobased TPUs (ODEDO-NDO-HPDMI) demonstrated comparable properties within acceptable tolerances, considering the impacts on physical properties due to the odd-even effect introduced by the HPDMI. This work is the first that establishes the production of linear thermoplastic polyurethanes entirely from lipid feedstock.

  15. Oxidation of terminal diols using an oxoammonium salt: a systematic study.

    PubMed

    Miller, Shelli A; Bobbitt, James M; Leadbeater, Nicholas E

    2017-03-28

    A systematic study of the oxidation of a range of terminal diols is reported, employing the oxoammonium salt 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (4-NHAc-TEMPO(+) BF4(-)) as the oxidant. For substrates bearing a hydrocarbon chain of seven carbon atoms or more, the sole product is the dialdehyde. A series of post-oxidation reactions have been performed showing that the product mixture resulting from the oxidation step can be taken on directly to a subsequent transformation. For diols containing four to six carbon atoms, the lactone product is the major product upon oxidation. In the case of 1,2-ethanediol and 1,3-propanediol, when using a 1 : 0.5 stoichiometric ratio of substrate to oxidant, the corresponding monoaldehyde is formed which reacts rapidly with further diol to yield the acetal product. This is of particular synthetic value given both the difficulty of their preparation using other approaches and also their potential application in further reaction chemistry.

  16. Studies directed toward the exploitation of vicinal diols in the synthesis of (+)-nebivolol intermediates

    PubMed Central

    Devi, Runjun

    2017-01-01

    While the exploitation of the Sharpless asymmetric dihydroxylation as the source of chirality in the synthesis of acyclic molecules and saturated heterocycles has been tremendous, its synthetic utility toward chiral benzo-annulated heterocycles is relatively limited. Thus, in the search for wider applications of Sharpless asymmetric dihydroxylation-derived diols for the synthesis of benzo-annulated heterocycles, we report herein our studies in the asymmetric synthesis of (R)-1-((R)-6-fluorochroman-2-yl)ethane-1,2-diol, (R)-1-((S)-6-fluorochroman-2-yl)ethane-1,2-diol and (S)-6-fluoro-2-((R)-oxiran-2-yl)chroman, which have been used as late-stage intermediates for the asymmetric synthesis of the antihypertensive drug (S,R,R,R)-nebivolol. Noteworthy is that a large number of racemic and asymmetric syntheses of nebivolol and their intermediates have been described in the literature, however, the Sharpless asymmetric dihydroxylation has never been employed as the sole source of chirality for this purpose.

  17. Zirconium-doped magnetic microspheres for the selective enrichment of cis-diol-containing ribonucleosides.

    PubMed

    Fan, Hua; Chen, Peihong; Wang, Chaozhan; Wei, Yinmao

    2016-05-27

    Zirconium-doped magnetic microspheres (Zr-Fe3O4) for the selective enrichment of cis-diol-containing biomolecules were easily synthesized via a one-step hydrothermal method. Characterization of the microspheres revealed that zirconium was successfully doped into the lattice of Fe3O4 at a doping level of 4.0 at%. Zr-Fe3O4 possessed good magnetic properties and high specificity towards cis-diol molecules, as shown using 28 compounds. For ribonucleosides, the adsorbent not only has favorable anti-interferential abilities but also has a high adsorption capacity up to 159.4μmol/g. As an example of a real application, four ribonucleosides in urine were efficiently enriched and detected via magnetic solid-phase extraction coupled with high-performance liquid chromatography. Under the optimized extraction conditions, the detection limits were determined to be between 0.005 and 0.017μg/mL, and the linearities ranged from 0.02 to 5.00μg/mL (R≥0.996) for these analytes. The accuracy of the analytical method was examined by studying the relative recoveries of the analytes in real urine samples, with recoveries varying from 77.8% to 119.6% (RSDs<10.6%, n=6). The results indicate that Zr-Fe3O4 is a suitable adsorbent for the analysis of cis-diol-containing biomolecules in practical applications.

  18. Hydrogen-bonded layered structures in two bis(tert-butyldimethylsilyloxy)-substituted cyclic diol derivatives.

    PubMed

    Foces-Foces, C; López-Rodríguez, M

    2008-12-01

    2,6-Bis(tert-butyldimethylsilyloxy)-9-oxabicyclo[3.3.1]nonane-3,7-diol, C(20)H(42)O(5)Si(2), (I), and 4,8-bis(tert-butyldimethylsilyloxy)-2,6-dioxatricyclo[3.3.1(3,7)]decane-1,3-diol, C(20)H(40)O(6)Si(2), (II), form layered structures that differ in the way the molecules are connected within each layer. The endocyclic O atom common to both structures plays an active role in the hydrogen-bonding network, whereas the second oxygen bridge in (II) does not participate in any interaction. This work reports the first structural analysis of two bis(tert-butyldimethylsilyloxy)-substituted cyclic diol derivatives and provides insight into the influence of small changes in the molecular structure on the supramolecular aggregation. The unbalanced hydrogen-bond acceptor/donor ratio, greater in (II) than in (I), does not result in the inclusion of water molecules in the structure.

  19. Peripheral FAAH and soluble epoxide hydrolase inhibitors are synergistically antinociceptive.

    PubMed

    Sasso, Oscar; Wagner, Karen; Morisseau, Christophe; Inceoglu, Bora; Hammock, Bruce D; Piomelli, Daniele

    2015-07-01

    We need better medicines to control acute and chronic pain. Fatty acid amide hydrolase (FAAH) and soluble epoxide hydrolase (sEH) catalyze the deactivating hydrolysis of two classes of bioactive lipid mediators--fatty acid ethanolamides (FAEs) and epoxidized fatty acids (EpFAs), respectively--which are biogenetically distinct but share the ability to attenuate pain responses and inflammation. In these experiments, we evaluated the antihyperalgesic activity of small-molecule inhibitors of FAAH and sEH, administered alone or in combination, in two pain models: carrageenan-induced hyperalgesia in mice and streptozocin-induced allodynia in rats. When administered separately, the sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU) and the peripherally restricted FAAH inhibitor URB937 were highly active in the two models. The combination TPPU plus URB937 was markedly synergistic, as assessed using isobolographic analyses. The results of these experiments reveal the existence of a possible functional crosstalk between FAEs and EpFAs in regulating pain responses. Additionally, the results suggest that combinations of sEH and FAAH inhibitors might be exploited therapeutically to achieve greater analgesic efficacy.

  20. Integrated process and dual-function catalyst for olefin epoxidation

    DOEpatents

    Zhou, Bing; Rueter, Michael

    2003-01-01

    The invention discloses a dual-functional catalyst composition and an integrated process for production of olefin epoxides including propylene oxide by catalytic reaction of hydrogen peroxide from hydrogen and oxygen with olefin feeds such as propylene. The epoxides and hydrogen peroxide are preferably produced simultaneously in situ. The dual-functional catalyst comprises noble metal crystallites with dimensions on the nanometer scale (on the order of <1 nm to 10 nm), specially dispersed on titanium silicalite substrate particles. The dual functional catalyst catalyzes both the direct reaction of hydrogen and oxygen to generate hydrogen peroxide intermediate on the noble metal catalyst surface and the reaction of the hydrogen peroxide intermediate with the propylene feed to generate propylene oxide product. Combining both these functions in a single catalyst provides a very efficient integrated process operable below the flammability limits of hydrogen and highly selective for the production of hydrogen peroxide to produce olefin oxides such as propylene oxide without formation of undesired co-products.

  1. Inhibition of the binding of 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene to DNA in mouse skin epidermis by 1-ethynylpyrene.

    PubMed

    Viaje, A; Lu, J Y; Hopkins, N E; Nettikumara, A N; DiGiovanni, J; Alworth, W L; Slaga, T J

    1990-07-01

    The effects of 1-ethynylpyrene (EP), 1-vinylpyrene (VP) and 2-ethynlnaphthalene (EN) on the covalent binding of 7,12-dimethylbenz[a]anthracene (DMBA) and of benzo[a]-pyrene (B[a]P) to the epidermal DNA in mouse skin were investigated. When applied topically, 5 min before an initiating dose of 10 nmol DMBA or of 200 nmol B[a]P, EP was an effective inhibitor of the formation of the covalent complexes of these procarcinogenic polycyclic aromatic hydrocarbons (PAHs) with the epidermal DNA. VP, applied under the same conditions, was a significantly less effective inhibitor of the binding of DMBA to DNA and showed even weaker inhibition of the binding of B[a]P. EN was ineffective as an inhibitor of the binding of either DMBA or B[a]P. These results establish that both the pyrene nucleus and the ethynyl substituent of EP contribute to the effective inhibition of the binding of DMBA and B[a]P to the epidermal DNA of mouse skin. No significant changes in the ratios of the anti- to the syndiol epoxide-DNA adducts of DMBA or of B[a]P were produced by doses of EP that produced inhibitions of the binding to DNA. At doses of VP that inhibited covalent binding of both DMBA and B[a]P, no changes in DMBA-DNA adduct distributions were observed but changes in the relative proportions of several B[a]P-DNA adducts were noted. These data are discussed in terms of the potential of aryl acetylenes to act as suicide inhibitors (mechanism-based inactivators) of cytochrome P450-dependent monooxygenase isozymes.

  2. Dietary effects on the uptake of benzo[a]pyrene.

    PubMed

    Stavric, B; Klassen, R

    1994-08-01

    It has been established that exposure to polycyclic aromatic hydrocarbons (PAHs), or more specifically benzo[a]pyrene (B[a]P), either by inhalation through cigarette smoking or by contact through occupational exposure of the lungs or skin, can result in cancerous lesions. It appears that the general population consumes more B[a]P from food than from smoking. Despite this, epidemiological studies have not implicated B[a]P from foods as a causative factor in some human cancers. This lack of an epidemiological correlation between cancer incidence and intake of dietary PAHs/B[a]P could be due to some 'protective' or 'detoxification' mechanism. Despite the abundance of literature regarding the food content of B[a]P, there are few data concerning its uptake from foods. In the present study we investigated the intestinal absorption of B[a]P from foods using bile duct cannulated rats and radioactive B[a]P. [14C]B[a]P was first added to solvents such as water, corn oil, liquid paraffin or 50% ethanol, which were the administered by gavage to rats fed diets with or without added carbon. Additionally, food polyphenols such as quercetin and chlorogenic acid were also tested for their effect on the absorption of B[a]P. The results indicated that the excretion of B[a]P in the bile was reduced by water, carbon, quercetin and chlorogenic acid but was potentiated by corn oil. To complement the in vivo studies, some in vitro tests to investigate the efficiency of B[a]P extraction from different foods using water or oil as solvents were also performed. These tests indicated that extraction of B[a]P from foods was affected by the solvent. It is postulated that reduced solubility, physical adsorption and the formation of chemical adducts between B[a]P and some food ingredients, play a sporadic, although still not well determined, role in reducing the absorption of B[a]P from the gut. The results of these studies suggest that B[a]P absorption from the intestinal tract is markedly

  3. 5α-Estrane-3β,17β-diol and 5β-estrane-3α,17β-diol: definitive screening biomarkers to sign nandrolone abuse in cattle?

    PubMed

    Dervilly-Pinel, Gaud; Rambaud, Lauriane; Sitthisack, Parina; Monteau, Fabrice; Hewitt, S Armstrong; Kennedy, D Glenn; Le Bizec, Bruno

    2011-09-01

    17β-Nandrolone (17β-NT) is one of the most frequently misused anabolic steroids in meat producing animals. As a result of its extensive metabolism combined with the possibility of interferences with other endogenous compounds, detection of its illegal use often turns out to be a difficult issue. In recent years, proving the illegal administration of 17β-NT became even more challenging since the presence of endogenous presence of 17β-NT or some of its metabolite in different species was demonstrated. In bovines, 17α-NT can occur naturally in the urine of pregnant cows and recent findings reported that both forms can be detected in injured animals. Because efficient control must both take into account metabolic patterns and associated kinetics of elimination, the purpose of the present study was to investigate further some estranediols (5α-estrane-3β,17β-diol (abb), 5β-estrane-3α,17β-diol (bab), 5α-estrane-3β,17α-diol (aba), 5α-estrane-3α,17β-diol (aab) and 5β-estrane-3α,17α-diol (baa)) as particular metabolites of 17β-NT on a large number of injured (n=65) or pregnant (n=40) bovines. Whereas the metabolites abb, bab, aba and baa have previously been detected in urine up to several days after 17β-NT administration, the present study showed that some of the isomers abb (5α-estrane-3β,17β-diol) and bab (5β-estrane-3α,17β-diol) could not be detected in injured or pregnant animals, even at very low levels. This result may open a new way for the screening of anabolic steroid administration considering these 2 estranediols as biomarkers to indicate nandrolone abuse in cattle.

  4. On the carcinogenic polycyclic aromatic hydrocarbon benzo(a)pyrene in volcano exhausts.

    PubMed

    Ilnitsky, A P; Belitsky, G A; Shabad, L M

    1976-05-01

    The content of benzo(a)pyrene in the juvenile ashes of the volcano Tyatya (Kunashir Island, Kuriles) and in the soil, vegetation and volcanic mud collected near volcanos in Kamchatka was studied. It was concluded that volcanic activity does not play a large role in forming the background level of this carcinogen in the human environment.

  5. IRIS Toxicological Review of Benzo[a]pyrene (Interagency Science Consultation Draft)

    EPA Science Inventory

    On August 21, 2013, the draft Toxicological Review of Benzo[a]pyrene and the draft charge to external peer reviewers were released for public review and comment. The Toxicological Review and charge were reviewed internally by EPA and by other federal agencies and White House Offi...

  6. Benzo(A)pyrene Decreases Brain and Ovarian Aromatase mRNA Expression

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The higher molecular weight polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BaP) are typically associated with genotoxicity, however newer evidence suggests that these compounds may also act as endocrine system disruptors. We hypothesized that a target for reproductive or development...

  7. Benzo[a]pyrene decreases global and gene specific DNA methylation during zebrafish development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    DNA methylation is important for gene regulation and is vulnerable to early-life exposure to environmental contaminants. We found that direct waterborne benzo[a]pyrene (BaP) exposure at 24 'g/L from 2.5 to 96 hours post fertilization (hpf) to zebrafish embryos significantly decreased global cytosine...

  8. Mechanism-based inactivation of benzo(a)pyrene hydroxylase by aryl acetylenes and aryl olefins

    SciTech Connect

    Gan, L.S.; Lu, J.Y.L.; Alworth, W.L.

    1986-05-01

    A series of aryl acetylenes and aryl olefins have been examined as substrates and inhibitors of cytochrome P-450 dependent monooxgenases in liver microsomes from 5,6-benzoflavone or phenobarbital pretreated rats. 1-Ethynylpyrene, 3-ethynylperylene, 2-ethynylfluorene, methyl 1-pyrenyl acetylene, cis- and trans-1-(2-bromovinyl)pyrene, and 1-allylpyrene serve as mechanism-based irreversible inactivators (suicide inhibitors) of benzo(a)pyrene hydroxylase, while 1-vinylpyrene and phenyl 1-pyrenyl acetylene do not cause a detectable suicide inhibition of benzo(a)pyrene hydroxylase. The mechanism-based loss of benzo(a)pyrene hydroxylase caused by the aryl acetylenes is not accompanied by a corresponding loss of the P-450 content of the microsomes (suicide destruction). The suicide inhibition by these aryl acetylenes therefore does not involve covalent binding to the heme moiety of the monooxygenase. Nevertheless, in the presence of NADPH, /sup 3/H-labeled 1-ethynylpyrene becomes covalently attached to the cytochrome P-450 protein; the measured stoichiometry of binding is one 1-ethynylpyrene per P-450 heme unit. The authors conclude that the inhibition of benzo(a)pyrene hydroxylase produced by 1-ethynylpyrene may be related to the mechanism of suicide inhibition of P-450 activity by chloramphenicol rather than the mechanism of suicide destruction of P-450 previously described for acetylene and propyne.

  9. IRIS Toxicological Review of Benzo[a]pyrene (Interagency Science Discussion Draft)

    EPA Science Inventory

    In January 2017, EPA finalized the IRIS assessment of Benzo[a]pyrene. The Toxicological Review was reviewed internally by EPA and by other federal agencies and White House Offices before public release. Consistent with the May 2009 IRIS assessment development process, all written...

  10. Transcriptomic changes in zebrafish embryos and larvae following benzo[a]pyrene exposure

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Benzo[a]pyrene (BaP) is an environmentally relevant carcinogenic and endocrine disrupting compound that causes immediate, long-term, and multigenerational health deficits in mammals and fish. Previously, we found that BaP alters DNA methylation patterns in developing zebrafish, which may affect gene...

  11. Benzo(a)pyrene induced structural and functional modifications in lung cystatin.

    PubMed

    Khan, Mohd Shahnawaz; Priyadarshini, Medha; Shah, Aaliya; Tabrez, Shams; Jagirdar, Haseeb; Alsenaidy, Abdulrahman M; Bano, Bilqees

    2013-10-01

    Cystatins are thiol proteinase inhibitors ubiquitously present in the mammalian body. They serve a protective function to regulate the activities of endogenous proteinases, which may cause uncontrolled proteolysis and damage. In the present study, the effect of benzo(a)pyrene [BaP] on lung cystatin was studied to explore the hazardous effects of environmental pollutant on structural and functional integrity of the protein. The basic binding interaction was studied by UV-absorption, FT-IR, and fluorescence spectroscopy. The enhancement of total protein fluorescence with a red shift of 5 nm suggests structural scratch of lung cystatin by benzo(a)pyrene. Further, ANS binding studies reaffirm the unfolding of the thiol protease inhibitor (GLC-I) after treating with benzo(a)pyrene. The results of FT-IR spectroscopy reflect perturbation of the secondary conformation (alpha-helix to β-sheet) in goat lung cystatin on interaction with BaP. Finally, functional inactivation of cystatin on association with BaP was checked by its papain inhibitory activity. Benzo(a)pyrene (10 μM) caused complete inactivation of goat lung cystatin. Benzo(a)pyrene-induced loss of structure and function in the thiol protease inhibitor could provide a caution for lung injury caused by the pollutants and smokers.

  12. Hydration of arene and alkene oxides by epoxide hydrase in human liver microsomes.

    PubMed

    Kapitulnik, J; Levin, W; Morecki, R; Dansette, P M; Jerina, D M; Conney, A H

    1977-02-01

    The comparative hydration of styrene 7,8-oxide, octene 1,2-oxide, naphthalene 1,2-oxide, phenanthrene 9,10-oxide, benzo[a]anthracene 5,6-oxide, 3-methylcholanthrene 11,12-oxide, dibenzo[a,h]anthracene 5,6-oxide, and benzo[a, 7,8-, 9,10-, and 11,12-oxides to their respective dihydrodiols was investigated in microsomes from nine human autopsy livers. The substrate specificity of the epoxide hydrase in human liver microsomes was very similar to that of the epoxide hydrase in rat liver microsomes. Phenanthrene 9,10-oxide was the best substrate for the human and rat epoxide hydrases and dibenzo[a,h]anthracene 5,6-oxide and benzo[a-a)pyrene 11, 12-oxide were the poorest substrates. Plotting epoxide hydrase activity obtained with one substrate against epoxide hydrase activity for another substrate for each of the nine human livers revealed excellent correlations for all combinations of the 11 substrates studied (r = 0.87 to 0.99). The data suggest the presence in human liver of a single epoxide hydrase with broad substrate specificity. However, the results do not exclude the possible presence in human liver of several epoxide hydrases that are under similar regulatory control. These results suggest the need for further investigation to determine whether there is a safe epoxide of a drug whose in vivo metabolism is predictive of the capacity of different individuals to metabolize a wide variety of epoxides of drugs and environmental chemicals.

  13. Evaluation of a tape-stripping technique for measuring dermal exposure to pyrene and benzo(a)pyrene.

    PubMed

    Kammer, Ronny; Tinnerberg, Håkan; Eriksson, Kåre

    2011-08-01

    Epidemiological studies have shown an increased incidence of cancer among workers occupationally exposed to polycyclic aromatic hydrocarbons (PAHs). As the dermal route is considered important for exposure to PAHs in the workplace, the aim of this study was to develop and evaluate a tape-stripping technique for monitoring dermal exposure to pyrene and benzo(a)pyrene. The tape-stripping method was evaluated by applying different concentrations of pyrene and benzo(a)pyrene directly onto tape strips (spiked tapes), clean glass plates, and on the skin of five volunteers. The glass plates were stripped using a single strip of tape and the skin of the volunteers was stripped with five consecutive strips of tape after 0 and 30 minutes. The method was also tested on five chimney sweeps at three exposure sites. High-performance liquid chromatography with fluorescence detection was employed for the quantification of pyrene and benzo(a)pyrene. The mean recovery from the spiked tapes was 97% for pyrene and 93% for benzo(a)pyrene. The mean overall recovery from the glass plates was 88% and 76% for pyrene and 88 and 85% for benzo(a)pyrene. The recovery from human skin was 70% and 63% for pyrene and 60 and 54% for benzo(a)pyrene, after 0 and 30 minutes, respectively. A concentration gradient was clearly detected between the five consecutive strips. Detectable amounts of pyrene and benzo(a)pyrene were found on all chimney sweeps at all exposure sites. This method can thus be used to detect and quantify dermal exposure to pyrene and benzo(a)pyrene. The results also show that pyrene and benzo(a)pyrene may be taken up by the skin.

  14. Aqueous benzene-diols react with an organic triplet excited state and hydroxyl radical to form secondary organic aerosol.

    PubMed

    Smith, Jeremy D; Kinney, Haley; Anastasio, Cort

    2015-04-21

    Chemical processing in atmospheric aqueous phases, such as cloud and fog drops, can play a significant role in the production and evolution of secondary organic aerosol (SOA). In this work we examine aqueous SOA production via the oxidation of benzene-diols (dihydroxy-benzenes) by the triplet excited state of 3,4-dimethoxybenzaldehyde, (3)DMB*, and by hydroxyl radical, ˙OH. Reactions of the three benzene-diols (catechol (CAT), resorcinol (RES) and hydroquinone (HQ)) with (3)DMB* or ˙OH proceed rapidly, with rate constants near diffusion-controlled values. The two oxidants exhibit different behaviors with pH, with rate constants for (3)DMB* increasing as pH decreases from pH 5 to 2, while rate constants with ˙OH decrease in more acidic solutions. Mass yields of SOA were near 100% for all three benzene-diols with both oxidants. We also examined the reactivity of atmospherically relevant mixtures of phenols and benzene-diols in the presence of (3)DMB*. We find that the kinetics of phenol and benzene-diol loss, and the production of SOA mass, in mixtures are generally consistent with rate constants determined in experiments containing a single phenol or benzene-diol. Combining our aqueous kinetic and SOA mass yield data with previously published gas-phase data, we estimate a total SOA production rate from benzene-diol oxidation in a foggy area with significant wood combustion to be nearly 0.6 μg mair(-3) h(-1), with approximately half from the aqueous oxidation of resorcinol and hydroquinone, and half from the gas-phase oxidation of catechol.

  15. Mechanism of olefin epoxidation in the presence of a titanium-containing zeolite

    NASA Astrophysics Data System (ADS)

    Danov, S. M.; Krasnov, V. L.; Sulimov, A. V.; Ovcharova, A. V.

    2013-11-01

    The effect of the nature of a solvent on the liquid-phase epoxidation of olefins with an aqueous solution of hydrogen peroxide over a titanium-containing zeolite is studied. Butanol-1, butanol-2, propanol-1, isopropanol, methanol, ethanol, water, acetone, methyl ethyl ketone, isobutanol, and tert-butanol are examined as solvents. A mechanism of olefin epoxidation with hydrogen peroxide in an alcohol medium over a titanium-containing zeolite is proposed. Epoxidation reactions involving hydrogen peroxide and different olefins are studied experimentally.

  16. First-Principles Chemical Kinetic Modeling of Methyl trans-3-Hexenoate Epoxidation by HO2.

    PubMed

    Cagnina, S; Nicolle, A; de Bruin, T; Georgievskii, Y; Klippenstein, S J

    2017-03-09

    The design of innovative combustion processes relies on a comprehensive understanding of biodiesel oxidation kinetics. The present study aims at unraveling the reaction mechanism involved in the epoxidation of a realistic biodiesel surrogate, methyl trans-3-hexenoate, by hydroperoxy radicals using a bottom-up theoretical kinetics methodology. The obtained rate constants are in good agreement with experimental data for alkene epoxidation by HO2. The impact of temperature and pressure on epoxidation pathways involving H-bonded and non-H-bonded conformers was assessed. The obtained rate constant was finally implemented into a state-of-the-art detailed combustion mechanism, resulting in fairly good agreement with engine experiments.

  17. Epoxidation reactions of unsaturated fatty esters with potassium peroxomonosulfate.

    PubMed

    Lie Ken Jie, M S; Pasha, M K

    1998-06-01

    Epoxidation of the double bond in methyl oleate, octadec-11E-en-9-ynoate, ricinoleate (12-hydroxy-octadec-9Z-enoate), iso-ricinoleate (9-hydroxy-octadec-12Z-enoate), and 12-oxo-octadec-9Z-enoate with potassium peroxomonosulfate (oxone, 2 KHSO5.KHSO4.K2SO4) in the presence of trifluoroacetone or methyl pyruvate gave the corresponding monoepoxy derivatives. Reaction of Oxone with methyl linoleate and octadeca-9Z,11E-dienoate furnished the corresponding diepoxystearate derivative. Methyl 9,12-dioxo-octadec-10Z-enoate was obtained when a C18 furanoid fatty ester (methyl 9,12-epoxy-9,11-octadecadienoate) was treated with Oxone. The yield of these reactions was very high (85-99%), and the epoxy derivatives were readily isolated by solvent extraction. The products were identified by spectroscopic methods.

  18. Vitamin K epoxide reductase: homology, active site and catalytic mechanism.

    PubMed

    Goodstadt, Leo; Ponting, Chris P

    2004-06-01

    Vitamin K epoxide reductase (VKOR) recycles reduced vitamin K, which is used subsequently as a co-factor in the gamma-carboxylation of glutamic acid residues in blood coagulation enzymes. VKORC1, a subunit of the VKOR complex, has recently been shown to possess this activity. Here, we show that VKORC1 is a member of a large family of predicted enzymes that are present in vertebrates, Drosophila, plants, bacteria and archaea. Four cysteine residues and one residue, which is either serine or threonine, are identified as likely active-site residues. In some plant and bacterial homologues the VKORC1 homologous domain is fused with domains of the thioredoxin family of oxidoreductases. These might reduce disulfide bonds of VKORC1-like enzymes as a prerequisite for their catalytic activities.

  19. Cesium promotion in styrene epoxidation on silver catalysts.

    PubMed

    Zhou, Ling; Gorin, Craig F; Madix, Robert J

    2010-01-20

    The adsorption of a small amount of cesium on Ag(110) redirects the partial oxidation products of styrene from phenylacetaldehyde and phenylketene to styrene oxide. The cesium stabilizes the oxametallacycle intermediate and hinders its transformation to the intermediate that leads to the other products. Cesium does not appear to create any electronic effects on the bonding of the intermediates. Low coverages of cesium induce a (1 x 2) missing-row reconstruction of the entire clean Ag(110) surface and a (3 x 5) surface oxide structure on the cesium-reconstructed Ag(110) surface. This (3 x 5)-ordered surface oxide is superimposed on the Ag(111) microfacets produced by the cesium-induced reconstruction, which leads to selectivity and reactivity very similar to those of the extended (111) surface. These studies provide insight into the microscopic origins of the structural effects of cesium in styrene epoxidation on silver catalysts.

  20. Characteristics of polyaniline cobalt supported catalysts for epoxidation reactions.

    PubMed

    Kowalski, Grzegorz; Pielichowski, Jan; Grzesik, Mirosław

    2014-01-01

    A study of polyaniline (PANI) doping with various cobalt compounds, that is, cobalt(II) chloride, cobalt(II) acetate, and cobalt(II) salen, is presented. The catalysts were prepared by depositing cobalt compounds onto the polymer surface. PANI powders containing cobalt ions were obtained by one- or two-step method suspending PANI in the following acetonitrile/acetic acid solution or acetonitrile and then acetic acid solution. Moreover different ratios of Co(II) : PANI were studied. Catalysts obtained with both methods and at all ratios were investigated using various techniques including AAS and XPS spectroscopy. The optimum conditions for preparation of PANI/Co catalysts were established. Catalytic activity of polyaniline cobalt(II) supported catalysts was tested in dec-1-ene epoxidation with molecular oxygen at room temperature. The relationship between the amount of cobalt species, measured with both AAS and XPS techniques, and the activity of PANI-Co catalysts has been established.

  1. Characteristics of Polyaniline Cobalt Supported Catalysts for Epoxidation Reactions

    PubMed Central

    Kowalski, Grzegorz; Pielichowski, Jan; Grzesik, Mirosław

    2014-01-01

    A study of polyaniline (PANI) doping with various cobalt compounds, that is, cobalt(II) chloride, cobalt(II) acetate, and cobalt(II) salen, is presented. The catalysts were prepared by depositing cobalt compounds onto the polymer surface. PANI powders containing cobalt ions were obtained by one- or two-step method suspending PANI in the following acetonitrile/acetic acid solution or acetonitrile and then acetic acid solution. Moreover different ratios of Co(II) : PANI were studied. Catalysts obtained with both methods and at all ratios were investigated using various techniques including AAS and XPS spectroscopy. The optimum conditions for preparation of PANI/Co catalysts were established. Catalytic activity of polyaniline cobalt(II) supported catalysts was tested in dec-1-ene epoxidation with molecular oxygen at room temperature. The relationship between the amount of cobalt species, measured with both AAS and XPS techniques, and the activity of PANI-Co catalysts has been established. PMID:24701183

  2. Structure of a bacterial homologue of vitamin K epoxide reductase

    SciTech Connect

    Li, Weikai; Schulman, Sol; Dutton, Rachel J.; Boyd, Dana; Beckwith, Jon; Rapoport, Tom A.

    2010-03-19

    Vitamin K epoxide reductase (VKOR) generates vitamin K hydroquinone to sustain {gamma}-carboxylation of many blood coagulation factors. Here, we report the 3.6 {angstrom} crystal structure of a bacterial homologue of VKOR from Synechococcus sp. The structure shows VKOR in complex with its naturally fused redox partner, a thioredoxin-like domain, and corresponds to an arrested state of electron transfer. The catalytic core of VKOR is a four transmembrane helix bundle that surrounds a quinone, connected through an additional transmembrane segment with the periplasmic thioredoxin-like domain. We propose a pathway for how VKOR uses electrons from cysteines of newly synthesized proteins to reduce a quinone, a mechanism confirmed by in vitro reconstitution of vitamin K-dependent disulphide bridge formation. Our results have implications for the mechanism of the mammalian VKOR and explain how mutations can cause resistance to the VKOR inhibitor warfarin, the most commonly used oral anticoagulant.

  3. Analyses of effects of α-cembratrien-diol on cell morphology and transcriptome of Valsa mali var. mali.

    PubMed

    Yan, Ning; Du, Yongmei; Liu, Xinmin; Zhang, Hongbo; Liu, Yanhua; Shi, John; Xue, Sophia Jun; Zhang, Zhongfeng

    2017-01-01

    The objective of this work was to study the underlying mechanisms of growth inhibition of Valsa mali var. mali, the causative pathogen of apple tree canker disease, by α-cembratrien-diol. The half maximal inhibitory concentration of α-cembratrien-diol against V. mali var. mali is 18.0mg/L. Treatment of V. mali var. mali with α-cembratrien-diol resulted in various mycelial and cellular abnormalities, and the up- and down-regulation of 94 and 170 differentially expressed genes, respectively. Gene Ontology term enrichment analysis revealed that α-cembratrien-diol substantially altered the expression of genes involved in the redox process, tetrapyrrole binding, coenzyme binding, heme binding, and iron binding. Kyoto Encyclopedia of Genes and Genomes enrichment analysis also showed significant enrichment of specific metabolic pathways involving the set of differentially expressed genes. The present study will assist in the development of alternative α-cembratrien-diol-based biological control agents and ultimately facilitate organic apple production.

  4. Solubility and thermodynamic behavior of vanillin in propane-1,2-diol+water cosolvent mixtures at different temperatures.

    PubMed

    Shakeel, Faiyaz; Haq, Nazrul; Siddiqui, Nasir A; Alanazi, Fars K; Alsarra, Ibrahim A

    2015-12-01

    The solubilities of bioactive compound vanillin were measured in various propane-1,2-diol+water cosolvent mixtures at T=(298-318)K and p=0.1 MPa. The experimental solubility of crystalline vanillin was determined and correlated with calculated solubility. The results showed good correlation of experimental solubilities of crystalline vanillin with calculated ones. The mole fraction solubility of crystalline vanillin was recorded highest in pure propane-1,2-diol (7.06×10(-2) at 298 K) and lowest in pure water (1.25×10(-3) at 298 K) over the entire temperature range investigated. Thermodynamic behavior of vanillin in various propane-1,2-diol+water cosolvent mixtures was evaluated by Van't Hoff and Krug analysis. The results showed an endothermic, spontaneous and an entropy-driven dissolution of crystalline vanillin in all propane-1,2-diol+water cosolvent mixtures. Based on solubility data of this work, vanillin has been considered as soluble in water and freely soluble in propane-1,2-diol.

  5. Detoxication strategy of epoxide hydrolase-the basis for a novel threshold for definable genotoxic carcinogens.

    PubMed

    Oesch, Franz; Hengstler, Jan Georg; Arand, Michael

    2004-01-01

    From our recent work on the three-dimensional structure of epoxide hydrolases we theoretically deduced the likelihood of a two-step catalytic mechanism that we and others have subsequently experimentally confirmed. Analysis of the rate of the two steps by us and by others show that the first step-responsible for removal of the reactive epoxide from the system-works extraordinarily fast (typically three orders of magnitude faster than the second step), sucking up the epoxide like a sponge. Regeneration of the free enzyme (the second step of the catalytic mechanism) is slow. This becomes a toxicological problem only at doses of the epoxide that titrate the enzyme out. Our genotoxicity work shows that indeed this generates a practical threshold below which no genotoxicity is observed. This shows that-contrary to old dogma-practical thresholds exist for definable genotoxic carcinogens.

  6. A Computational Study of Acid Catalyzed Aerosol Reactions of Atmospherically Relevant Epoxides

    EPA Science Inventory

    Epoxides are important intermediates of atmospheric isoprene oxidation. Their subsequent reactions in the particle phase lead to the production of organic compounds detected in ambient aerosols. We apply density functional theory to determine the important kinetic factors that ...

  7. Biobased composites from thermoplastic polyurethane elastomer and cross-linked acrylated-epoxidized soybean oil

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Soybean oil is an important sustainable material. Crosslinked acrylated epoxidized soybean oil (AESO) is brittle without flexibility and the incorporation of thermoplastic polyurethane improves its toughness for industrial applications. The hydrophilic functional groups from both oil and polyurethan...

  8. The Role of Long Chain Fatty Acids and Their Epoxide Metabolites in Nociceptive Signaling

    PubMed Central

    Wagner, Karen; Vito, Steve; Inceoglu, Bora; Hammock, Bruce D.

    2014-01-01

    Lipid derived mediators contribute to inflammation and the sensing of pain. The contributions of omega-6 derived prostanoids in enhancing inflammation and pain sensation are well known. Less well explored are the opposing anti-inflammatory and analgesic effects of the omega-6 derived epoxyeicosatrienoic acids. Far less has been described about the epoxidized metabolites derived from omega-3 long chain fatty acids. The epoxide metabolites are turned over rapidly with enzymatic hydrolysis by the soluble epoxide hydrolase being the major elimination pathway. Despite this, the overall understanding of the role of lipid mediators in the pathology of chronic pain is growing. Here we review the role of long chain fatty acids and their metabolites in alleviating both acute and chronic pain conditions. We focus specifically on the epoxidized metabolites of omega-6 and omega-3 long chain fatty acids as well as a novel strategy to modulate their activity in vivo. PMID:25240260

  9. Poly(monothiocarbonate)s from the Alternating and Regioselective Copolymerization of Carbonyl Sulfide with Epoxides.

    PubMed

    Luo, Ming; Zhang, Xing-Hong; Darensbourg, Donald J

    2016-10-18

    Carbonyl sulfide (COS) is an air pollutant that causes acid rain, ozonosphere damage, and carbon dioxide (CO2) generation. It is a heterocumulene and structural analogue of CO2. Relevant to organic synthesis, it is a source of C═O or C═S groups and thus an ideal one-carbon (C1) building block for synthesizing sulfur-containing polymers through the similar route of CO2 copolymerization. In contrast, traditional synthesis of sulfur-containing polymers often involves the condensation of thiols with phosgene and ring-opening polymerization of cyclic thiocarbonates that are generally derived from thiols and phosgene; thus, COS/epoxide copolymerization is a "greener" route to supplement or supplant current processes for the production of sulfur-containing polymers. This Accounts highlights our efforts on the discovery of the selective formation of poly(monothiocarbonate)s from COS with epoxides via heterogeneous zinc-cobalt double metal cyanide complex (Zn-Co(III) DMCC) and homogeneous (salen)CrX complexes. The catalytic activity and selectivity of Zn-Co(III) DMCC for COS/epoxide copolymerization are similar to those for CO2/epoxide copolymerization. (salen)CrX complexes accompanied by onium salts exhibited high activity and selectivity for COS/epoxide copolymerization under mild conditions, affording copolymers with >99% monothiocarbonate units and high tail-to-head content up to 99%. By way of contrast, these catalysts often show moderate or low activity for CO2/epoxide copolymerization. Of note, a specialty of COS/epoxide copolymerization is the occurrence of an oxygen-sulfur exchange reaction (O/S ER), which may produce carbonate and dithiocarbonate units. O/S ER, which are induced by the metal-OH bond regenerated by chain transfer reactions, can be kinetically inhibited by changing the reaction conditions. We provide a thorough mechanistic understanding of the electronic/steric effect of the catalysts on the regioselectivity of COS copolymerization. The

  10. Renewable non-isocyanate based thermoplastic polyurethanes via polycondensation of dimethyl carbamate monomers with diols.

    PubMed

    Unverferth, Maike; Kreye, Oliver; Prohammer, Alexander; Meier, Michael A R

    2013-10-01

    1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD)-catalyzed polycondensation reactions of fatty acid derived dimethyl dicarbamates and diols are introduced as a versatile, non-isocyanate route to renewable polyurethanes. The key step for the synthesis of dimethyl carbamate monomers from plant-oil-derived dicarboxylic acids is based on a sustainable base-catalyzed Lossen rearrangement. The formed polyurethanes with molecular weights up to 25 kDa are characterized by SEC, DSC, and NMR analysis.

  11. Exploiting Acid Phosphatases in the Synthesis of Phosphorylated Monoalcohols and Diols

    PubMed Central

    Tasnádi, Gábor; Lukesch, Michael; Zechner, Michaela; Jud, Wolfgang; Hall, Mélanie; Ditrich, Klaus; Baldenius, Kai; Hartog, Aloysius F.; Wever, Ron

    2015-01-01

    Abstract A set of phosphatases was evaluated for their potential to catalyze the regio‐ and stereoselective phosphorylation of alcohols using a high‐energy inorganic phosphate donor, such as di‐, tri‐ and polyphosphate. Parameters such as type and amount of phosphate donor and pH of the reaction were investigated in order to minimize the thermodynamically favored hydrolysis of the phosphate donor and the formed phosphate ester. Diols were monophosphorylated with high selectivities. This biocatalytic phosphorylation method provides selectively activated and/or protected synthetic intermediates for further chemical and/or enzymatic transformations and is applicable to a large scale (6.86 g) in a flow setup with immobilized phosphatase.

  12. Two new 5-deoxyflavan-3,4-diol glucosides from roots of Albizia chevalieri.

    PubMed

    Tchoukoua, Abdou; Kuiate Tabopda, Turibio; Uesugi, Shota; Kimura, Ken-Ichi; Kwon, Eunsang; Momma, Hiroyuki; Ngadjui, Bonaventure Tchaleu; Koseki, Takuya; Shiono, Yoshihito

    2016-11-01

    Phytochemical investigation of the roots of Albizia chevalieri led to the isolation of two new 5-deoxyflavan-3,4-diol glucosides from roots of A. chevalieri, Chevalieriflavanosides A and B. Their structures were established by 2D NMR techniques, UV, IR, CD, and mass spectrometry. Cytotoxicity of the two compounds was evaluated against acute promyelocytic leukemia HL60 cells. The antibacterial activities of 1 and 2 also were evaluated against Pseudomonas aeruginosa and Staphylococcus aureus using the agar diffusion test. Copyright © 2016 John Wiley & Sons, Ltd.

  13. Enantioselective Ethylation of Various Aldehydes Catalyzed by Readily Accessible Chiral Diols.

    PubMed

    Gök, Yaşar; Kiliçarslan, Seda; Gök, Halil Zeki; Karayiğit, İlker Ümit

    2016-08-01

    Four chiral C2 -symmetric diols were synthesized in a straightforward three-step reaction and demonstrated excellent enantioselectivities and good overall yields. Their catalytic activities were examined via the addition of diethylzinc to various aldehydes. The enantioselective addition of diethylzinc to 2-methoxybenzaldehyde gave the corresponding chiral secondary alcohol with high yields (up to 95%) and moderate to good enantiomeric excess (up to 88%). All synthesized ligands were evaluated in the addition of diethylzinc to various aldehydes in the presence of an additional metal such as Ti(IV) complexes. Chirality 28:593-598, 2016. © 2016 Wiley Periodicals, Inc.

  14. Characterization of a recombinant 7,8-linoleate diol synthase from Glomerella cingulate.

    PubMed

    Seo, Min-Ju; Shin, Kyung-Chul; An, Jung-Ung; Kang, Woo-Ri; Ko, Yoon-Joo; Oh, Deok-Kun

    2016-04-01

    A putative diol synthase from the fungus Glomerella cingulate was cloned and expressed in Escherichia coli. The putative diol synthase from G. cingulate was purified by His-Trap affinity chromatography with a specific activity of 0.87 U mg(-1), an eightfold purification, and a yield of 28%. One unit of activity was defined as the amount of enzyme required to produce 1 μmol of 7,8-dihydroxy-9,12(Z,Z)-octadecadienoic acid (7,8-DiHODE) per min. The purified enzyme was estimated as a 127-kDa tetramer with a molecular mass of 510 kDa by gel filtration chromatography. The enzyme converted linoleic acid to a product, identified as 7S,8S-DiHODE by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) and nuclear magnetic resonance (NMR) spectroscopy. The specific activity and catalytic efficiency (k cat/K m) of 7,8-diol synthase from G. cingulate for the conversion of fatty acid to dihydroxy fatty acid followed the order linoleic acid > α-linolenic acid > oleic acid > palmitoleic acid, indicating that the enzyme is a 7,8-linoleate diol synthase (7,8-LDS). The activity of the enzyme for the conversion of 7,8-DiHODE from linoleic acid was maximal at pH 6.5, 40 °C, and 2.5% (v/v) dimethyl sulfoxide (DMSO). Under these conditions, 7,8-LDS from G. cingulate converted 1.0 mM linoleic acid to 0.62 mM 7,8-DiHODE for 30 min, with a conversion yield of 62% (mol/mol), via 8-hydroperoxy-9,12(Z,Z)-octadecadienoic acid (8-HPODE) as an intermediate. The accumulation of 8-HPODE was due to a higher 8-dioxygenase activity in the N-terminal domain than hydroperoxide isomerase activity in the C-terminal domain.

  15. Systemic excretion of benzo(a)pyrene in the control and microsomally induced rat: the influence of plasma lipoproteins and albumin as carrier molecules

    SciTech Connect

    Shu, H.P.; Bymun, E.N.

    1983-02-01

    In vitro studies have previously indicated that benzo(a)pyrene distributes primarily into the plasma lipoprotein fraction when incubated with whole plasma. Hydroxylated metabolites of benzo(a)pyrene distribute increasingly into the albumin fraction as the degree of metabolite hydroxylation increases. This report assesses the influence of plasma lipoproteins and albumin as carriers for benzo(a)pyrene on carcinogen excretion in the control and microsomally induced rat. Male Sprague-Dawley rats cannulated in the bile duct received i.v. injections of radiolabeled benzo(a)pyrene noncovalently bound to the very-low-density, low-density, or high-density lipoproteins in equimolar amounts. Bile was collected and measured for radioactivity. Cumulative biliary excretions of benzo(a)pyrene complexed with rat lipoproteins were 39.6 +/- 9.7 (S.D.), 24.6 +/- 1.3, and 21.2 +/- 8.8% for very low-density, low-density, and high-density lipoprotein, respectively. Values for excretion of benzo(a)pyrene complexed with rat or human lipoproteins were comparable. These data suggest that the transport molecule can effect a 2-fold difference in benzo(a)pyrene excretion under conditions of the present study. Thus, excretion increased as the degree of benzo(a)pyrene hydroxylation increased. The effect of microsomal enzyme induction on excretion of lipoprotein-bound benzo(a)pyrene was also assessed. Contrary to expectation, excretion of benzo(a)pyrene bound to the very-low-density, low-density, or high-density lipoproteins in Aroclor-induced rats was not greater than that of control animals. Hence, under the conditions of the present study, 60 to 80% of the injected benzo(a)pyrene and 50 to 60% of the injected benzo(a)pyrene metabolites were not excreted immediately in control or microsomally induced animals. This benzo(a)pyrene may represent a carcinogen pool that is slowly excreted.

  16. A domino ring-opening/epoxidation of 1,2-dioxines.

    PubMed

    Greatrex, Ben W; Taylor, Dennis K; Tiekink, Edward R T

    2004-04-02

    When allowed to react with alkaline hydrogen peroxide, monocyclic 1,2-dioxines ring-open to their isomeric gamma-hydroxyenone intermediates which are rapidly epoxidized to afford trans-4-hydroxy-2,3-epoxyketones in 21-81% yield. In the case of meso-1,2-dioxines, Co(II) complex catalyzed asymmetric ring-opening of the 1,2-dioxine may be employed to furnish enantioenriched epoxides

  17. Hydroxyl-Substituted Ladder Polyethers via Selective Tandem Epoxidation/Cyclization Sequence

    PubMed Central

    Czabaniuk, Lara C.; Jamison, Timothy F.

    2015-01-01

    A new and highly selective method for the synthesis of hydroxyl-substituted tetrahydropyrans is described. This method utilizes titanium(IV) iso-propoxide and diethyl tartrate to perform a diastereoselective epoxidation followed by in situ epoxide activation and highly selective endo-cyclization to form the desired tetrahydropyran ring. The HIJ ring fragment of the marine ladder polyether yessotoxin was synthesized using this two-stage tactic that proceeds with high efficiency and excellent regioselectivity. PMID:25647091

  18. Mechanistic investigation leads to a synthetic improvement in the hydrolytic kinetic resolution of terminal epoxides.

    PubMed

    Nielsen, Lars P C; Stevenson, Christian P; Blackmond, Donna G; Jacobsen, Eric N

    2004-02-11

    The mechanism of the hydrolytic kinetic resolution (HKR) of terminal epoxides was investigated by kinetic analysis using reaction calorimetry. The chiral (salen)Co-X complex (X = OAc, OTs, Cl) undergoes irreversible conversion to (salen)Co-OH during the course of the HKR and thus serves as both precatalyst and cocatalyst in a cooperative bimetallic catalytic mechanism. This insight led to the identification of more active catalysts for the HKR of synthetically useful terminal epoxides.

  19. Hydroxyl-substituted ladder polyethers via selective tandem epoxidation/cyclization sequence.

    PubMed

    Czabaniuk, Lara C; Jamison, Timothy F

    2015-02-20

    A new and highly selective method for the synthesis of hydroxyl-substituted tetrahydropyrans is described. This method utilizes titanium(IV) isopropoxide and diethyl tartrate to perform a diastereoselective epoxidation followed by in situ epoxide activation and highly selective endo-cyclization to form the desired tetrahydropyran ring. The HIJ ring fragment of the marine ladder polyether yessotoxin was synthesized using this two-stage tactic that proceeds with high efficiency and excellent regioselectivity.

  20. Opening of Aryl-Substituted Epoxides to form Quaternary Stereogenic Centers: Synthesis of (−)-Mesembrine

    PubMed Central

    Taber, Douglass F.; He, Yigang

    2011-01-01

    Cycloalkanones are easily converted into aryl-substituted cyclic alkenes by the addition of an aryl Grignard reagent followed by dehydration. These alkenes are good substrates for asymmetric epoxidation. We have found that the addition of allylic and benzylic Grignard reagents can occur preferentially at the benzylic position of the derived epoxides, to give the quaternary stereogenic center. This approach led to a short synthesis of the nanomolar serotonin re-uptake inhibitor (−)-mesembrine. PMID:16149803

  1. Epoxidation of Short-Chain Alkenes by Resting-Cell Suspensions of Propane-Grown Bacteria

    PubMed Central

    Hou, Ching T.; Patel, Ramesh; Laskin, Allen I.; Barnabe, Nancy; Barist, Irene

    1983-01-01

    Sixteen new cultures of propane-utilizing bacteria were isolated from lake water from Warinanco Park, Linden, N.J. and from lake and soil samples from Bayway Refinery, Linden, N.J. In addition, 19 known cultures obtained from culture collections were also found to be able to grow on propane as the sole carbon and energy source. In addition to their ability to oxidize n-alkanes, resting-cell suspensions of both new cultures and known cultures grown on propane oxidize short-chain alkenes to their corresponding 1,2-epoxides. Among the substrate alkenes, propylene was oxidized at the highest rate. In contrast to the case with methylotrophic bacteria, the product epoxides are further metabolized. Propane and other gaseous n-alkanes inhibit the epoxidation of propylene. The optimum conditions for in vivo epoxidation are described. Results from inhibition studies indicate that a propane monooxygenase system catalyzes both the epoxidation and hydroxylation reactions. Experiments with cell-free extracts show that both hydroxylation and epoxidation activities are located in the soluble fraction obtained after 80,000 × g centrifugation. PMID:16346338

  2. Preparation of Rh[16aneS4-diol](211)At and Ir[16aneS4-diol](211)At complexes as potential precursors for astatine radiopharmaceuticals. Part I: Synthesis.

    PubMed

    Pruszyński, Marek; Bilewicz, Aleksander; Zalutsky, Michael R

    2008-04-01

    The goal of this study was to evaluate a new approach that can be applied for labeling biomolecules with (211)At. Many astatine compounds that have been synthesized are unstable in vivo, providing motivation for seeking different (211)At labeling strategies. The approach evaluated in this study was to attach astatide anions to soft metal cations, which are also complexed by a bifunctional ligand. Ultimately, this complex could in principle be subsequently conjugated to a biomolecule with the proper selection of ligand functionality. We report here the attachment of (211)At(-) and *I(-) (*I = (131)I or (125)I) anions to the soft metal cations Rh(III) and Ir(III), which are complexed by the 1,5,9,13-tetrathiacyclohexadecane-3,11-diol (16aneS4-diol) ligand. Radioactive *I(-) anions were used for preliminary studies directed at the optimization of reaction conditions and to provide a baseline for comparison of results with (211)At. Four complexes Rh[16aneS4-diol]*I/(211)At and Ir[16aneS4-diol]*I/(211)At were synthesized in high yield in a one-step procedure, and the products were characterized mainly by paper electrophoresis and reversed-phase HPLC. The influences of time and temperature of heating and concentrations of metal cations and sulfur ligand 16aneS4-diol, as well as pH on the reaction yields were determined. Yields of about 80% were obtained when the quantities of Rh(III) or Ir(III) cations and 16aneS4-diol ligand in the solutions were 62.5 nmol and 250 nmol, respectively, and the pH ranged 3.0-4.0. Syntheses required heating for 1-1.5 h at 75-80 degrees C. The influence of microwave heating on the time and completeness of the complexation reaction was evaluated and compared with the conventional method of heating in an oil bath. Microwave synthesis accelerates reactions significantly. With microwave heating, yields of about 75% for Rh[16aneS4-diol](131)I and Ir[16aneS4-diol](131)I complexes were obtained after only 20 min exposure of the reaction mixtures to

  3. Long-term trends of benzo(a)pyrene concentration on the eastern coast of the Baltic Sea

    NASA Astrophysics Data System (ADS)

    Milukaite, Audrone R.

    Concentration of benzo(a)pyrene (B(a)P) was investigated in atmospheric air at Preila background station located on the eastern coast of the Baltic Sea in 1980-2002. A significant difference in daily concentration of benzo(a)pyrene, reaching more than two orders of magnitude, was determined during the period of investigation. The variability of benzo(a)pyrene daily concentration was considered. The main part of extreme benzo(a)pyrene daily concentration of over 5 ng m -3 was related to the air masses coming to the background site from W-SW to N-NW over the period of 1980-1994. Owing to the variability of benzo(a)pyrene daily concentration, the monthly concentration of benzo(a)pyrene in atmospheric air of the background site varied from 0.18 to 3.30 ng m -3 in cold season and from 0.02 to 1.72 ng m -3 in warm season. A slowly decreasing trend of benzo(a)pyrene monthly concentration was determined in both seasons during the whole period of investigation. Comparison of B(a)P monthly concentration determined at Preila background station with that in other countries since 1994 (according to the EMEP program) has shown that monthly concentration of benzo(a)pyrene is nearly of the same level in the Czech Republic and it is by one order of magnitude higher than at Scandinavian background stations. The course of carcinogen concentration at Preila background station is similar to that of Swedish stations with tendency to decrease from 1999.

  4. C(2)-Symmetric bis-sulfoxide: A novel chiral auxiliary for asymmetric desymmetrization of cyclic meso-1,2-diols

    PubMed

    Maezaki; Sakamoto; Nagahashi; Soejima; Li; Imamura; Kojima; Ohishi; Sakaguchi; Iwata; Tanaka

    2000-06-02

    A new heterocyclic compound, C(2)-symmetric bis-sulfoxide 1, has been found to be an efficient chiral auxiliary for asymmetric desymmetrization of cyclic meso-1,2-diols via diastereoselective acetal fission. Both (R,R)- and (S,S)-1 are readily synthesized with high optical purity via asymmetric oxidation of 1, 5-benzodithiepan-3-one (2). After acetalization of meso-1,2-diols 6a-e and a mono-TMS ether 6f with this chiral auxiliary 1, the resulting acetals 7a-f were subjected to base-promoted acetal fission upon treatment with potassium hexamethyldisilazide (KHMDS) followed by acetylation or benzylation to give the desymmetrized diol derivatives 8a-f with high diastereoselectivity. The chiral auxiliary 1 is readily removed by acid-promoted hydrolysis and can be recovered without a loss in enantiomeric excess.

  5. Serum 5alpha-androstane-3alpha,17beta-diol, androsterone, and testosterone concentrations in the male rat. Influence of age and gonadotropin stimulation.

    PubMed

    Moger, W H

    1977-04-01

    Serum concentrations of testosterone plus dihydrotestosterone (T-DHT), 5 alpha-androstane-3 alpha, 17 beta-diol (Diol) and androsterone were measured during sexual maturation in male rats. Diol concentrations of 1 to 2.25 ng/ml were found in animals 10-90 days of age with no significant changes. Diol was the major androgen (5.75-8 times T-DHT) from age 20-40 days. Androsterone rose to 1.25 ng/ml at 25 days of age and declined to values of greater than 0.5 ng/ml from age 30-90 days. Testosterone-DHT levels were 1 ng/ml or less from 10-40 days of age, and then rose to a peak at 60 days. The ratio of Diol toT-DHT was significantly elevated from age 20-35 days, indicating that Diol is the major androgen in circulation at this time. Acute treatment of 33 day old rats with LH, but not with FSH, resulted in a dose-dependent increase in serum T-DHT, Diol, and androsterone. The dose-response and time course of response for the three steriods were nearly identical. Changes in testes capacity to secrete androgens were assessed 25, 33, 40 and 60 days of age by administering a maximum dose of LH before blood collection. Maximum response (sum of androsterone, Diol and T-DHT) occurred at 40 days with no further increase at 60 days.

  6. Rhenium-catalyzed didehydroxylation of vicinal diols to alkenes using a simple alcohol as a reducing agent.

    PubMed

    Arceo, Elena; Ellman, Jonathan A; Bergman, Robert G

    2010-08-25

    A new method for the catalytic didehydroxylation of vicinal diols is described. Employing a readily available low-valent rhenium carbonyl complex and a simple alcohol as a reducing agent, both terminal and internal vicinal diols are deoxygenated to olefins in good yield. The optional addition of acid (TsOH, H(2)SO(4)) provides access to lower reaction temperatures. This new system enables the transformation of a four-carbon sugar polyol into an oxygen-reduced compound, providing promising evidence for its practical application to produce unsaturated compounds from biomass-derived materials.

  7. Catalytic deoxydehydration of diols to olefins by using a bulky cyclopentadiene-based trioxorhenium catalyst.

    PubMed

    Raju, Suresh; Jastrzebski, Johann T B H; Lutz, Martin; Klein Gebbink, Robertus J M

    2013-09-01

    A bulky cyclopentadienyl (Cp)-based trioxorhenium compound was developed for the catalytic deoxydehydration of vicinal diols to olefins. The 1,2,4-tri(tert-butyl)cyclopentadienyl trioxorhenium (2) catalyst was synthesised in a two-step synthesis procedure. Dirhenium decacarbonyl was converted into 1,2,4-tri(tert-butyl)cyclopentadienyl tricarbonyl rhenium, followed by a biphasic oxidation with H2 O2 . These two new three-legged compounds with a 'piano-stool' configuration were fully characterised, including their single crystal X-ray structures. Deoxydehydration reaction conditions were optimised by using 2 mol % loading of 2 for the conversion of 1,2-octanediol into 1-octene. Different phosphine-based and other, more conventional, reductants were tested in combination with 2. Under optimised conditions, a variety of vicinal diols (aromatic and aliphatic, internal and terminal) were converted into olefins in good to excellent yields, and with minimal olefin isomerisation. A high turnover number of 1400 per Re was achieved for the deoxydehydration of 1,2-octanediol. Furthermore, the biomass-derived polyols (glycerol and erythritol) were converted into their corresponding olefinic products by 2 as the catalyst.

  8. Biotransformation of 1,3-propanediol cyclic sulfate and its derivatives to diols by Rhodococcus sp.

    PubMed

    He, Yu-Cai; Tao, Zhi-Cheng; Zhang, Dan-Ping; Yang, Zhen-Xing; Gao, Shan; Ma, Cui-Luan

    2015-01-01

    Rhodococcus sp. CGMCC 4911 transformed 1,3-propanediol cyclic sulfate (1,3-PDS) and its derivatives into corresponding diols. Ethylene sulfate, glycol sulfide, 1,3-PDS, and 1,2-propanediol cyclic sulfate were effectively hydrolyzed with growing cells. (R)-1,2-Propanediol (>99 % e.e.) was obtained at 44 % yield with growing cells. Glycol sulfide, ethylene sulfate, and 1,3-PDS were converted into the corresponding diols at 94.6, 96.3, and 98.3 %, respectively. Optimal reaction conditions with lyophilized resting cells were 30 °C, pH 7.5, and cell dosage 17.9 mg cell dry wt/ml. 1,3-Propanediol was obtained from 50 mM 1,3-PDS at 97.2 % yield by lyophilized cells after 16 h. Lyophilized cells were entrapped in calcium alginate with a half-life of 263 h at 30 °C, and the total operational time of the immobilized biocatalysts could reach over 192 h with a high conversion rate.

  9. Determination of benzo(a)pyrene in the total particulate matter of cigarette smoke

    SciTech Connect

    Risner, C.H.

    1988-03-01

    A procedure for the isolation and determination of benzo(a)pyrene in the total particulate matter of cigarette smoke is described. Two high-pressure liquid chromatographic (HPLC) techniques are employed: a normal-phase, mu Bondapak-NH2, amino column is used for isolation of the benzo(a)pyrene fraction and a reversed-phase, Vydac 201TP54, polymeric octadecyl silane column is used for quantitation. Fluorescence detection is used in both modes of chromatography. The wavelengths of excitation and emission are evaluated for analytical detection. Extraction media and various isolation techniques are compared for their extraction efficiency and isolation from interferences, respectively. The procedure is efficient, reproducible, sensitive (3 pg), and gives results that compare favorably with other techniques reported in the literature for the B(a)P content of reference cigarettes, 1R1 and 1R4F.

  10. Biotin-mediated epigenetic modifications: Potential defense against the carcinogenicity of benzo[a]pyrene.

    PubMed

    Xia, Bo; Pang, Li; Zhuang, Zhi-xiong; Liu, Jian-jun

    2016-01-22

    Environmental pollution and an unhealthy lifestyle result in direct exposure to dangerous chemicals that can modify endogenous pathways and induce malignant transformation of human cells. Although the molecular mechanisms of tumorigenesis are still not well understood, epigenetic alteration may be associated with exogenous chemical-induced carcinogenicity. Given the association between nutrition and cancer, nutrient supplementation may reduce aberrant epigenetic modifications induced by chemicals, thus decreasing carcinogenesis. This paper provides an overview of the epigenetic events caused by benzo[a]pyrene, a procarcinogenic and environmental pollutant, and biotin, an essential water-soluble vitamin, and investigates potential connections between them. This paper also discusses the potential inhibitory effect of biotin-related epigenetic modifications on the carcinogenicity of benzo[a]pyrene. The effect of nutritional supplementation on tumorigenesis involving epigenetic modifications is also discussed.

  11. Epoxidation Activities of Human Cytochromes P450c17 and P450c21

    PubMed Central

    2015-01-01

    Some cytochrome P450 enzymes epoxidize unsaturated substrates, but this activity has not been described for the steroid hydroxylases. Physiologic steroid substrates, however, lack carbon–carbon double bonds in the parts of the pregnane molecules where steroidogenic hydroxylations occur. Limited data on the reactivity of steroidogenic P450s toward olefinic substrates exist, and the study of occult activities toward alternative substrates is a fundamental aspect of the growing field of combinatorial biosynthesis. We reasoned that human P450c17 (steroid 17-hydroxylase/17,20-lyase, CYP17A1), which 17- and 16α-hydroxylates progesterone, might catalyze the formation of the 16α,17-epoxide from 16,17-dehydroprogesterone (pregna-4,16-diene-3,20-dione). CYP17A1 catalyzed the novel 16α,17-epoxidation and the ordinarily minor 21-hydroxylation of 16,17-dehydroprogesterone in a 1:1 ratio. CYP17A1 mutation A105L, which has reduced progesterone 16α-hydroxylase activity, gave a 1:5 ratio of epoxide:21-hydroxylated products. In contrast, human P450c21 (steroid 21-hydroxylase, CYP21A2) converted 16,17-dehydroprogesterone to the 21-hydroxylated product and only a trace of epoxide. CYP21A2 mutation V359A, which has significant 16α-hydroxylase activity, likewise afforded the 21-hydroxylated product and slightly more epoxide. CYP17A1 wild-type and mutation A105L do not 21- or 16α-hydroxylate pregnenolone, but the enzymes 21-hydroxylated and 16α,17-epoxidized 16,17-dehydropregnenolone (pregna-5,16-diene-3β-ol-20-one) in 4:1 or 12:1 ratios, respectively. Catalase and superoxide dismutase did not prevent epoxide formation. The progesterone epoxide was not a time-dependent, irreversible CYP17A1 inhibitor. Our substrate modification studies have revealed occult epoxidase and 21-hydroxylase activities of CYP17A1, and the fraction of epoxide formed correlated with the 16α-hydroxylase activity of the enzymes. PMID:25386927

  12. Impact of Stereochemistry on Ligand Binding: X-ray Crystallographic Analysis of an Epoxide-Based HIV Protease Inhibitor.

    PubMed

    Benedetti, Fabio; Berti, Federico; Campaner, Pietro; Fanfoni, Lidia; Demitri, Nicola; Olajuyigbe, Folasade M; De March, Matteo; Geremia, Silvano

    2014-09-11

    A new pseudopeptide epoxide inhibitor, designed for irreversible binding to HIV protease (HIV-PR), has been synthesized and characterized in solution and in the solid state. However, the crystal structure of the complex obtained by inhibitor-enzyme cocrystallization revealed that a minor isomer, with inverted configuration of the epoxide carbons, has been selected by HIV-PR during crystallization. The structural characterization of the well-ordered pseudopeptide, inserted in the catalytic channel with its epoxide group intact, provides deeper insights into inhibitor binding and HIV-PR stereoselectivity, which aids development of future epoxide-based HIV inhibitors.

  13. Heritable reproductive effects of benzo[a]pyrene on the fathead minnow (Pimephales promelas)

    SciTech Connect

    White, P.A.; Robitaille, S.; Rasmussen, J.B.

    1999-08-01

    Environmental toxicologists rarely investigate multigeneration effects of aquatic contaminants. In this study the authors investigated the survivorship of fathead minnow larvae two generations removed from an exposure to the potent mutagen benzo[a]pyrene. The F2 broods with a grandparental exposure history showed a marked decrease in survival. In the highest-exposure group, reproductive capacity and larval survivorship were significantly lower than the solvent control.

  14. Indigenous and enhanced mineralization of pyrene, benzo(a)pyrene, and carbazole in soils

    SciTech Connect

    Grosser, R.J.; Warshawsky, D.; Vestal, J.R. )

    1991-12-01

    The authors studied the mineralization of pyrene, carbazole, and benzo(a)pyrene in soils obtained from three abandoned coal gasification plants in southern Illinois. The soils had different histories of past exposure to hydrocarbon contamination and different amounts of total organic carbon, microbial biomass, and microbial activity. Mineralization was measured by using serum bottle radiorespirometry. The levels of indigenous mineralization of {sup 14}C-labeled compounds ranged from 10 to 48% for pyrene, from undetectable to 46% for carbazole, and from undetectable to 25% for benzo(a)pyrene following long-term (<180-day) incubations. Pyrene and carbazole were degraded with short or no lag periods in all soils, but benzo(a)pyrene mineralization occurred after a 28-day lag period. Mineralization was not dependent on high levels of microbial biomass and activity in the soils. Bacterial cultures that were capable of degrading pyrene and carbazole were isolated by enrichment, grown in pure culture, and reintroduced into soils. Reintroduction of a pyrene-degrading bacterium enhanced mineralization to a level of 55% within 2 days, compared with a level of 1% for the indigenous population. The carbazole degrader enhanced mineralization to a level of 45% after 7 days in a soil that showed little indigenous carbazole mineralization. The pyrene and carbazole degraders which they isolated were identified as a Mycobacterium sp. and Xanthamonas sp., respectively.

  15. Activation of Prodrug Treosulfan at pH 7.4 and 37°C Accompanied by Hydrolysis of Its Active Epoxides: Kinetic Studies with Clinical Relevance.

    PubMed

    Romański, Michał; Urbaniak, Bartosz; Kokot, Zenon; Główka, Franciszek K

    2015-12-01

    Treosulfan (TREO), originally registered for treatment of ovarian cancer, is currently being investigated for conditioning prior to hematopoietic stem cell transplantation. TREO is a prodrug, which undergoes a pH- and temperature-dependent two-step conversion to active monoepoxide [S,S-EBDM, (2S,3S)-1,2-epoxybutane-3,4-diol-4-methanesulfonate] and diepoxide [S,S-DEB, (2S,3S)-1,2:3,4-diepoxybutane]. In this paper, the kinetics of the nonenzymatic transformation of TREO at pH 7.4 and 37°C were studied for the first time including the effects of the TREO concentration, buffer concentration, ionic strength, and the presence of NaCl. Transformation of TREO was well described by a kinetic model, which included first-order reactions for TREO activation, that is, TREO → S,S-EBDM → S,S-DEB, and pseudo-first-order reactions for the hydrolytic decomposition of S,S-EBDM and S,S-DEB. In contrast to the two-step activation of TREO, the hydrolysis of epoxides was influenced by electrolytes. In phosphate-buffered saline, decomposition of S,S-EBDM and S,S-DEB (mean half-lives 25.7 and 15.4 h) proceeded much slower than their formation (mean half-lives 1.5 and 3.5 h). In conclusion, the kinetics of the nonenzymatic transformation of TREO in the presence of plasma electrolytes cannot contribute to the very low levels of S,S-EBDM and S,S-DEB observed in patient plasma. The results also indicate that elimination of TREO proceeds primarily via conversion to S,S-EBDM.

  16. Final Report: Experimental and Theoretical Studies of Surface Oxametallacycles - Connections to Heterogeneous Olefin Epoxidation

    SciTech Connect

    Mark A. Barteau

    2009-09-15

    This project has aimed at the rational design of catalysts for direct epoxidation of olefins. This chemistry remains one of the most challenging problems in heterogeneous catalysis. Although the epoxidation of ethylene by silver catalysts to form ethylene oxide (EO) has been practiced for decades, little progress has been made in expanding this technology to other products and processes. We have made significant advances through the combination of surface science experiments, Density Functional Theory (DFT) calculations, and catalytic reactor experiments, toward understanding the mechanism of this reaction on silver catalysts, and to the rational improvement of selectivity. The key has been our demonstration of surface oxametallacycle intermediates as the species that control reaction selectivity. This discovery permits the influence of catalyst promoters on selectivity to be probed, and new catalyst formulations to be developed. It also guides the development of new chemistry with potential for direct epoxidation of more complex olefins. During the award period we have focused on 1. the formation and reaction selectivity of complex olefin epoxides on silver surfaces, and 2. the influence of co-adsorbed oxygen atoms on the reactions of surface oxametallacycles on silver, and 3. the computational prediction, synthesis, characterization and experimental evaluation of bimetallic catalysts for ethylene epoxidation. The significance of these research thrusts is as follows. Selective epoxidation of olefins more complex than ethylene requires suppression of not only side reactions available to the olefin such as C-H bond breaking, but it requires formation and selective ring closure of the corresponding oxametallacycle intermediates. The work carried out under this grant has significantly advanced the field of catalyst design from first principles. The combination of computational tools, surface science, and catalytic reactor experiments in a single laboratory has few

  17. Epoxide-mediated differential packaging of Cif and other virulence factors into outer membrane vesicles.

    PubMed

    Ballok, Alicia E; Filkins, Laura M; Bomberger, Jennifer M; Stanton, Bruce A; O'Toole, George A

    2014-10-01

    Pseudomonas aeruginosa produces outer membrane vesicles (OMVs) that contain a number of secreted bacterial proteins, including phospholipases, alkaline phosphatase, and the CFTR inhibitory factor (Cif). Previously, Cif, an epoxide hydrolase, was shown to be regulated at the transcriptional level by epoxides, which serve as ligands of the repressor, CifR. Here, we tested whether epoxides have an effect on Cif levels in OMVs. We showed that growth of P. aeruginosa in the presence of specific epoxides but not a hydrolysis product increased Cif packaging into OMVs in a CifR-independent fashion. The outer membrane protein, OprF, was also increased under these conditions, but alkaline phosphatase activity was not significantly altered. Additionally, we demonstrated that OMV shape and density were affected by epoxide treatment, with two distinct vesicle fractions present when cells were treated with epibromohydrin (EBH), a model epoxide. Vesicles isolated from the two density fractions exhibited different protein profiles in Western blotting and silver staining. We have shown that a variety of clinically or host-relevant treatments, including antibiotics, also alter the proteins packaged in OMVs. Proteomic analysis of purified OMVs followed by an analysis of transposon mutant OMVs yielded mutants with altered vesicle packaging. Finally, epithelial cell cytotoxicity was reduced in the vesicles formed in the presence of EBH, suggesting that this epoxide alters the function of the OMVs. Our data support a model whereby clinically or host-relevant signals mediate differential packaging of virulence factors in OMVs, which results in functional consequences for host-pathogen interactions.

  18. Patulin biosynthesis: Epoxidation of toluquinol and gentisyl alcohol by particulate preparations from Penicillium patulum

    SciTech Connect

    Priest, J.W.; Light, R.J. )

    1989-11-14

    A crude extract that catalyzes the epoxidation of toluquinol and gentisyl alcohol was isolated from cultures of Penicillium patulum. About 60% of the activity sedimented from crude extract upon centrifugation at 105000g for 2 h, and at 30000g for 30 min after precipitation with 30% ammonium sulfate and resuspension in buffer. The quinone epoxide phyllostine, a product of gentisyl alcohol epoxidation, has previously been shown to be an intermediate in the biosynthesis of patulin and was shown to be further converted to neopatulin by the extract. The epoxide product of toluquinol, desoxyphyllostine (2-methyl-5,6-epoxy-1,4-benzoquinone), has not been reported previously from fungal cultures. Its structure was confirmed by GC-mass spectrometry and proton and {sup 13}C NMR. Its CD spectrum showed the same shape and signs as that of phyllostine, indicating that it too is an enzymatic product with a similar absolute configuration. Whereas chemical epoxidation of toluquinone and gentisly quinone occurs with hydrogen peroxide, the enzymatic epoxidation utilized oxygen and the hydroquinone. The epoxidation was inhibited by 1,10-phenanthroline, EDTA, and {rho}-(chloromercuri)benzenesulfonic acid and by degassing with nitrogen, but no inhibition was observed with KCN, catalase, or CO. The apparent K{sub m}'s were similar for the two substrates with both substrates showing inhibition at 1.0 mM. The rate of desoxyphyllostine formation was more than 10 times that of phyllostine formation at equivalent substrate concentrations. Gentisaldehyde was not a substrate for the enzyme. The epoxidase was induced in late fermentor cultures of P. patulum with the same kinetics as m-hydroxybenzyl alcohol dehydrogenase, another enzyme associated with the induction of patulin biosynthesis.

  19. Discovery of enantioselectivity of urea inhibitors of soluble epoxide hydrolase.

    PubMed

    Manickam, Manoj; Pillaiyar, Thanigaimalai; Boggu, PullaReddy; Venkateswararao, Eeda; Jalani, Hitesh B; Kim, Nam-Doo; Lee, Seul Ki; Jeon, Jang Su; Kim, Sang Kyum; Jung, Sang-Hun

    2016-07-19

    Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) in the metabolic pathway of arachidonic acid and has been considered as an important therapeutic target for chronic diseases such as hypertension, diabetes and inflammation. Although many urea derivatives are known as sEH inhibitors, the enantioselectivity of the inhibitors is not highlighted in spite of the stereoselective hydrolysis of EETs by sEH. In an effort to explore the importance of enantioselectivity in the urea scaffold, a series of enantiomers with the stereocenter adjacent to the urea nitrogen atom were prepared. The selectivity of enantiomers of 1-(α-alkyl-α-phenylmethyl)-3-(3-phenylpropyl)ureas showed wide range differences up to 125 fold with the low IC50 value up to 13 nM. The S-configuration with planar phenyl and small alkyl groups at α-position is crucial for the activity and selectivity. However, restriction of the free rotation of two α-groups with indan-1-yl or 1,2,3,4-tetrahydronaphthalen-1-yl moiety abolishes the selectivity between the enantiomers, despite the increase in activity up to 13 nM. The hydrophilic group like sulfonamido group at para position of 3-phenylpropyl motif of 1-(α-alkyl-α-phenylmethyl-3-(3-phenylpropyl)urea improves the activity as well as enantiomeric selectivity. All these ureas are proved to be specific inhibitor of sEH without inhibition against mEH.

  20. Soluble epoxide hydrolase inhibitory activity of anthraquinone components from Aloe.

    PubMed

    Sun, Ya Nan; Kim, Jang Hoon; Li, Wei; Jo, A Reum; Yan, Xi Tao; Yang, Seo Young; Kim, Young Ho

    2015-10-15

    Aloe is a short-stemmed succulent herb widely used in traditional medicine to treat various diseases and as raw material in cosmetics and heath foods. In this study, we isolated and identified two new anthraquinone derivatives, aloinoside C (6) and aloinoside D (7), together with six known compounds from an aqueous dissolved Aloe exudate. Their structures were identified by spectroscopic analysis. The inhibitory effects of the isolated compounds on soluble epoxide hydrolase (sEH) were evaluated. Compounds 1-8 inhibited sEH activity potently, with IC50 values ranging from 4.1±0.6 to 41.1±4.2 μM. A kinetic analysis of compounds 1-8 revealed that the inhibitory actions of compounds 1, 6 and 8 were non-competitive, whereas those of compounds 2-5 and 7 were the mixed-type. Molecular docking increases our understanding of receptor-ligand binding of all compounds. These results demonstrate that compounds 1-8 from Aloe are potential sEH inhibitors.

  1. A2E-epoxides damage DNA in retinal pigment epithelial cells. Vitamin E and other antioxidants inhibit A2E-epoxide formation.

    PubMed

    Sparrow, Janet R; Vollmer-Snarr, Heidi R; Zhou, Jilin; Jang, Young P; Jockusch, Steffen; Itagaki, Yasuhiro; Nakanishi, Koji

    2003-05-16

    The autofluorescent pigments that accumulate in retinal pigment epithelial cells with aging and in some retinal disorders have been implicated in the etiology of macular degeneration. The major constituent is the fluorophore A2E, a pyridinium bisretinoid. Light-exposed A2E-laden retinal pigment epithelium exhibits a propensity for apoptosis with light in the blue region of the spectrum being most damaging. Efforts to understand the events precipitating the death of the cells have revealed that during irradiation (430 nm), A2E self-generates singlet oxygen with the singlet oxygen in turn reacting with A2E to generate epoxides at carbon-carbon double bonds. Here we demonstrate that A2E-epoxides, independent of singlet oxygen, exhibit reactivity toward DNA with oxidative base changes being at least one of these lesions. Mass spectrometry revealed that the antioxidants vitamins E and C, butylated hydroxytoluene, resveratrol, a trolox analogue (PNU-83836-E), and bilberry extract reduce A2E-epoxidation, whereas single cell gel electrophoresis and cell viability studies revealed a corresponding reduction in the incidence of DNA damage and cell death. Vitamin E, a lipophilic antioxidant, produced a more pronounced decrease in A2E-epoxidation than vitamin C, and treatment with both vitamins simultaneously did not confer additional benefit. Studies in which singlet oxygen was generated by endoperoxide in the presence of A2E revealed that vitamin E, butylated hydroxytoluene, resveratrol, the trolox analogue, and bilberry reduced A2E-epoxidation by quenching singlet oxygen. Conversely, vitamin C and ginkgolide B were not efficient quenchers of singlet oxygen under these conditions.

  2. Photo and biodegradation of pyrene and benzo(a)pyrene in a model of the near surface environment

    SciTech Connect

    Parmer, K.D.

    1993-01-01

    A statistical model that describes the photodegradation of two polycyclic aromatic hydrocarbons (PAH), pyrene and benzo(a)pyrene, in a model of the near surface aqueous environment containing suspended silica (0-18 mg/l) and humic materials (0-0.2 AU) was developed. Literature describing source and occurrence, physicochemical properties, and toxicity of the two PAH relating to the research was reviewed. Environmental parameters affecting fate and transport of the two PAH were identified using the exposure analysis model EXAMS using input from calculated or literature values of chemical properties. Molar absorptivities of pyrene and benzo(a)pyrene in an aqueous environment at concentrations near their solubility limit were estimated in the 336- to 400-nm wavelength region. Actinometer corrected direct and indirect photolysis rates of the two PAH at concentrations near their solubility limits were determined, as well as quantum yields which varied over a sixfold range for benzo(a)pyrene and an eightfold range for pyrene. Effects of potential sensitizers, pH, suspended sediment, or humic materials are attributed to photolysis rate statistically. For pyrene, humic material was the most important parameter affecting rate of photodegradation; humic material was most important for benzo(a)pyrene. Direct photodegradation products were characterized using gas chromatography/mass spectroscopy. Fifteen baseline resolved isomers of benzo(a)pyrene photodegradation products as well as three other classes of products were observed. Similar results were observed for pyrene. Respiration of microbes given parent PAH or photolyzed PAH as sole carbon source was measured as an indicator of biodegradation. Photodegraded pyrene increased respiration of microbes. A difference between respiration of microbes utilizing benzo(a)pyrene as sole carbon source versus respiration of microbes utilizing photolysis products of benzo(a)pyrene could not be supported by statistical analysis.

  3. Enantioselective Synthesis of Vicinal (R,R)-Diols by Saccharomyces cerevisiae Butanediol Dehydrogenase

    PubMed Central

    Calam, Eduard; González-Roca, Eva; Fernández, M. Rosario; Dequin, Sylvie; Parés, Xavier; Virgili, Albert

    2016-01-01

    Butanediol dehydrogenase (Bdh1p) from Saccharomyces cerevisiae belongs to the superfamily of the medium-chain dehydrogenases and reductases and converts reversibly R-acetoin and S-acetoin to (2R,3R)-2,3-butanediol and meso-2,3-butanediol, respectively. It is specific for NAD(H) as a coenzyme, and it is the main enzyme involved in the last metabolic step leading to (2R,3R)-2,3-butanediol in yeast. In this study, we have used the activity of Bdh1p in different forms—purified enzyme, yeast extracts, permeabilized yeast cells, and as a fusion protein (with yeast formate dehydrogenase, Fdh1p)—to transform several vicinal diketones to the corresponding diols. We have also developed a new variant of the delitto perfetto methodology to place BDH1 under the control of the GAL1 promoter, resulting in a yeast strain that overexpresses butanediol dehydrogenase and formate dehydrogenase activities in the presence of galactose and regenerates NADH in the presence of formate. While the use of purified Bdh1p allows the synthesis of enantiopure (2R,3R)-2,3-butanediol, (2R,3R)-2,3-pentanediol, (2R,3R)-2,3-hexanediol, and (3R,4R)-3,4-hexanediol, the use of the engineered strain (as an extract or as permeabilized cells) yields mixtures of the diols. The production of pure diol stereoisomers has also been achieved by means of a chimeric fusion protein combining Fdh1p and Bdh1p. Finally, we have determined the selectivity of Bdh1p toward the oxidation/reduction of the hydroxyl/ketone groups from (2R,3R)-2,3-pentanediol/2,3-pentanedione and (2R,3R)-2,3-hexanediol/2,3-hexanedione. In conclusion, Bdh1p is an enzyme with biotechnological interest that can be used to synthesize chiral building blocks. A scheme of the favored pathway with the corresponding intermediates is proposed for the Bdh1p reaction. PMID:26729717

  4. Metabolism of acetoin in mammalian liver slices and extracts. Interconversion with butane-2,3-diol and biacetyl.

    PubMed

    Gabriel, M A; Jabara, H; al-Khalidi, U A

    1971-10-01

    1. [(14)C]Acetoin was enzymically synthesized from [(14)C]pyruvate with a pyruvate decarboxylase preparation. Its optical activity was [alpha](20) (d)-78 degrees . 2. Large amounts (1000-fold higher than physiological concentrations) of acetoin were incubated with rat liver mince. Acetoin disappeared but very little (14)CO(2) was evolved. A compound accumulated, which was purified and identified as butane-2,3-diol. Chromatography on borate-impregnated paper indicated the presence of both the erythro and threo forms. 3. Liver extracts capable of interconverting biacetyl, acetoin and butane-2,3-diol were obtained. These interconversions were catalysed by two different enzymes: acetoin dehydrogenase (EC 1.1.1.5) and butane-2,3-diol dehydrogenase (EC 1.1.1.4), previously identified in bacteria. Both required NAD(+) or NADP(+) as cofactors and were different from alcohol dehydrogenase. The equilibrium in both cases favoured the more reduced compound. 4. The activity of butane-2,3-diol dehydrogenase was decreased by dialysis against EDTA: the addition of Co(2+), Cu(2+), Zn(2+) and other bivalent metal ions restored activity. 5. Biacetyl reductase was resolved into multiple forms by CM-Sephadex chromatography and electrophoresis.

  5. Synthesis and SAR of 4-methyl-5-pentylbenzene-1,3-diol (MPBD), produced by Dictyostelium discoideum.

    PubMed

    Murata, Chihiro; Ogura, Tetsuhiro; Narita, Shuhei; Kondo, Anna P; Iwasaki, Natsumi; Saito, Tamao; Usuki, Toyonobu

    2016-03-01

    4-Methyl-5-pentylbenzene-1,3-diol (MPBD) is a secondary metabolite of SteelyA polyketide synthase, which controls cell aggregation and spore maturation of Dictyostelium discoideum. In this study, chemical synthesis of MPBD and its derivatives was achieved. Structure-activity relationship (SAR) studies for antimicrobial activities against Escherichia coli and Bacillus subtilis were also conducted.

  6. THE PHASE BEHAVIOR OF FLUORINATED DIOLS, DIVINYL ADIPATE, AND A FLUORINATED POLYESTER IN SUPERCRITICAL CARBON DIOXIDE. (R828131)

    EPA Science Inventory

    The use of supercritical carbon dioxide as a reaction medium for polyester synthesis is hindered by the low solubility of diols in CO2. However, it has been previously demonstrated that fluorinated compounds can exhibit greater miscibility with carbon dioxide than t...

  7. Bile acids. 38. Conversion of 5 -cholestane-3 ,7 -diol to allo bile acids by the rat.

    PubMed

    Noll, B W; Doisy, E A; Elliott, W H

    1973-07-01

    5alpha-[4-(14)C, 3alpha-(3)H]Cholestane-3beta,7alpha-diol was prepared from individual samples of 5alpha-[3alpha-(3)H]cholestane-3beta,7alpha-diol and 5alpha-[4-(14)C]cholestane-3beta,7alpha-diol, each derived from 3beta-acetoxycholest-5-en-7-one. Bile was collected for 11 days from adult male rats, with cannulated bile ducts, that had received intraperitoneally 0.90-0.92 mg of the doubly labeled diol. Bile from the first 10 hr, containing 63% of the administered (14)C and 6% of the (3)H, was hydrolyzed, and the bile acids were separated by acetic acid partition chromatography. Allochenodeoxycholic and allocholic acids contained at least 20.6% and 48.6%, respectively, of the (14)C retained in the biliary acids. Small amounts of (14)C (2.5% and 1.9%, respectively) were present in the 3beta isomers of these acids, but the tritium content totaled more than half of that found in the bile acid fraction. No evidence was obtained for presence of the extensive quantities of the allomuricholates.

  8. Synthesis and physicochemical properties of epoxidized Tmp trioleate by in situ method

    SciTech Connect

    Samidin, Salma; Salimon, Jumat

    2014-09-03

    Tmp trioleate was initially synthesized via esterification of trimetilolprapane and oleic acid (90%) using 1.5% of H{sub 2}SO{sub 4} as a catalyst. The production of Tmp trioleate was observed at 98% (w/w). The iodine value of Tmp trioleate was analyzed for further reaction of epoxidation. Epoxide was important reaction as an intermediate for preparation of chemical modified lubricants from vegetable oils. Finding the best way of epoxidation process will give high quality for further modification of oil instead of reduce the cost and time for the preparation process during reaction of epoxidation. In this study, the epoxidation of unsaturation Tmp trioleate with peroxyformic acid generated in-situ from hydrogen peroxide 30% in H{sub 2}O{sub 2} with formic acid was studied. 95% conversion to oxygen oxirane content (OOC) ring was obtained. The derivatization showed an improvement of the compound's oxidative stability evidenced from pressurized differential scanning calorimetry (PDSC) data which are 177°C to 200°C. Physicochemical properties showed increasing of temperature of flash point from 280°C to 300°C and viscosity index (VI) from 146 to 154. However, the pour point showed increasing temperature which was −58.81°C to −17.32°C. From the data obtained, these derivatives have shown better performance of lubricity properties. Overall, the data indicates that these performances are compatible to the commercial lubricants.

  9. Synthesis and physicochemical properties of epoxidized Tmp trioleate by in situ method

    NASA Astrophysics Data System (ADS)

    Samidin, Salma; Salimon, Jumat

    2014-09-01

    Tmp trioleate was initially synthesized via esterification of trimetilolprapane and oleic acid (90%) using 1.5% of H2SO4 as a catalyst. The production of Tmp trioleate was observed at 98% (w/w). The iodine value of Tmp trioleate was analyzed for further reaction of epoxidation. Epoxide was important reaction as an intermediate for preparation of chemical modified lubricants from vegetable oils. Finding the best way of epoxidation process will give high quality for further modification of oil instead of reduce the cost and time for the preparation process during reaction of epoxidation. In this study, the epoxidation of unsaturation Tmp trioleate with peroxyformic acid generated in-situ from hydrogen peroxide 30% in H2O2 with formic acid was studied. 95% conversion to oxygen oxirane content (OOC) ring was obtained. The derivatization showed an improvement of the compound's oxidative stability evidenced from pressurized differential scanning calorimetry (PDSC) data which are 177°C to 200°C. Physicochemical properties showed increasing of temperature of flash point from 280°C to 300°C and viscosity index (VI) from 146 to 154. However, the pour point showed increasing temperature which was -58.81°C to -17.32°C. From the data obtained, these derivatives have shown better performance of lubricity properties. Overall, the data indicates that these performances are compatible to the commercial lubricants.

  10. Synthetic, crystallographic, computational, and biological studies of 1,4-difluorobenzo[c]phenanthrene and its metabolites.

    PubMed

    Bae, Suyeal; Mah, Heduck; Chaturvedi, Surendrakumar; Jeknic, Tamara Musafia; Baird, William M; Katz, Amy K; Carrell, H L; Glusker, Jenny P; Okazaki, Takao; Laali, Kenneth K; Zajc, Barbara; Lakshman, Mahesh K

    2007-09-28

    1,4-Difluorobenzo[c]phenanthrene (1,4-DFBcPh) and its putative metabolites, the dihydrodiol and diol epoxides, have been synthesized and structurally characterized, and the extent of DNA binding by the metabolites has been assessed. 1,4-DFBcPh and 1,4-difluoro-10-methoxybenzo[c]phenanthrene were prepared by photochemical cyclization of appropriate naphthylphenylethylenes. The dihydrodiol was synthesized from 1,4-difluoro-10-methoxybenzo[c]phenanthrene, and the diol epoxides were diastereoselectively synthesized from the dihydrodiol. Interesting differences were noted in 1H NMR spectra of the series 1 (syn) diol epoxides of benzo[c]phenanthrene (BcPh) and 1,4-DFBcPh; the BcPh diol epoxide displays a quasi-diequatorial orientation of the hydroxyl groups, but in the 1,4-DFBcPh case these are diaxially disposed. This difference probably stems from the presence of the fjord-region fluorine atom in 1,4-DFBcPh. A through-space, fjord-region H-F coupling has also been observed for 1,4-DFBcPh and its derivatives. Comparative X-ray crystallographic analyses of BcPh and 1,4-DFBcPh and their dihydrodiols show that introduction of fluorine increases the molecular distortion by about 6-7 degrees . As a guide to estimating the molecular distortion and its effects, and for comparison with the X-ray structures in known cases, optimized structures of BcPh, 1,4-DFBcPh, and 1,4-DMBcPh (the dimethyl analogue) as well as their dihydrodiols and diol epoxides were computed. Relative aromaticities of these compounds were assessed by nucleus-independent chemical shift calculations, and 13C NMR chemical shifts were computed by gauge-inducing atomic orbital calculations. 1,4-DFBcPh and its dihydrodiol were subjected to metabolism, and the amount of DNA binding in human breast cancer MCF-7 cells was assessed. The extent of DNA binding was then compared with that for BcPh and its dihydrodiol and the potent carcinogen benzo[a]pyrene. The 1,4-DFBcPh series 2 (anti) diol epoxide-derived DNA

  11. Dehydration polycondensation of dicarboxylic acids and diols using sublimating strong brønsted acids.

    PubMed

    Moyori, Takaya; Tang, Tang; Takasu, Akinori

    2012-05-14

    We investigated catalytic activities of strong brønsted acids for dehydration polycondensations of dicarboxylic acids and diols, which were carried out at low temperature (<100 °C) under reduced pressure (0.3-3 mmHg). Strong Brønsted acids, bis(perfluoroalkanesulfonyl)imide and perfluoroalkanesulfonic acid, showed higher activity than p-toluenesulfonic acid or rare-earth catalysts at 60 °C. In particular, bis(nonafluorobutanesulfonyl)imide (Nf(2)NH) showed the highest activity to synthesize not only aliphatic polyester (M(n) > 19000) but also aromatic polyester (M(n) > 7000). The used Nf(2)NH was sublimated from the reaction flask during polycondensation, and the sublimate, Nf(2)NH, was extra pure so that we can reuse the catalyst without loss of the activity in the dehydration polycondensations.

  12. Dispersion of Vesicles Composed of Industrially Produced Alkyl (Oligo) Glucoside Using Diol-Boron Complexation.

    PubMed

    Aikawa, Tatsuo; Asano, Yuuka; Kondo, Takeshi; Yuasa, Makoto

    2016-07-01

    Alkyl (oligo)glucosides (AOG) are known to be environmentally compatible amphiphiles whose commercial applicability should be broadened. The present paper describes the preparation of molecular assemblies of industrially produced AOG, which is a mixture composed of different length of alkyl chains (C9-C12) with oligoglucoside moiety with a few (1-3) of glucose units. It was also described that regulation of the dispersibility of the molecular assemblies prepared by diol-boron complexation between the sugar moiety on AOG and boric acid in a dispersion medium. The molecular assembly of AOG was successfully formed by mixing AOG and cholesterols (CH). When using a suitable amount of CH (20-40 mol% with respect to AOG), the molecular assembly formed a vesicle structure. The dispersion ability of the resulting vesicle was dependent on both the boric acid concentration and pH of the dispersion medium. The light-scattering and ζ-potential measurements revealed that high concentrations (≥10 mM) of boric acid improved dispersibility the vesicles. In contrast, the vesicle agglomerated at low concentrations of boric acid (1-7.5 mM). In the absence of boric acid in dispersion medium, the vesicles were completely agglomerated. The optimum pH range for vesicle dispersion was found to be from neutral to basic (7.4-10.1). The (11)B NMR study revealed that borate ester formation occurred between boric acid and the diol of the sugar moiety on AOG vesicle. The present data suggest that borate ester formation that occurred on the surface of the vesicle provided negative charge to the vesicles, contributing to their dispersion via repulsive forces.

  13. 40 CFR 721.10313 - Fatty acids, C16-18 and C18-unsatd., Me esters, epoxidized.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...., Me esters, epoxidized. 721.10313 Section 721.10313 Protection of Environment ENVIRONMENTAL PROTECTION... New Uses for Specific Chemical Substances § 721.10313 Fatty acids, C16-18 and C18-unsatd., Me esters... identified as fatty acids, C16-18 and C18-unsatd., Me esters, epoxidized (PMN P-02-249; CAS No....

  14. 40 CFR 721.10313 - Fatty acids, C16-18 and C18-unsatd., Me esters, epoxidized.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...., Me esters, epoxidized. 721.10313 Section 721.10313 Protection of Environment ENVIRONMENTAL PROTECTION... New Uses for Specific Chemical Substances § 721.10313 Fatty acids, C16-18 and C18-unsatd., Me esters... identified as fatty acids, C16-18 and C18-unsatd., Me esters, epoxidized (PMN P-02-249; CAS No....

  15. 40 CFR 721.10313 - Fatty acids, C16-18 and C18-unsatd., Me esters, epoxidized.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...., Me esters, epoxidized. 721.10313 Section 721.10313 Protection of Environment ENVIRONMENTAL PROTECTION... New Uses for Specific Chemical Substances § 721.10313 Fatty acids, C16-18 and C18-unsatd., Me esters... identified as fatty acids, C16-18 and C18-unsatd., Me esters, epoxidized (PMN P-02-249; CAS No....

  16. Epoxidation of alkenes through oxygen activation over a bifunctional CuO/Al2O3 catalyst.

    PubMed

    Scotti, Nicola; Ravasio, Nicoletta; Zaccheria, Federica; Psaro, Rinaldo; Evangelisti, Claudio

    2013-03-07

    The epoxidation of alkenes was carried out over a CuO/Al(2)O(3) catalyst using cumene as an oxygen carrier, through a one-pot reaction, giving high conversion and selectivity with different substrates. Trans-β-methylstyrene gave the corresponding epoxide in 95% yield after 3 h.

  17. Successive transformation of benzo[a]pyrene by laccase of Trametes versicolor and pyrene-degrading Mycobacterium strains.

    PubMed

    Zeng, Jun; Lin, Xiangui; Zhang, Jing; Zhu, Hong; Chen, Hong; Wong, Ming Hung

    2013-04-01

    We previously hypothesized that polycyclic aromatic hydrocarbon (PAH)-degrading bacteria that produce laccase may enhance the degree of benzo[a]pyrene mineralization. However, whether the metabolites of benzo[a]pyrene oxidized by laccase can be further transformed by PAH degraders remains unknown. In this study, pyrene-degrading mycobacteria with diverse degradation properties were isolated and employed for investigating the subsequent transformation on the metabolites of benzo[a]pyrene oxidized by fungal laccase of Trametes versicolor. The results confirm the successive transformation of benzo[a]pyrene metabolites, 6-benzo[a]pyrenyl acetate, and quinones by Mycobacterium strains, and report the discovery of the involvement of a O-methylation mediated pathway in the process. In detail, the vast majority of metabolite 6-benzo[a]pyrenyl acetate was transformed into benzo[a]pyrene quinones or methoxybenzo[a]pyrene, via two distinct steps that were controlled by the catechol-O-methyltransferase mediated O-methylation, while quinones were reduced to dihydroxybenzo[a]pyrene and further transformed into dimethoxy derivatives.

  18. Effects of cooking methods and tea marinades on the formation of benzo[a]pyrene in grilled pork belly (Samgyeopsal).

    PubMed

    Park, Keun-Cheol; Pyo, HeeSoo; Kim, WooSeok; Yoon, Ki Sun

    2017-02-14

    We investigated the effects of different grilling tools, temperatures, and tea marinades on the formation of benzo[a]pyrene in grilled pork belly as well as the antioxidant capacities of tea marinades. The least amount of benzo[a]pyrene was detected in modified charcoal-grilled pork belly (1.28μg/kg). The highest risk factors for the formation of benzo[a]pyrene are direct contact with flames and fat excess on the heating source. A modified charcoal grill can be used as an alternative grilling tool to meet consumer needs for safety and taste. The marination of pork bellies with tea increased radical-scavenging activity and prevented lipid oxidation in proportion to the concentration of tea infusion and marinating time. The yerba mate tea marinade significantly increased the radical-scavenging activity and prevented benzo[a]pyrene formation more than the green tea marinade. Tea marinade can be applied to seasoning or sauce as pretreatment to preserve the quality of meat and to decrease benzo[a]pyrene formation during cooking.

  19. Benzo(a)pyrene and 7,12-dimethylbenz(a)anthrecene differentially affect bone marrow cells of the lymphoid and myeloid lineages

    SciTech Connect

    Galvan, Noe; Page, Todd J.; Czuprynski, Charles J.; Jefcoate, Colin R. . E-mail: jefcoate@facstaff.wisc.edu

    2006-06-01

    Polycyclic aromatic hydrocarbons (PAHs) are common environmental contaminants that are carcinogenic and immunosuppressive. Benzo(a)pyrene (BP) and 7,12-dimethylbenz(a)anthracene (DMBA) are two prototypic PAHs known to impair the cell-mediated and humoral immune responses. We have previously shown that, in C57BL/6J mice, total bone marrow (BM) cellularity decreased two-fold following intraperitoneal DMBA treatment but not BP treatment. Here, we have used flow cytometry to demonstrate that BP and DMBA differentially alter the lymphoid and myeloid lineages. Following DMBA treatment, the pro/pre B-lymphocytes (B220{sup lo}/IgM{sup -}) and the immature B-lymphocytes (B220{sup lo}/IgM{sup +}) significantly decreased, while the mature B-lymphocytes (B220{sup hi}/IgM{sup +}) remained unaffected. In contrast, BP treatment decreased the pro/pre B-lymphocytes, and did not affect the immature B-lymphocytes or mature B-lymphocytes. The Gr-1{sup +} cells of the myeloid lineage were depleted 50% following DMBA treatment and only minimally depleted following BP treatment. Interestingly, the monocytes (7/4{sup +}1A8{sup lo}) and neutrophils (7/4{sup +}1A8{sup hi}) within this Gr-1{sup +} population were differentially affected by these PAHs. Monocytes and neutrophils were depleted following DMBA treatment whereas neutrophils decreased and monocytes increased following BP treatment. Although TNF{alpha} and CYP1B1 are implicated as essential mediators of hypocellularity, the similar induction of TNF{alpha} mRNA and CYP1B1 mRNA in the BM by BP and DMBA suggests that they are not limiting factors in mediating the different effects of these PAHs. Given that similar amounts of BP and DMBA reach the BM when administered intraperitoneally, their differential effects on the lymphoid and myeloid lineages probably stem from differences in reactive metabolites such as PAH quinones and PAH-dihydrodiol-epoxides.

  20. Soluble epoxide hydrolase limits mechanical hyperalgesia during inflammation

    PubMed Central

    2011-01-01

    Background Cytochrome-P450 (CYP450) epoxygenases metabolise arachidonic acid (AA) into four different biologically active epoxyeicosatrienoic acid (EET) regioisomers. Three of the EETs (i.e., 8,9-, 11,12- and 14,15-EET) are rapidly hydrolysed by the enzyme soluble epoxide hydrolase (sEH). Here, we investigated the role of sEH in nociceptive processing during peripheral inflammation. Results In dorsal root ganglia (DRG), we found that sEH is expressed in medium and large diameter neurofilament 200-positive neurons. Isolated DRG-neurons from sEH-/- mice showed higher EET and lower DHET levels. Upon AA stimulation, the largest changes in EET levels occurred in culture media, indicating both that cell associated EET concentrations quickly reach saturation and EET-hydrolyzing activity mostly effects extracellular EET signaling. In vivo, DRGs from sEH-deficient mice exhibited elevated 8,9-, 11,12- and 14,15-EET-levels. Interestingly, EET levels did not increase at the site of zymosan-induced inflammation. Cellular imaging experiments revealed direct calcium flux responses to 8,9-EET in a subpopulation of nociceptors. In addition, 8,9-EET sensitized AITC-induced calcium increases in DRG neurons and AITC-induced calcitonin gene related peptide (CGRP) release from sciatic nerve axons, indicating that 8,9-EET sensitizes TRPA1-expressing neurons, which are known to contribute to mechanical hyperalgesia. Supporting this, sEH-/- mice showed increased nociceptive responses to mechanical stimulation during zymosan-induced inflammation and 8,9-EET injection reduced mechanical thresholds in naive mice. Conclusion Our results show that the sEH can regulate mechanical hyperalgesia during inflammation by inactivating 8,9-EET, which sensitizes TRPA1-expressing nociceptors. Therefore we suggest that influencing the CYP450 pathway, which is actually highly considered to treat cardiovascular diseases, may cause pain side effects. PMID:21970373

  1. Soluble epoxide hydrolase: a novel therapeutic target in stroke

    PubMed Central

    Zhang, Wenri; Koerner, Ines P; Noppens, Ruediger; Grafe, Marjorie; Tsai, Hsing-Ju; Morisseau, Christophe; Luria, Ayala; Hammock, Bruce D; Falck, John R; Alkayed, Nabil J

    2009-01-01

    The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are produced in brain and perform important biological functions, including protection from ischemic injury. The beneficial effect of EETs, however, is limited by their metabolism via soluble epoxide hydrolase (sEH). We tested the hypothesis that sEH inhibition is protective against ischemic brain damage in vivo by a mechanism linked to enhanced cerebral blood flow (CBF). We determined expression and distribution of sEH immunoreactivity (IR) in brain, and examined the effect of sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE) on CBF and infarct size after experimental stroke in mice. Mice were administered a single intraperitoneal injection of AUDA-BE (10 mg/kg) or vehicle at 30 mins before 2-h middle cerebral artery occlusion (MCAO) or at reperfusion, in the presence and absence of P450 epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH). Immunoreactivity for sEH was detected in vascular and non-vascular brain compartments, with predominant expression in neuronal cell bodies and processes. 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid butyl ester was detected in plasma and brain for up to 24 h after intraperitoneal injection, which was associated with inhibition of sEH activity in brain tissue. Finally, AUDA-BE significantly reduced infarct size at 24 h after MCAO, which was prevented by MS-PPOH. However, regional CBF rates measured by iodoantipyrine (IAP) autoradiography at end ischemia revealed no differences between AUDA-BE- and vehicle-treated mice. The findings suggest that sEH inhibition is protective against ischemic injury by non-vascular mechanisms, and that sEH may serve as a therapeutic target in stroke. PMID:17440491

  2. Increased silver activity for direct propylene epoxidation via subnanometer size effects.

    SciTech Connect

    Lei, Y.; Mehmood, F.; Lee, S.; Greeley, J. P.; Lee, B.; Seifert, S.; Winans, R. E.; Elam, J. E.; Meyer, R. J.; Redfern, P. C.; Teschner, D.; Schlogl, R.; Pellin, M. J.; Curtiss, L. A.; Vajda, S.; Univ. of Illinois at Chicago; Fritz-Haber Inst. der Max-Planck-Gesellschaft; Yale Univ.

    2010-04-09

    Production of the industrial chemical propylene oxide is energy-intensive and environmentally unfriendly. Catalysts based on bulk silver surfaces with direct propylene epoxidation by molecular oxygen have not resolved these problems because of substantial formation of carbon dioxide. We found that unpromoted, size-selected Ag{sub 3} clusters and {approx}3.5-nanometer Ag nanoparticles on alumina supports can catalyze this reaction with only a negligible amount of carbon dioxide formation and with high activity at low temperatures. Density functional calculations show that, relative to extended silver surfaces, oxidized silver trimers are more active and selective for epoxidation because of the open-shell nature of their electronic structure. The results suggest that new architectures based on ultrasmall silver particles may provide highly efficient catalysts for propylene epoxidation.

  3. Increased Silver Activity for Direct Propylene Epoxidation via Subnanometer Size Effects

    SciTech Connect

    Lei, Y.; Mehmood, Faisal; Lee, Sang Soo; Greeley, Jeffrey P.; Lee, Byeongdu; Seifert, Soenke; Winans, R. E.; Elam, J. W.; Meyer, R. J.; Redfern, Paul C.; Teschner, D.; Schlogl, Robert; Pellin, M. J.; Curtiss, Larry A.; Vajda, S.

    2010-04-09

    Production of the industrial chemical propylene oxide is energy-intensive and environmentally unfriendly. Catalysts based on bulk silver surfaces with direct propylene epoxidation by molecular oxygen have not resolved these problems because of substantial formation of carbon dioxide. We found that unpromoted, size-selected Ag3 clusters and ~3.5-nanometer Ag nanoparticles on alumina supports can catalyze this reaction with only a negligible amount of carbon dioxide formation and with high activity at low temperatures. Density functional calculations show that, relative to extended silver surfaces, oxidized silver trimers are more active and selective for epoxidation because of the open-shell nature of their electronic structure. The results suggest that new architectures based on ultrasmall silver particles may provide highly efficient catalysts for propylene epoxidation.

  4. A broadly applicable and practical oligomeric (salen) Co catalyst for enantioselective epoxide ring-opening reactions

    PubMed Central

    White, David E.; Tadross, Pamela M.; Lu, Zhe

    2014-01-01

    The (salen) Co catalyst (4a) can be prepared as a mixture of cyclic oligomers in a short, chromatography-free synthesis from inexpensive, commercially available precursors. This catalyst displays remarkable enhancements in reactivity and enantioselectivity relative to monomeric and other multimeric (salen) Co catalysts in a wide variety of enantioselective epoxide ring-opening reactions. The application of catalyst 4a is illustrated in the kinetic resolution of terminal epoxides by nucleophilic ring-opening with water, phenols, and primary alcohols; the desymmetrization of meso epoxides by addition of water and carbamates; and the desymmetrization of oxetanes by intramolecular ring opening with alcohols and phenols. The favorable solubility properties of complex 4a under the catalytic conditions facilitated mechanistic studies, allowing elucidation of the basis for the beneficial effect of oligomerization. Finally, a catalyst selection guide is provided to delineate the specific advantages of oligomeric catalyst 4a relative to (salen) Co monomer 1 for each reaction class. PMID:25045188

  5. A broadly applicable and practical oligomeric (salen) Co catalyst for enantioselective epoxide ring-opening reactions.

    PubMed

    White, David E; Tadross, Pamela M; Lu, Zhe; Jacobsen, Eric N

    2014-07-08

    The (salen) Co catalyst (4a) can be prepared as a mixture of cyclic oligomers in a short, chromatography-free synthesis from inexpensive, commercially available precursors. This catalyst displays remarkable enhancements in reactivity and enantioselectivity relative to monomeric and other multimeric (salen) Co catalysts in a wide variety of enantioselective epoxide ring-opening reactions. The application of catalyst 4a is illustrated in the kinetic resolution of terminal epoxides by nucleophilic ring-opening with water, phenols, and primary alcohols; the desymmetrization of meso epoxides by addition of water and carbamates; and the desymmetrization of oxetanes by intramolecular ring opening with alcohols and phenols. The favorable solubility properties of complex 4a under the catalytic conditions facilitated mechanistic studies, allowing elucidation of the basis for the beneficial effect of oligomerization. Finally, a catalyst selection guide is provided to delineate the specific advantages of oligomeric catalyst 4a relative to (salen) Co monomer 1 for each reaction class.

  6. Inhibiting an Epoxide Hydrolase Virulence Factor from Pseudomonas aeruginosa Protects CFTR.

    PubMed

    Bahl, Christopher D; Hvorecny, Kelli L; Bomberger, Jennifer M; Stanton, Bruce A; Hammock, Bruce D; Morisseau, Christophe; Madden, Dean R

    2015-08-17

    Opportunistic pathogens exploit diverse strategies to sabotage host defenses. Pseudomonas aeruginosa secretes the CFTR inhibitory factor Cif and thus triggers loss of CFTR, an ion channel required for airway mucociliary defense. However, the mechanism of action of Cif has remained unclear. It catalyzes epoxide hydrolysis, but there is no known role for natural epoxides in CFTR regulation. It was demonstrated that the hydrolase activity of Cif is strictly required for its effects on CFTR. A small-molecule inhibitor that protects this key component of the mucociliary defense system was also uncovered. These results provide a basis for targeting the distinctive virulence chemistry of Cif and suggest an unanticipated role of physiological epoxides in intracellular protein trafficking.

  7. Epoxidized natural rubber toughened aqueous resole type liquefied EFB resin: Physical and chemical characterization

    NASA Astrophysics Data System (ADS)

    Amran, Umar Adli; Zakaria, Sarani; Chia, Chin Hua

    2013-11-01

    A preliminary study on the reaction between aqueous resole type resinified liquefied palm oil empty fruit bunches fibres (RLEFB) with epoxidized natural rubber (ENR). Liquefaction of empty fruit bunches (EFB) is carried out at different ratio of phenol to EFB (P:EFB). Resole type phenolic resin is prepared using sodium hydroxide (NaOH) as the catalyst with the ratio of liquefied EFB (LEFB) to formaldehyde (LEFB:F) of 1:1.8. 50% epoxidation of epoxidized natural rubber (ENR-50) is used to react with resole resin by mixing with ENR with aqueous resole resin. The cured resin is characterized with FT-IR and SEM. Aqueous system have been found to be unsuitable medium in the reaction between resin and ENR. This system produced a highly porous product when RLEFB/ENR resin is cured.

  8. Enantioselective epoxidation with chiral MN(III)(salen) catalysts: kinetic resolution of aryl-substituted allylic alcohols.

    PubMed

    Adam, W; Humpf, H U; Roschmann, K J; Saha-Möller, C R

    2001-08-24

    A set of aryl-substituted allylic alcohols rac-2 has been epoxidized by chiral Mn(salen*) complexes 1 as the catalyst and iodosyl benzene (PhIO) as the oxygen source. Whereas one enantiomer of the allylic alcohol 2 is preferentially epoxidized to give the threo- or cis-epoxy alcohol 3 (up to 80% ee) as the main product (dr up to >95:5), the other enantiomer of 2 is enriched (up to 53% ee). In the case of 1,1-dimethyl-1,2-dihydronaphthalen-2-ol (2c), the CH oxidation to the enone 4c proceeds enantioselectively and competes with the epoxidation. The absolute configurations of the allylic alcohols 2 and their epoxides 3 have been determined by chemical correlation or CD spectroscopy. The observed diastereo- and enantioselectivities in the epoxidation reactions are rationalized in terms of a beneficial interplay between the hydroxy-directing effect and the attack along the Katsuki trajectory.

  9. A simple and effective catalytic system for epoxidation of aliphatic terminal alkenes with manganese(II) as the catalyst.

    PubMed

    Ho, Kam-Piu; Wong, Wing-Leung; Lam, Kin-Ming; Lai, Cheuk-Piu; Chan, Tak Hang; Wong, Kwok-Yin

    2008-01-01

    A simple catalytic system that uses commercially available manganese(II) perchlorate as the catalyst and peracetic acid as the oxidant is found to be very effective in the epoxidation of aliphatic terminal alkenes with high product selectivity at ambient temperature. Many terminal alkenes are epoxidised efficiently on a gram scale in less than an hour to give excellent yields of isolated product (>90 %) of epoxides in high purity. Kinetic studies with some C9-alkenes show that the catalytic system is more efficient in epoxidising terminal alkenes than internal alkenes, which is contrary to most commonly known epoxidation systems. The reaction rate for epoxidation decreases in the order: 1-nonene>cis-3-nonene>trans-3-nonene. ESI-MS and EPR spectroscopic studies suggest that the active form of the catalyst is a high-valent oligonuclear manganese species, which probably functions as the oxygen atom-transfer agent in the epoxidation reaction.

  10. Synthesis of a precursor for the preparation of 9 alpha,11 alpha-tritiated 5 alpha-androstane-3 alpha,17 beta-diol 17-glucuronide

    SciTech Connect

    Rao, P.N.; Damodaran, K.M.

    1984-03-01

    Starting from 11 beta-hydroxytestosterone, the synthesis of a strategic precursor, C-9 (11) unsaturated 5 alpha-androstane-3 alpha, 17 beta-diol 17-glucuronide (9a), for the preparation of 9 alpha,11 alpha-tritiated 5 alpha-androstane-3 alpha, 17 beta-diol 17-glucuronide has been achieved. The authors optimized the reaction conditions for catalytic reduction employing hydrogen and subsequent base hydrolysis followed by purification on Amberlite XAD-2 resin to obtain the saturated 5 alpha-androstane-3 alpha, 17 beta-diol 17-glucuronide.

  11. Induction of hepatic cytochrome P450 isozymes, benzo(a)pyrene metabolism and DNA binding following exposure to polycyclic aromatic hydrocarbon residues generated during repeated fish fried oil in rats

    SciTech Connect

    Pandey, Manoj K.; Yadav, Sanjay; Parmar, Devendra; Das, Mukul . E-mail: mditrc@rediffmail.com

    2006-06-01

    In the present study the effect of repeated fish fried oil (RFFO) and its extract (RFFE) on hepatic cytochrome P450 (CYP) isozymes, benzo(a)pyrene (BP) metabolism and DNA adduct formation was undertaken. HPLC analysis of RFFO showed the presence of several polycyclic aromatic hydrocarbons. CYP in microsomes from control and RFFO-treated animals showed a peak at 450 nm; however, a shift of 2 nm in the SORET region along with significant induction was observed in microsomes prepared from 3-methylcholanthrene (MC)- and RFFE-treated animals. Activities of hepatic ethoxyresorufin-O-deethylase, methoxyresorufin-O-deethylase, aryl hydrocarbon hydroxylase and erythromycin-N-demethylase were found to be significantly (P < 0.05) induced following exposure of RFFE, whereas none of these enzymes were altered in RFFO-treated group. Immunoblot analysis revealed that RFFE and MC were potent inducers of CYP1A1, 1A1/2 and 3A1 isozymes, where as RFFO showed no change in these protein levels. RT-PCR analysis showed induction of cDNA of CYP1A1 and CYP3A1 by RFFE treatment. Hepatic microsomes prepared from RFFE exposed animals enhanced BP metabolism with a concomitant increase in the relative proportion of BP 7,8-diol. Hepatic microsomes prepared from animals pretreated with RFFE and MC significantly enhanced the binding of [{sup 3}H]-BP to calf thymus DNA. The overall results suggest that exposure to RFFE may induce hepatic CYP isozymes thereby producing enhanced reactive metabolites with a potential to bind with DNA that may result in cancer.

  12. Asymmetric epoxidation of allylic alcohols catalyzed by vanadium-binaphthylbishydroxamic Acid complex.

    PubMed

    Noji, Masahiro; Kobayashi, Toshihiro; Uechi, Yuria; Kikuchi, Asami; Kondo, Hisako; Sugiyama, Shigeo; Ishii, Keitaro

    2015-03-20

    A vanadium-binaphthylbishydroxamic acid (BBHA) complex-catalyzed asymmetric epoxidation of allylic alcohols is described. The optically active binaphthyl-based ligands BBHA 2a and 2b were synthesized from (S)-1,1'-binaphthyl-2,2'-dicarboxylic acid and N-substituted-O-trimethylsilyl (TMS)-protected hydroxylamines via a one-pot, three-step procedure. The epoxidations of 2,3,3-trisubstituted allylic alcohols using the vanadium complex of 2a were easily performed in toluene with a TBHP water solution to afford (2R)-epoxy alcohols in good to excellent enantioselectivities.

  13. Synthesis of Marine Polycyclic Polyethers via Endo-Selective Epoxide-Opening Cascades

    PubMed Central

    Vilotijevic, Ivan; Jamison, Timothy F.

    2010-01-01

    The proposed biosynthetic pathways to ladder polyethers of polyketide origin and oxasqualenoids of terpenoid origin share a dramatic epoxide-opening cascade as a key step. Polycyclic structures generated in these biosynthetic pathways display biological effects ranging from potentially therapeutic properties to extreme lethality. Much of the structural complexity of ladder polyether and oxasqualenoid natural products can be traced to these hypothesized cascades. In this review we summarize how such epoxide-opening cascade reactions have been used in the synthesis of ladder polyethers and oxasqualenoid natural products. PMID:20411125

  14. Enantioselective epoxidation of non-functionalized alkenes using carbohydrate based salen-Mn(III) complexes.

    PubMed

    Zhao, Shanshan; Zhao, Jiquan; Zhao, Dongmin

    2007-02-05

    Three new salen ligands with carbohydrate moieties were prepared from a salicylaldehyde derivative obtained by reaction of 1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose with 3-tert-butyl-5-(chloro-methyl)-2-hydroxybenzaldehyde. These ligands were coordinated with Mn(III) to give three chiral salen-Mn(III) complexes. The complexes were characterized and employed in the asymmetric epoxidation of unfunctionalized alkenes. Catalytic results showed that although there are no chiral groups on the diimine bridge, these complexes had some enantioselectivity, which indicates the carbohydrate moiety has an asymmetric inducing effect in the epoxidation reaction.

  15. The selection reaction of homogeneous catalyst in soy-epoxide hydroxylation

    NASA Astrophysics Data System (ADS)

    Elvistia Firdaus, Flora

    2014-04-01

    Hydroxylation reaction of soy-epoxide has resulted soy-polyol; a prepolymeric material for polyurethane. The conversion and selectivity of soy-epoxide butanol based to hydroxylation was found higher than soy-ethylene glycol (EG) based. These reactions were performed by sulfur acid which commonly known as homogeneous catalyst. Conversion and selectivity of homogeneous catalyst compared to bentonite; a heteregeneous catalyst was lower as in fact the mixtures were more viscous. The catalysis were significantly effected to cell morphology. Foams were conducted by heterogeneous catalyst resulted an irregular form of windows while homogeneous catalyst are more ordered.

  16. Miscibility study of hexanoyl chitosan in blend with epoxidized natural rubber by viscometric analysis

    NASA Astrophysics Data System (ADS)

    Jamal, Asheila; Chan, C. H.; Muhammad, F. H.; Winie, Tan

    2015-08-01

    Miscibility of blends of hexanoyl chitosan and epoxidized natural rubber with 25 mol% epoxidation level (ENR25) was investigated by dilute solution viscometry (DSV). Experimental results obey the Huggins' equation in the concentration range under investigation. Intrinsic viscosities are found to vary linearly with blend composition. The difference between experimental and ideal Huggins coefficients, κ =K12-√{K1ṡK2 } is proposed to evaluate the miscibility behavior of the blends. Negative deviations from the ideal behavior indicated immiscibility between hexanoyl chitosan and ENR25.

  17. Different tumours induced by benzo(a)pyrene and its 7,8-dihydrodiol injected into adult mouse salivary gland.

    PubMed Central

    Wigley, C. B.; Amos, J.; Brookes, P.

    1978-01-01

    A comparison has been made between the carcinogenic activities of benzo(a)pyrene and the proposed proximate carcinogen, benzo(a)pyrene 7,8-dihydrodiol, in the adult C57BL mouse submandibular salivary gland. In preliminary studies using a range of doses, the dihydrodiol was slightly less active than the parent hydrocarbon in this system. There was a difference in the type of tumour induced by the 2 compounds. Benzo(a)pyrene induced tumours of the salivary glands at the site of injection, whereas the dihydrodiol induced malignant lymphosarcomas, particularly of the thymus, which were often metastatic to other orgnas. Possible reasons for the different sites of action of the 2 compounds are discussed. PMID:580763

  18. Cancer risk estimation for mixtures of coal tars and benzo(a)pyrene

    SciTech Connect

    Gaylor, D.W.; Culp, S.J.; Goldstein, L.S.; Beland, F.A.

    2000-02-01

    Two-year chronic bioassays were conducted by using B6C3F1 female mice fed several concentrations of two different mixtures of coal tars from manufactured gas waste sites or benzo(a)pyrene (BaP). The purpose of the study was to obtain estimates of cancer potency of coal tar mixtures, by using conventional regulatory methods, for use in manufactured gas waste site remediation. A secondary purpose was to investigate the validity of using the concentration of a single potent carcinogen, in this case benzo(a)pyrene, to estimate the relative risk for a coal tar mixture. The study has shown that BaP dominates the cancer risk when its concentration is greater than 6,300 ppm in the coal tar mixture. In this case the most sensitive tissue site is the forestomach. Using low-dose linear extrapolation, the lifetime cancer risk for humans is estimated to be: Risk < 1.03 x 10{sup {minus}4} (ppm coal tar in total diet) + 240 x 10{sup {minus}4} (ppm BaP in total diet), based on forestomach tumors. If the BaP concentration in the coal tar mixture is less than 6,300 ppm, the more likely case, then lung tumors provide the largest estimated upper limit of risk, Risk < 2.55 x 10{sup {minus}4} (ppm coal tar in total diet), with no contribution of BaP to lung tumors. The upper limit of the cancer potency (slope factor) for lifetime oral exposure to benzo(a)pyrene is 1.2 x 10{sup {minus}3} per {micro}g per kg body weight per day from this Good Laboratory Practice (GLP) study compared with the current value of 7.3 x 10{sup {minus}3} per {micro}g per kg body weight per day listed in the US EPA Integrated Risk Information System.

  19. Cancer risk estimation for mixtures of coal tars and benzo(a)pyrene.

    PubMed

    Gaylor, D W; Culp, S J; Goldstein, L S; Beland, F A

    2000-02-01

    Two-year chronic bioassays were conducted by using B6C3F1 female mice fed several concentrations of two different mixtures of coal tars from manufactured gas waste sites or benzo(a)pyrene (BaP). The purpose of the study was to obtain estimates of cancer potency of coal tar mixtures, by using conventional regulatory methods, for use in manufactured gas waste site remediation. A secondary purpose was to investigate the validity of using the concentration of a single potent carcinogen, in this case benzo(a)pyrene, to estimate the relative risk for a coal tar mixture. The study has shown that BaP dominates the cancer risk when its concentration is greater than 6,300 ppm in the coal tar mixture. In this case the most sensitive tissue site is the forestomach. Using low-dose linear extrapolation, the lifetime cancer risk for humans is estimated to be: Risk < 1.03 x 10(-4) (ppm coal tar in total diet) + 240 x 10(-4) (ppm BaP in total diet), based on forestomach tumors. If the BaP concentration in the coal tar mixture is less than 6,300 ppm, the more likely case, then lung tumors provide the largest estimated upper limit of risk, Risk < 2.55 x 10(-4) (ppm coal tar in total diet), with no contribution of BaP to lung tumors. The upper limit of the cancer potency (slope factor) for lifetime oral exposure to benzo(a)pyrene is 1.2 x 10(-3) per microgram per kg body weight per day from this Good Laboratory Practice (GLP) study compared with the current value of 7.3 x 10(-3) per microgram per kg body weight per day listed in the U.S. EPA Integrated Risk Information System.

  20. NADH:Cytochrome b5 Reductase and Cytochrome b5 Can Act as Sole Electron Donors to Human Cytochrome P450 1A1-Mediated Oxidation and DNA Adduct Formation by Benzo[a]pyrene

    PubMed Central

    2016-01-01

    Benzo[a]pyrene (BaP) is a human carcinogen that covalently binds to DNA after activation by cytochrome P450 (P450). Here, we investigated whether NADH:cytochrome b5 reductase (CBR) in the presence of cytochrome b5 can act as sole electron donor to human P450 1A1 during BaP oxidation and replace the canonical NADPH:cytochrome P450 reductase (POR) system. We also studied the efficiencies of the coenzymes of these reductases, NADPH as a coenzyme of POR, and NADH as a coenzyme of CBR, to mediate BaP oxidation. Two systems containing human P450 1A1 were utilized: human recombinant P450 1A1 expressed with POR, CBR, epoxide hydrolase, and cytochrome b5 in Supersomes and human recombinant P450 1A1 reconstituted with POR and/or with CBR and cytochrome b5 in liposomes. BaP-9,10-dihydrodiol, BaP-7,8-dihydrodiol, BaP-1,6-dione, BaP-3,6-dione, BaP-9-ol, BaP-3-ol, a metabolite of unknown structure, and two BaP-DNA adducts were generated by the P450 1A1-Supersomes system, both in the presence of NADPH and in the presence of NADH. The major BaP-DNA adduct detected by 32P-postlabeling was characterized as 10-(deoxyguanosin-N2-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydro-BaP (assigned adduct 1), while the minor adduct is probably a guanine adduct derived from 9-hydroxy-BaP-4,5-epoxide (assigned adduct 2). BaP-3-ol as the major metabolite, BaP-9-ol, BaP-1,6-dione, BaP-3,6-dione, an unknown metabolite, and adduct 2 were observed in the system using P450 1A1 reconstituted with POR plus NADPH. When P450 1A1 was reconstituted with CBR and cytochrome b5 plus NADH, BaP-3-ol was the predominant metabolite too, and an adduct 2 was also generated. Our results demonstrate that the NADH/cytochrome b5/CBR system can act as the sole electron donor both for the first and second reduction of P450 1A1 during the oxidation of BaP in vitro. They suggest that NADH-dependent CBR can replace NADPH-dependent POR in the P450 1A1-catalyzed metabolism of BaP. PMID:27404282

  1. [The contamination of feed, fruits and vegetables with benzo(a)pyrene in Land Brandenburg].

    PubMed

    Stoyke, M; Lusky, K; Doberschütz, K D; Göbel, R

    1994-01-01

    Benzo(a)pyren (BaP) was analysed in 218 samples of grass, hay, straw, grains, lettuce, curly kale and apples by means of thin-layer chromatography und analysing other polycyclic aromatic hydrocarbons (PAH) by capillary gas chromatography and mass-spectrometry. Despite the fact that normally BaP concentrations were relatively low, up to 13.5 micrograms BaP per kg hay (dry matter) and 19.3 micrograms BaP per kg lettuce (dry matter) could be detected at some places.

  2. A laser-excited synchronous fluorescence spectrometer for benzo(a)pyrene

    SciTech Connect

    Huebedr, D.M.; Iruela Del Olmo, M.; Stevenson, C.L.; Vo-Dinh, T.

    1995-09-01

    A laser-based synchronous scanning fluorimeter was developed for detecting polycyclic aromatic hydrocarbons (PAHs). Although extensive sample cleanup and separation are usually required, fluorescence has long been used for determination of PAHs. Amount of sample pretreatment can often be reduced when synchronous fluorescence (SF) is used, and the sensitivity of SF can be increased by the high power and narrow profile of a laser source. A small, portable, pulsed dye laser was used in this study. The instrument and its application to the determination of the carcinogen benzo(a)pyrene are described.

  3. Stereoselective synthesis of cis-p-menth-8-ene-1,7-diol, cis-p-menthane-1,7-diol, and cis-p-menthane-1,7,8-triol.

    PubMed

    Kobler, Christoph; Effenberger, Franz

    2005-04-22

    The natural products cis-p-menthane-1,7-diol (cis-IV), cis-p-menth-8-ene-1,7-diol (cis-I) and cis-p-menthane-1,7,8-triol (cis-II) are obtained starting from the corresponding cis-cyanohydrins, cis-2 and cis-7, respectively, by chemical transformation of the cyano into the hydroxymethyl group. The key step of the synthesis is the very high cis-selectivity (> or = 96 %) of the MeHNL-catalyzed HCN addition to 4-alkylcyclohexanones. From 4-isopropylcyclohexanone (1) the cyanohydrin cis-2 and from 4-(1-methylvinyl)cyclohexanone (6) the cyanohydrin cis-7 result almost quantitatively. Regioselective hydroxylation of cis-I affords the triol cis-II. X-ray crystal structure determinations of the final products confirm their cis-configuration.

  4. Investigation of the role of the 2',3'-epoxidation pathway in the bioactivation and genotoxicity of dietary allylbenzene analogs.

    PubMed

    Guenthner, T M; Luo, G

    2001-03-07

    The genotoxic potential of naturally occurring allylbenzene analogs, including safrole, eugenol, estragole, and others, has been examined in many studies over the past 30 years. It has been established that these compounds are subject to biotransformation in the liver, which can lead to the formation of reactive electrophilic intermediates. The major route of bioactivation is via hydroxylation of the 1' carbon atom of the allylic side chain. We have synthesized 2',3'- (allylic) epoxide derivatives of allylbenzene, estragole eugenol and safrole, and have used them to characterize the genotoxic potential of epoxidation at the allylic double bond for allylbenzene and its naturally occurring analogs. In order to assert that this pathway has the potential for genotoxicity, it is necessary to demonstrate (1) that epoxide metabolites of these compounds are capable of forming covalent adducts with DNA bases; and (2) that these epoxide metabolites are actually formed in vivo. We have demonstrated that allylic epoxides derived from allylbenzene and estragole are capable of forming covalent adducts with all four deoxyribonucleotides in vitro and, in the case of deoxyguanosine, form at least four different adducts. We also deduce, from evidence obtained using the isolated perfused rat liver, that formation of potentially genotoxic 2',3' epoxide metabolites occurs readily in vivo, but that these metabolites are rapidly further metabolized to less toxic dihydrodiol or glutathione conjugates. We conclude that 2',3' epoxide metabolites of allylbenzene analogs are formed in vivo and that these epoxides are sufficiently reactive to facilely form covalent bonds with DNA bases. Epoxide formation at the allylic double bond represents, therefore, a potentially genotoxic bioactivation pathway for allylbenzene analogs. However, comparison of the relative kinetics of epoxide metabolism and epoxide formation suggests that a wide margin of protection from DNA covalent adduct formation exists

  5. Prostaglandin endoperoxide synthetase and the activation of benzo(a)pyrene to reactive metabolites in vivo in guinea pigs

    SciTech Connect

    Garattini, E.; Coccia, P.; Romano, M.; Jiritano, L.; Noseda, A.; Salmona, M.

    1984-11-01

    The role of prostaglandin endoperoxide synthetase in the in vivo activation of benzo(a)pyrene to reactive metabolites capable of interacting irreversibly with cellular macromolecules was studied in guinea pig liver, lung, kidney, spleen, small intestine, colon, and brain. DNA and protein covalent binding experiments were made after systemic administration of acetylsalicylic acid (200 mg/kg) followed by radiolabeled benzo(a)pyrene (4 microgram/kg). Results are compared with a control situation in which the prostaglandin endoperoxide synthetase inhibitor (acetylsalicylic acid) was not administered. No decrease in the level of DNA or protein benzo(a)pyrene-derived covalent binding was observed in any of the tissues studied.

  6. Preparation and characterization of fluorophenylboronic acid-functionalized affinity monolithic columns for the selective enrichment of cis-diol-containing biomolecules.

    PubMed

    Li, Qianjin; Liu, Zhen

    2015-01-01

    Boronate affinity monolithic columns have been developed into an important means for the selective recognition and capture of cis-diol-containing biomolecules, such as glycoproteins, nucleosides and saccharides. The ligands of boronic acids are playing an important role in boronate affinity monolithic columns. Although several boronate affinity monoliths with high affinity toward cis-diol-containing biomolecules have been reported, only few publications are focused on their detailed procedures for preparation and characterization. This chapter describes in detail the preparation and characterization of a boronate affinity monolithic column applying 2,4-difluoro-3-formyl-phenylboronic acid (DFFPBA) as a ligand. The DFFPBA-functionalized monolithic column not only exhibited an ultrahigh boronate affinity toward cis-diol-containing biomolecules, but also showed great potential for the selective enrichment of cis-diol-containing biomolecules in real samples.

  7. Long chain diol index (LDI) as an organic-based sea surface temperature proxy in the Korean East Sea (NW Pacific)

    NASA Astrophysics Data System (ADS)

    Gal, Jong-Ku; Kim, Jung-Hyun; Kang, Su-Jin; Lee, Dong-Hun; Shin, Kyung-Hoon

    2016-04-01

    Long chain diol index (LDI) was introduced as an organic-based sea surface temperature (SST) proxy. LDI is expressed as the C30 1,15-diol abundance relative to those of C28 1,13-, C30 1,13- and C30 1,15-diols. There were a few studies which accessed the potential of LDI based on the culture, core top sediments, suspended particulate organic matters, and down-core sediments. However it is still unknown about the source of the diols and robustness as the SST proxy in the various marine environments. In the current study, we examined the applicability of the LDI in the East Sea of Korea where productivity and thus sedimentation rates are high. We will compare the LDI data with those of alkenone-based UK'37 by analyzing two multicores covering the last 100 year.

  8. 40 CFR 721.1800 - 3,3′,5,5′-Tetra-methyl-bi-phenyl-4,4′-diol.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false 3,3â²,5,5â²-Tetra-methyl-bi-phenyl-4,4â²-diol. 721.1800 Section 721.1800 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.1800 3,3′,5,5′-Tetra-methyl-bi-phenyl-4,4′-diol. (a) Chemical...

  9. 40 CFR 721.1800 - 3,3′,5,5′-Tetra-methyl-bi-phenyl-4,4′-diol.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false 3,3â²,5,5â²-Tetra-methyl-bi-phenyl-4,4â²-diol. 721.1800 Section 721.1800 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.1800 3,3′,5,5′-Tetra-methyl-bi-phenyl-4,4′-diol. (a) Chemical...

  10. 40 CFR 721.1800 - 3,3′,5,5′-Tetra-methyl-bi-phenyl-4,4′-diol.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false 3,3â²,5,5â²-Tetra-methyl-bi-phenyl-4,4â²-diol. 721.1800 Section 721.1800 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.1800 3,3′,5,5′-Tetra-methyl-bi-phenyl-4,4′-diol. (a) Chemical...

  11. 40 CFR 721.1800 - 3,3′,5,5′-Tetra-methyl-bi-phenyl-4,4′-diol.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false 3,3â²,5,5â²-Tetra-methyl-bi-phenyl-4,4â²-diol. 721.1800 Section 721.1800 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.1800 3,3′,5,5′-Tetra-methyl-bi-phenyl-4,4′-diol. (a) Chemical...

  12. 40 CFR 721.1800 - 3,3′,5,5′-Tetra-methyl-bi-phenyl-4,4′-diol.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false 3,3â²,5,5â²-Tetra-methyl-bi-phenyl-4,4â²-diol. 721.1800 Section 721.1800 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.1800 3,3′,5,5′-Tetra-methyl-bi-phenyl-4,4′-diol. (a) Chemical...

  13. Conversion of 1-alkenes into 1,4-diols through an auxiliary-mediated formal homoallylic C-H oxidation.

    PubMed

    Ghavtadze, Nugzar; Melkonyan, Ferdinand S; Gulevich, Anton V; Huang, Chunhui; Gevorgyan, Vladimir

    2014-02-01

    The ubiquitous nature of C-H bonds in organic molecules makes them attractive as a target for rapid complexity generation, but brings with it the problem of achieving selective reactions. In developing new methodologies for C-H functionalization, alkenes are an attractive starting material because of their abundance and low cost. Here we describe the conversion of 1-alkenes into 1,4-diols. The method involves the installation of a new Si,N-type chelating auxiliary group on the alkene followed by iridium-catalysed C-H silylation of an unactivated δ-C(sp(3))-H bond to produce a silolane intermediate. Oxidation of the C-Si bonds affords a 1,4-diol. The method is demonstrated to have broad scope and good functional group compatibility by application to the selective 1,4-oxygenation of several natural products and derivatives.

  14. Regioselective, borinic acid-catalyzed monoacylation, sulfonylation and alkylation of diols and carbohydrates: expansion of substrate scope and mechanistic studies.

    PubMed

    Lee, Doris; Williamson, Caitlin L; Chan, Lina; Taylor, Mark S

    2012-05-16

    Synthetic and mechanistic aspects of the diarylborinic acid-catalyzed regioselective monofunctionalization of 1,2- and 1,3-diols are presented. Diarylborinic acid catalysis is shown to be an efficient and general method for monotosylation of pyranoside derivatives bearing three secondary hydroxyl groups (7 examples, 88% average yield). In addition, the scope of the selective acylation, sulfonylation, and alkylation is extended to 1,2- and 1,3-diols not derived from carbohydrates (28 examples); the efficiency, generality, and operational simplicity of this method are competitive with those of state-of-the-art protocols including the broadly applied organotin-catalyzed or -mediated reactions. Mechanistic details of the organoboron-catalyzed processes are explored using competition experiments, kinetics, and catalyst structure-activity relationships. These experiments are consistent with a mechanism in which a tetracoordinate borinate complex reacts with the electrophilic species in the turnover-limiting step of the catalytic cycle.

  15. Recyclable polyurea-microencapsulated Pd(0) nanoparticles: an efficient catalyst for hydrogenolysis of epoxides.

    PubMed

    Ley, Steven V; Mitchell, Claire; Pears, David; Ramarao, Chandrashekar; Yu, Jin-Quan; Zhou, Wuzong

    2003-11-27

    [reaction: see text] Pd nanoparticles (approximately 2 nm in size) microencapsulated in polyurea is an efficient and recyclable catalyst for reductive ring-opening hydrogenolysis of epoxides, using either HCOOH/Et(3)N or H(2) as a hydrogen donor.

  16. A new efficient iron catalyst for olefin epoxidation with hydrogen peroxide.

    PubMed

    Mikhalyova, Elena A; Makhlynets, Olga V; Palluccio, Taryn D; Filatov, Alexander S; Rybak-Akimova, Elena V

    2012-01-18

    A new aminopyridine ligand derived from bipiperidine (the product of full reduction of bipyridine, bipy) coordinates to iron(II) in a cis-α fashion, yielding a new selective catalyst for olefin epoxidation with H(2)O(2) under limiting substrate conditions.

  17. Synthesis of epoxidized cardanol and its antioxidative properties for vegetable oils and biodiesel

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A novel antioxidant epoxidized cardanol (ECD), derived from cardanol, was synthesized and characterized by FT-IR, 1H-NMR and 13C-NMR. Oxidative stability of ECD used in vegetable oils and biodiesel was evaluated by pressurized differential scanning calorimetry (PDSC) and the Rancimat method, respect...

  18. Jacobsen protocols for large-scale epoxidation of cyclic dienyl sulfones: application to the (+)-pretazettine core.

    PubMed

    Ebrahimian, G Reza; du Jourdin, Xavier Mollat; Fuchs, Philip L

    2012-05-18

    A Jacobsen epoxidation protocol using H2O2 as oxidant was designed for the large-scale preparation of various epoxy vinyl sulfones. A number of cocatalysts were screened, and pH control led to increased reaction rate, higher turnover number, and improved reliability.

  19. Epoxide hydrolase activities and epoxy fatty acids in the mosquito Culex quinquefasciatus

    PubMed Central

    Xu, Jiawen; Morisseau, Christophe; Yang, Jun; Mamatha, Dadala M.

    2015-01-01

    Culex mosquitoes have emerged as important model organisms for mosquito biology, and are disease vectors for multiple mosquito-borne pathogens, including West Nile virus. We characterized epoxide hydrolase activities in the mosquito Culex quinquefasciatus, which suggested multiple forms of epoxide hydrolases were present. We found EH activities on epoxy eicosatrienoic acids (EETs). EETs and other eicosanoids are well-established lipid signaling molecules in vertebrates. We showed EETs can be synthesized in vitro from arachidonic acids by mosquito lysate, and EETs were also detected in vivo both in larvae and adult mosquitoes by LC-MS/MS. The EH activities on EETs can be induced by blood feeding, and the highest activity was observed in the midgut of female mosquitoes. The enzyme activities on EETs can be inhibited by urea-based inhibitors designed for mammalian soluble epoxide hydrolases (sEH). The sEH inhibitors have been shown to play diverse biological roles in mammalian systems, and they can be useful tools to study the function of EETs in mosquitoes. Besides juvenile hormone metabolism and detoxification, insect epoxide hydrolases may also play a role in regulating lipid signaling molecules, such as EETs and other epoxy fatty acids, synthesized in vivo or obtained from blood feeding by female mosquitoes. PMID:25686802

  20. Application of hydrated and anhydrous fluroantimonic acids in the polymerization of epoxidized soybean oil

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Polymerizations of epoxidized soybean oil (ESO) were catalyzed by the superacids, fluroantimonic acid hexahydrate (HSbF6•6H2O) and anhydrous fluroantimonic acid (HSbF6) using ethyl acetate solvent. This work was conducted in an effort to develop useful biodegradable polymers from renewable resources...

  1. Catalyzed ring-opening polymerization of epoxidized soybean oil by hydrated and anhydrous fluoroantimonic acids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ring-opening polymerization of epoxidized soybean oil (ESO) catalyzed by the super acid, fluroantimonic acid hexahydrate (HSbF6-6H2O), and the anhydrous form (HSbF6) in ethyl acetate was conducted in an effort to develop useful biodegradable polymers. The resulting polymerized ESO (SA-RPESO and SAA-...

  2. Catalytic epoxidation activity of keplerate polyoxomolybdate nanoball toward aqueous suspension of olefins under mild aerobic conditions.

    PubMed

    Rezaeifard, Abdolreza; Haddad, Reza; Jafarpour, Maasoumeh; Hakimi, Mohammad

    2013-07-10

    Catalytic efficiency of a sphere-shaped nanosized polyoxomolybdate {Mo132} in the aerobic epoxidation of olefins in water at ambient temperature and pressure in the absence of reducing agent is exploited which resulted good-to-high yields and desired selectivity.

  3. Engineering of an epoxide hydrolase for efficient bioresolution of bulky pharmaco substrates

    PubMed Central

    Kong, Xu-Dong; Yuan, Shuguang; Li, Lin; Chen, She; Xu, Jian-He; Zhou, Jiahai

    2014-01-01

    Optically pure epoxides are essential chiral precursors for the production of (S)-propranolol, (S)-alprenolol, and other β-adrenergic receptor blocking drugs. Although the enzymatic production of these bulky epoxides has proven difficult, here we report a method to effectively improve the activity of BmEH, an epoxide hydrolase from Bacillus megaterium ECU1001 toward α-naphthyl glycidyl ether, the precursor of (S)-propranolol, by eliminating the steric hindrance near the potential product-release site. Using X-ray crystallography, mass spectrum, and molecular dynamics calculations, we have identified an active tunnel for substrate access and product release of this enzyme. The crystal structures revealed that there is an independent product-release site in BmEH that was not included in other reported epoxide hydrolase structures. By alanine scanning, two mutants, F128A and M145A, targeted to expand the potential product-release site displayed 42 and 25 times higher activities toward α-naphthyl glycidyl ether than the wild-type enzyme, respectively. These results show great promise for structure-based rational design in improving the catalytic efficiency of industrial enzymes for bulky substrates. PMID:25331869

  4. Iron(II)-Catalyzed Asymmetric Epoxidation of Trisubstituted α,β-Unsaturated Esters

    PubMed Central

    Luo, Lan

    2015-01-01

    An asymmetric epoxidation of trisubstituted α,β-unsaturated esters is described. The oxidation utilizes a pseudo-C2-symmetric iron(II) catalyst [Fe(L*)2(CH3CN)(OTf)](OTf) and peracetic acid as oxidant, yielding the α,β-epoxyesters in high enantiomeric purity (up to 99% ee). PMID:26146482

  5. (Salen)Mn(III) Catalyzed Asymmetric Epoxidation Reactions by Hydrogen Peroxide in Water: A Green Protocol

    PubMed Central

    Ballistreri, Francesco Paolo; Gangemi, Chiara M. A.; Pappalardo, Andrea; Tomaselli, Gaetano A.; Toscano, Rosa Maria; Trusso Sfrazzetto, Giuseppe

    2016-01-01

    Enantioselective epoxidation reactions of some chosen reactive alkenes by a chiral Mn(III) salen catalyst were performed in H2O employing H2O2 as oxidant and diethyltetradecylamine N-oxide (AOE-14) as surfactant. This procedure represents an environmentally benign protocol which leads to e.e. values ranging from good to excellent (up to 95%). PMID:27420047

  6. Thermal behavior of epoxidized cardanol diethyl phosphate as novel renewable plasticizer for poly(vinyl chloride)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A novel plasticizer, epoxidized cardanol diethyl phosphate (ECEP), based on cardanol was synthesized. Chemical structure of ECEP was characterized by fourier transform infrared (FTIR), 1H-nuclear magnetic resonance(1H NMR) and 13C-nuclear magnetic resonance(13C NMR) spectroscopy. Effects of ECEP sub...

  7. Signature motifs identify an Acinetobacter Cif virulence factor with epoxide hydrolase activity.

    PubMed

    Bahl, Christopher D; Hvorecny, Kelli L; Bridges, Andrew A; Ballok, Alicia E; Bomberger, Jennifer M; Cady, Kyle C; O'Toole, George A; Madden, Dean R

    2014-03-14

    Endocytic recycling of the cystic fibrosis transmembrane conductance regulator (CFTR) is blocked by the CFTR inhibitory factor (Cif). Originally discovered in Pseudomonas aeruginosa, Cif is a secreted epoxide hydrolase that is transcriptionally regulated by CifR, an epoxide-sensitive repressor. In this report, we investigate a homologous protein found in strains of the emerging nosocomial pathogens Acinetobacter nosocomialis and Acinetobacter baumannii ("aCif"). Like Cif, aCif is an epoxide hydrolase that carries an N-terminal secretion signal and can be purified from culture supernatants. When applied directly to polarized airway epithelial cells, mature aCif triggers a reduction in CFTR abundance at the apical membrane. Biochemical and crystallographic studies reveal a dimeric assembly with a stereochemically conserved active site, confirming our motif-based identification of candidate Cif-like pathogenic EH sequences. Furthermore, cif expression is transcriptionally repressed by a CifR homolog ("aCifR") and is induced in the presence of epoxides. Overall, this Acinetobacter protein recapitulates the essential attributes of the Pseudomonas Cif system and thus may facilitate airway colonization in nosocomial lung infections.

  8. Boron Trifluoride Catalized Ring-Opening Polymerization of Epoxidized Soybean Oil in Liquid Carbon Dioxide

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Boron trifluoride diethyl etherate (BF3.OEt2) catalyzed ring-opening polymerization of epoxidized soybean oil (ESO), in liquid carbon dioxide, was conducted in an effort to develop useful biobased biodegradable polymers. The resulting polymers (RPESO) were characterized by FTIR spectroscopy, differ...

  9. Lewis Acid Catalyzed Ring-opening Polymerization of Epoxidized Soybean Oil in Liquid Carbon Dioxide

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ring-opening polymerization of epoxidized soybean oil (ESO) catalyzed by boron trifluoride diethyl etherate (BF3•OEt2), in liquid carbon dioxide, was conducted in an effort to develop useful biobased biodegradable polymers. The resulting polymers (RPESO) were characterized by FTIR spectroscopy, diff...

  10. Formation of furan fatty alkyl esters from their bis-epoxide fatty esters

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Reactions of epoxidized alkyl soyate with four different alcohols: ethanol, isopropyl alcohol, 2-ethylhexanol, benzyl alcohol, in the presence of Bronsted acid catalyst, were investigated. Products that were not reported in prior studies of similar reactions were found. These were furan fatty acid a...

  11. Formation of furan fatty alkyl esters from their bis-epoxide fatty esters

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Reactions of epoxidized alkyl soyate with four different alcohols: ethanol, isopropyl alcohol, 2-ethylhexanol, and benzyl alcohol were investigated in the presence of Bronsted acid catalyst. Products not reported in prior studies of similar reactions were found. These were furan fatty acid alkyl est...

  12. Assessment of rat liver microsomal epoxide hydrolase as a marker of hepatocarcinogenesis.

    PubMed

    Kizer, D E; Clouse, J A; Ringer, D P; Hanson-Painton, O; Vaz, A D; Palakodety, R B; Griffin, M J

    1985-05-15

    The influence of eleven xenobiotics on the activity and amount of hepatic microsomal epoxide hydrolase was determined. Activity was assayed using three different substrates after rats were fed, throughout 3 weeks, diets containing one of six hepatocarcinogens, viz. 2-acetylaminofluorene, 3'-methyl-4-dimethylaminoazobenzene, 4'-fluoro-4-dimethylaminoazobenzene, thioacetamide, aflatoxin B1 and ethionine. Five hepatocarcinogens induced activity 4- to 10-fold; ethionine was relatively ineffective as an inducer. Two non-carcinogenic analogues of hepatocarcinogens, viz. fluorene and p-aminoazobenzene, caused no appreciable increase in enzyme activity, but phenobarbital, barbital and 1-naphthylisothiocyanate induced activity 2- to 3-fold. All eleven xenobiotics increased the amount of microsomal epoxide hydrolase 2- to 9-fold when examined immunochemically using either a radial diffusion assay or an enzyme-linked immunosorbent assay (ELISA). Serum glutamic oxaloacetic acid transaminase activity was not appreciably elevated by feeding ten of the xenobiotics, suggesting that inductions were not owing to toxicity. Using ELISA, microsomal epoxide hydrolase was detected in post-microsomal (PM) supernatant fractions from control rat liver, thus confirming an earlier report by Gill et al. [Carcinogenesis 3, 1307 (1982)]. The eleven xenobiotics induced the amount of ELISA-detectable antigen in PM supernatant fractions by 3- to 34-fold. Longer centrifugation of PM supernatant fractions yielded a pellet fraction that contained 92 +/- 1.2% of the ELISA-detectable antigen irrespective of the xenobiotic regimen. Relationships between xenobiotic induction of microsomal epoxide hydrolase activity and amount and hepatocarcinogenesis are discussed.

  13. Synthesis of an Epoxide Carbonylation Catalyst: Exploration of Contemporary Chemistry for Advanced Undergraduates

    ERIC Educational Resources Information Center

    Getzler, Yutan D. Y. L.; Schmidt, Joseph A. R.; Coates, Geoffrey W.

    2005-01-01

    A class of highly active, well-defined compounds for the catalytic carbonylation of epoxides and aziridines to beta-lactones and beta-lactams are introduced. The synthesis of one of the catalysts involves a simple imine condensation to form the ligand followed by air-sensitive metalation and salt metathesis steps.

  14. The strained sesquiterpene β-caryophyllene as a probe for the solvent-assisted epoxidation mechanism.

    PubMed

    Steenackers, Bart; Neirinckx, Alexander; De Cooman, Luc; Hermans, Ive; De Vos, Dirk

    2014-04-04

    In our attempt to synthesize β-caryophyllene oxide in food-compatible conditions, we observed the uncatalyzed and highly selective epoxidation of β-caryophyllene, a strained bicyclic sesquiterpene, in ethanol with aqueous H2 O2 under radical-suppressing conditions without the addition of a catalyst. The unusual reactivity of β-caryophyllene allowed us to use it as a probe for the mechanism of the solvent-assisted epoxidation in a wide range of organic solvents. A kinetic study was performed to investigate the epoxidation mechanism; an excellent correlation was found between the observed epoxidation rates in different solvents and the Abraham's hydrogen bond formation parameters of these solvents. By means of computational analysis, it was found that the main role of the solvent consists of the stabilization of the elongated OO bond of H2 O2 in the transition state through hydrogen-bond donation to the leaving OH moiety of H2 O2 . α-Humulene was found to possess similar reactivity as β-caryophyllene whereas isocaryophyllene-the unstrained isomer of β-caryophyllene-was unreactive.

  15. EPOXIDATION OF SMALL ORGANIC MOLECULES USING A SPINNING TUBE-IN-TUBE REACTOR

    EPA Science Inventory

    The commodity-scale epoxidation of several organic molecules has been carried out using a Spinning Tube-in-Tube (STTr) reactor (manufactured by Kreido Laboratories). This reactor, which embodies and facilitates the use of Green Chemistry principles and Process Intensification, a...

  16. On the interaction between supercritical CO2 and epoxides combining infrared absorption spectroscopy and quantum chemistry calculations.

    PubMed

    Foltran, Stéphanie; Méreau, Raphaël; Tassaing, Thierry

    2011-05-28

    The nature and strength of the interactions occurring between epoxides and CO(2) have been investigated by combining infrared spectroscopy with quantum chemistry calculations. A series of infrared absorption experiments on four model epoxide molecules highly diluted in supercritical CO(2) have been performed at constant temperature T = 40 °C for various CO(2) pressures varying from 1 to 30 MPa. Then, we carried out a theoretical analysis based on quantum chemistry calculations using Density Functional Theory (B3PW91 and CAM-B3LYP) and ab initio (MP2) computational methods. A very good agreement between experimental and calculated vibrational frequency shifts of the epoxide ring vibrations group was obtained using the CAM-B3LYP functional, hence validating the calculated optimized geometries of the epoxide-CO(2) complexes. Whatever the epoxide considered, CO(2) is found to be on average above the oxygen atom of the epoxy ring and interacts with the carbon atom of CO(2) through a Lewis acid-Lewis base type of interaction. The substituents on the epoxide ring are found to influence the stability of the epoxide-CO(2) complexes mainly because of the partial charge on the oxygen atom that is sensitive to the nature of the substituent.

  17. The impact of p53 on DNA damage and metabolic activation of the environmental carcinogen benzo[a]pyrene: effects in Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice.

    PubMed

    Krais, Annette M; Speksnijder, Ewoud N; Melis, Joost P M; Indra, Radek; Moserova, Michaela; Godschalk, Roger W; van Schooten, Frederik-J; Seidel, Albrecht; Kopka, Klaus; Schmeiser, Heinz H; Stiborova, Marie; Phillips, David H; Luijten, Mirjam; Arlt, Volker M

    2016-04-01

    The tumour suppressor p53 is one of the most important cancer genes. Previous findings have shown that p53 expression can influence DNA adduct formation of the environmental carcinogen benzo[a]pyrene (BaP) in human cells, indicating a role for p53 in the cytochrome P450 (CYP) 1A1-mediated biotransformation of BaP in vitro. We investigated the potential role of p53 in xenobiotic metabolism in vivo by treating Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice with BaP. BaP-DNA adduct levels, as measured by (32)P-postlabelling analysis, were significantly higher in liver and kidney of Trp53(-/-) mice than of Trp53(+/+) mice. Complementarily, significantly higher amounts of BaP metabolites were also formed ex vivo in hepatic microsomes from BaP-pretreated Trp53(-/-) mice. Bypass of the need for metabolic activation by treating mice with BaP-7,8-dihydrodiol-9,10-epoxide resulted in similar adduct levels in liver and kidney in all mouse lines, confirming that the influence of p53 is on the biotransformation of the parent compound. Higher BaP-DNA adduct levels in the livers of Trp53(-/-) mice correlated with higher CYP1A protein levels and increased CYP1A enzyme activity in these animals. Our study demonstrates a role for p53 in the metabolism of BaP in vivo, confirming previous in vitro results on a novel role for p53 in CYP1A1-mediated BaP metabolism. However, our results also suggest that the mechanisms involved in the altered expression and activity of the CYP1A1 enzyme by p53 in vitro and in vivo are different.

  18. A Useful Allene for the Stereoselective Synthesis of Protected Quaternary 2-Amino-2-vinyl-1,3-diols.

    PubMed

    Rodríguez, Aleix; Ariza, Xavier; Contreras, Miguel A; Garcia, Jordi; Lloyd-Williams, Paul; Mercadal, Nerea; Sánchez, Carolina

    2017-02-03

    Treatment of readily available allene 1 with Cy2BH followed by addition of an aldehyde led to quaternary protected 2-amino-2-vinyl-1,3-diols in high yield and excellent stereochemical purity. The choice of benzoyl as N-protecting group is critical since the observed N- to O-Bz transfer during the process prevents later undesired isomerizations in the adducts and keeps all heteroatoms protected.

  19. Theoretical investigations of the reaction between 1,4-dithiane-2,5-diol and azomethine imines: mechanisms and diastereoselectivity.

    PubMed

    Zheng, Linjie; Qiao, Yan; Lu, Mengxue; Chang, Junbiao

    2015-07-21

    In the present study, mechanistic insights into the domino reaction between 1,4-dithiane-2,5-diol and azomethine imines were derived from the computational study with B3LYP and M06-2X functionals. On the whole, the domino process comprises two consecutive reactions: cleavage of 1,4-dithiane-2,5-diol leading to mercaptoacetaldehyde and [3 + 3] cycloaddition of mercaptoacetaldehyde with azomethine imines. The cleavage of 1,4-dithiane-2,5-diol can take place via multiple possible pathways (1A-1E), and pathway 1E in which double-methanol molecules mediate the proton transfer process is the most energetically favorable, with an energy barrier of 19.9 kcal mol(-1). For the [3 + 3] cycloaddition, three possible pathways (2F-2H) were explored. The calculated energy profiles reveal that pathway 2H with activation energies ranging from 6.9 to 10.2 kcal mol(-1) is more energetically favorable than pathways 2F and 2G. Specifically, pathway 2H comprises three reaction steps: deprotonation of mercaptoacetaldehyde by DABCO allows for the formation of the thiol anion, which subsequently launches a nucleophilic attack on azomethine imines followed by intramolecular cyclization resulting in the final products. The calculated results are in agreement with the experimental observations that the reaction can proceed most efficiently in the presence of both DABCO and methanol. Furthermore, the hydrogen bonding interaction is identified to be the main factor determining the observed diastereoselectivity The current systematic theoretical study gives a full scenario of the reaction between 1,4-dithiane-2,5-diol and azomethine imines catalyzed by DABCO, and thus provides some valuable clues for further investigation and development of this kind of important reaction.

  20. Stereoselective synthesis of 1,3-anti diols by an Ipc-mediated domino aldol-coupling/reduction sequence.

    PubMed

    Dieckmann, Michael; Menche, Dirk

    2013-01-04

    A novel domino process for 1,3-anti diol synthesis by the union of a methyl ketone with an aldehyde is described. The operationally simple procedure is based on an Ipc-boron-aldol coupling and subsequent Ipc-mediated reduction of the intermediate β-hydroxy-ketone. The sequence proceeds with excellent anti-selectivities and enables the rapid construction of complex polyketide fragments.

  1. Dielectric and ferroelectric sensing based on molecular recognition in Cu(1,10-phenlothroline)2SeO4.(diol) systems

    NASA Astrophysics Data System (ADS)

    Ye, Heng-Yun; Liao, Wei-Qiang; Zhou, Qionghua; Zhang, Yi; Wang, Jinlan; You, Yu-Meng; Wang, Jin-Yun; Chen, Zhong-Ning; Li, Peng-Fei; Fu, Da-Wei; Huang, Songping D.; Xiong, Ren-Gen

    2017-02-01

    The process of molecular recognition is the assembly of two or more molecules through weak interactions. Information in the process of molecular recognition can be transmitted to us via physical signals, which may find applications in sensing and switching. The conventional signals are mainly limited to light signal. Here, we describe the recognition of diols with Cu(1,10-phenlothroline)2SeO4 and the transduction of discrete recognition events into dielectric and/or ferroelectric signals. We observe that systems of Cu(1,10-phenlothroline)2SeO4.(diol) exhibit significant dielectric and/or ferroelectric dependence on different diol molecules. The compounds including ethane-1,2-diol or propane-1,2-diol just show small temperature-dependent dielectric anomalies and no reversible polarization, while the compound including ethane-1,3-diol shows giant temperature-dependent dielectric anomalies as well as ferroelectric reversible spontaneous polarization. This finding shows that dielectricity and/or ferroelectricity has the potential to be used for signalling molecular recognition.

  2. Dielectric and ferroelectric sensing based on molecular recognition in Cu(1,10-phenlothroline)2SeO4·(diol) systems

    PubMed Central

    Ye, Heng-Yun; Liao, Wei-Qiang; Zhou, Qionghua; Zhang, Yi; Wang, Jinlan; You, Yu-Meng; Wang, Jin-Yun; Chen, Zhong-Ning; Li, Peng-Fei; Fu, Da-Wei; Huang, Songping D.; Xiong, Ren-Gen

    2017-01-01

    The process of molecular recognition is the assembly of two or more molecules through weak interactions. Information in the process of molecular recognition can be transmitted to us via physical signals, which may find applications in sensing and switching. The conventional signals are mainly limited to light signal. Here, we describe the recognition of diols with Cu(1,10-phenlothroline)2SeO4 and the transduction of discrete recognition events into dielectric and/or ferroelectric signals. We observe that systems of Cu(1,10-phenlothroline)2SeO4·(diol) exhibit significant dielectric and/or ferroelectric dependence on different diol molecules. The compounds including ethane-1,2-diol or propane-1,2-diol just show small temperature-dependent dielectric anomalies and no reversible polarization, while the compound including ethane-1,3-diol shows giant temperature-dependent dielectric anomalies as well as ferroelectric reversible spontaneous polarization. This finding shows that dielectricity and/or ferroelectricity has the potential to be used for signalling molecular recognition. PMID:28216653

  3. Polar forms of benzo[a]pyrene may be ubiquitous in the environment

    SciTech Connect

    Ismail, Y.; Giese, R.W.; Lafleur, A.L.

    1998-09-01

    Previously, the authors reported that polar polycyclic aromatic compounds (polar PAC) can be detected by first oxidizing them with KO{sub 2}/O{sub 2} and then detecting the carboxylic acid products, after pentafluorobenzylation, by gas chromatography electron capture mass spectrometry. For example, the authors used the method in the cited study to detect a benzo[a]pyrene tetrahydrotetraol hydrolysis product derived from benzo[a]pyrene-exposed lymphocytes after isolation of the DNA. However, the method was limited in its sensitivity by the presence of an interfering, analyte-like peak in the final mass chromatograms. Now, the results of the current work strongly suggest that the contamination leading to the unwanted peak is ubiquitous in the urban environment. Results from the analysis of a standard reference sample of urban particulate matter yielded a level of 10 ng of contaminant in a 5-mg sample. The concentration of this polar contaminant is comparable to the certified value for benzo[a]pyrene of 14.5 ng. Furthermore, the mass spectral data show evidence for the presence of many other polar PAC in the sample. These observations add to the concern raised by related environmental health studies focused on the potential impact of airborne polar PAC on human health.

  4. Identification and characterization of dimeric oxidation products of p-cymene-2,3-diol isolated from Thymus vulgaris L.

    PubMed

    Rainis, Guido; Ternes, Waldemar

    2014-01-08

    The aim of this study was to investigate the oxidation products of p-cymene-2,3-diol, a major antioxidative constituent of thyme (Thymus vulgaris L.). Although a dimeric form of p-cymene-2,3-diol and some derivative substances exhibiting valuable food technological and health-promoting properties have been reported in earlier publications, no obvious correlation has been shown between these substances. A modified HPLC-ESI-MS method made it possible to prove that two dimers, 3,4,3',4'-tetrahydroxy-5,5'-diisopropyl-2,2'-dimethylbiphenyl (1) and the newly identified 3',4'-dihydroxy-5,5'-diisopropyl-2,2'-dimethylbiphenyl-3,4-dione (2), are oxidation products of p-cymene-2,3-diol. 2 was characterized by the fragmentation pattern determined by multiple mass spectrometry, (1)H NMR, (13)C NMR, H-H COSY, HSQC, and HMBC. Both biphenyls were also quantitated in freeze-dried thyme as well as in a food matrix spiked with thyme extract. Model experiments using raw and cooked minced pork meat as matrix and sodium nitrite as oxidizing and reduction agent with and without ascorbic acid as protective reagent showed the correlation between food processing and dimer generation.

  5. COMPARISON OF THE GENOTOXIC ACTIVITIES OF THE K-REGION DIHYDRODIOL OF BENZO[A]PYRENE WITH BENZO[A]PYRENE IN MAMMALIAN CELLS: MORPHOLOGICAL CELL TRANSFORMATION; DNA DAMAGE; AND STABLE COVALENT DNA ADDUCTS

    EPA Science Inventory

    Benzo[a]pyrene (B[a]P) has been the most thoroughly studied polycyclic aromatic hydrocarbon (PAH) with regard to its occurrence, metabolism, toxicological and carcinogenic activities. Many mechanisms have been suggested to explain its carcinogenic activity, yet many questions sti...

  6. Kinetics and mechanism of styrene epoxidation by chlorite: role of chlorine dioxide.

    PubMed

    Leigh, Jessica K; Rajput, Jonathan; Richardson, David E

    2014-07-07

    An investigation of the kinetics and mechanism for epoxidation of styrene and para-substituted styrenes by chlorite at 25 °C in the pH range of 5-6 is described. The proposed mechanism in water and water/acetonitrile includes seven oxidation states of chlorine (-I, 0, I, II, III, IV, and V) to account for the observed kinetics and product distributions. The model provides an unusually detailed quantitative mechanism for the complex reactions that occur in mixtures of chlorine species and organic substrates, particularly when the strong oxidant chlorite is employed. Kinetic control of the reaction is achieved by the addition of chlorine dioxide to the reaction mixture, thereby eliminating a substantial induction period observed when chlorite is used alone. The epoxidation agent is identified as chlorine dioxide, which is continually formed by the reaction of chlorite with hypochlorous acid that results from ClO produced by the epoxidation reaction. The overall stoichiometry is the result of two competing chain reactions in which the reactive intermediate ClO reacts with either chlorine dioxide or chlorite ion to produce hypochlorous acid and chlorate or chloride, respectively. At high chlorite ion concentrations, HOCl is rapidly eliminated by reaction with chlorite, minimizing side reactions between HOCl and Cl2 with the starting material. Epoxide selectivity (>90% under optimal conditions) is accurately predicted by the kinetic model. The model rate constant for direct reaction of styrene with ClO2(aq) to produce epoxide is (1.16 ± 0.07) × 10(-2) M(-1) s(-1) for 60:40 water/acetonitrile with 0.20 M acetate buffer. Rate constants for para substituted styrenes (R = -SO3(-), -OMe, -Me, -Cl, -H, and -NO2) with ClO2 were determined. The results support the radical addition/elimination mechanism originally proposed by Kolar and Lindgren to account for the formation of styrene oxide in the reaction of styrene with chlorine dioxide.

  7. Pilot scale production, characterization, and optimization of epoxidized vegetable oil-based resins

    NASA Astrophysics Data System (ADS)

    Monono, Ewumbua Menyoli

    Novel epoxidized sucrose soyate (ESS) resins perform much better than other vegetable oil-based resins; thus, they are of current interest for commercial scale production and for a wide range of applications in coatings and polymeric materials. However, no work has been published that successfully scaled-up the reaction above a 1 kg batch size. To achieve this goal, canola oil was first epoxidized at a 300 g scale to study the epoxidation rate and thermal profile at different hydrogen peroxide (H2O2) addition rates, bath temperatures, and reaction times. At least 83% conversion of double bonds to oxirane was achieved by 2.5 h, and the reaction temperature was 8-15 °C higher than the water bath temperature within the first 30-40 min of epoxidation. A 38 L stainless steel kettle was modified as a reactor to produce 10 kg of ESS. Twenty 7-10 kg batches of ESS were produced with an overall 87.5% resin yield and > 98% conversion after batch three. The conversion and resin quality were consistent across the batches due to the modifications on the reaction that improved mixing and reaction temperature control within 55-65 oC. The total production time was reduced from 8 to 4 days due to the fabrication of a 40 L separatory funnel for both washing and filtration. A math model was developed to optimize the epoxidation process. This was done by using the Box-Behnken design to model the conversion at various acetic acid, H2O2, and Amberlite ratios and at various reaction temperatures and times. The model had an adjusted R2 of 97.6% and predicted R2 of 96.8%. The model showed that reagent amounts and time can be reduced by 18% without compromising the desired conversion value and quality.

  8. Analysis of serum PAH`s and PAH adducts by LC/MS

    SciTech Connect

    McClure, P.C.; Barr, J.R.; Maggio, V.L.

    1995-12-31

    Polycyclic aromatic hydrocarbons are an important class of chemical carcinogens. Benzo[a]pyrene is the most extensively studied and best understood carcinogenic PAH It is believed that Benzo[a]pyrene is metabolized in vitro to the diol epoxide, Benzo[a]pyrene-7,8-dihydrodiol-9, 10-epoxide which then can react with various nucleophilic centers on DNA. The major alkylation product appears to be the reaction of the Benzo[a]pyrene diol epoxide with the N{sup 2} position of guanine sites on DNA. Methods that can measure exposure and biological response to carcinogens such as PAH`s are needed. Human Blood can be separated into plasma, lymphocytes, and red blood cells. The plasma should contain native PAH`s which may yield some useful information about recent exposure. The red blood cells contain hemoglobin and adducts of PAH`s. Hemoglobin has an average lifetime of 120 days so quantification of hemoglobin adducts should give an average of a persons exposure over four months. Also, the electrophilic metabolites that react with hemoglobin to form adducts are the same metabolites that form DNA adducts which can lead to mutations and cancer. Lymphocytes contain DNA and therefore DNA adducts. DNA adducts can be repaired by a series of enzymes so quantification of these adducts will only yield information about recent or non-repairable adducts. DNA adduct formation is believed to be the first important step in chemical carcinogenesis so quantification of these adducts should yield some information on exposure and a great deal of important data on biological response and risk from specific PAH`s.

  9. Discrete metal-based catalysts for the copolymerization of CO2 and epoxides: discovery, reactivity, optimization, and mechanism.

    PubMed

    Coates, Geoffrey W; Moore, David R

    2004-12-10

    Most synthetic polymers are made from petroleum feedstocks. Given the non-renewable nature of these materials, there is increasing interest in developing routes to polymeric materials from renewable resources. In addition, there is a growing demand for biodegradable polymeric materials. Polycarbonates made from CO(2) and epoxides have the potential to meet these goals. Since the discovery of catalysts for the copolymerization of CO(2) and epoxides in the late 1960's by Inoue, a significant amount of research has been directed toward the development of catalysts of improved activity and selectivity. Reviewed here are well-defined catalysts for epoxide-CO(2) copolymerization and related reactions.

  10. Novel Synthesis of Anionic Gemini Surfactants from 1, 4-Diol as a Key Block Material.

    PubMed

    Kawase, Tokuzo; Nakagawa, Mami; Higuchi, Yuuya; Oida, Tatsuo

    2015-01-01

    In this study, a series of all-hydrocarbon anionic gemini surfactants containing COOH (adipic acid-type and suberic acid-type), SO3Na, OSO3Na, and OP=O(OH)2 functional groups was developed from 1,4-diol and 1,4-diketone as a key block material. The effect of the surfactant head groups on the surface properties was investigated by surface tension and surface pressure-area (π-A) measurements. We found that the critical micelle concentrations (CMC) of the studied geminis were smaller by one order of magnitude than those of the corresponding 1+l-type surfactants. From π-A measurements, the limiting areas of COOH-type geminis were less than twofold of the area of the corresponding 1+1-type, which indicates that the gemini structure enabled tighter packing than is possible in surfactants of the 1+l-type. In contrast, the limiting area of the OP=O(OH)2-type gemini was larger than those of the COOH-type geminis. Furthermore, the suberic acid-type gemini showed a smaller limiting area than that of adipic acid-type gemini. Therefore, we can conclude that the flexibility of the gemini at the connecting position has a significant effect on formation of the monolayer at the air/water interface.

  11. Identification of novel regulatory cholesterol metabolite, 5-cholesten, 3β,25-diol, disulfate.

    PubMed

    Ren, Shunlin; Kim, Jin Koung; Kakiyama, Genta; Rodriguez-Agudo, Daniel; Pandak, William M; Min, Hae-Ki; Ning, Yanxia

    2014-01-01

    Oxysterol sulfation plays an important role in regulation of lipid metabolism and inflammatory responses. In the present study, we report the discovery of a novel regulatory sulfated oxysterol in nuclei of primary rat hepatocytes after overexpression of the gene encoding mitochondrial cholesterol delivery protein (StarD1). Forty-eight hours after infection of the hepatocytes with recombinant StarD1 adenovirus, a water-soluble oxysterol product was isolated and purified by chemical extraction and reverse-phase HPLC. Tandem mass spectrometry analysis identified the oxysterol as 5-cholesten-3β, 25-diol, disulfate (25HCDS), and confirmed the structure by comparing with a chemically synthesized compound. Administration of 25HCDS to human THP-1-derived macrophages or HepG2 cells significantly inhibited cholesterol synthesis and markedly decreased lipid levels in vivo in NAFLD mouse models. RT-PCR showed that 25HCDS significantly decreased SREBP-1/2 activities by suppressing expression of their responding genes, including ACC, FAS, and HMG-CoA reductase. Analysis of lipid profiles in the liver tissues showed that administration of 25HCDS significantly decreased cholesterol, free fatty acids, and triglycerides by 30, 25, and 20%, respectively. The results suggest that 25HCDS inhibits lipid biosynthesis via blocking SREBP signaling. We conclude that 25HCDS is a potent regulator of lipid metabolism and propose its biosynthetic pathway.

  12. [Occurrence of 3-monochloropropane-1,2-diol (3-MCPD) in food products].

    PubMed

    Gawarska, Halina; Sawilska-Rautenstrauch, Dorota; Starski, Andrzej; Karłowski, Kazimierz

    2009-01-01

    3-Monochloropropane-1,2-diol (3-MCPD) is a contaminant belongs to a group of chemicals called chloropropanols. 3-MCPD can be formed in foods as result of processing or storage condition. At the beginning 3-MCPD was identified as a contaminant of the acid-hydrolysed vegetable protein, which is produced using hydrochloric acid and high temperature. Studies have shown that 3-MCPD is carcinogenic for rats, however genotoxic adverse effect was not observed in vivo. The purpose of this studies was determination of 3-MCPD amounts in retail food products and comparison with the EC legislative limit. 99 samples of foodstuffs was tested: soya sauce, hydrolysed vegetable protein (HVP), sugar, instant soups, stock cubes, bakery products, chips and edible fats. 3-MCPD was detected at levels below 10 microg/kg in 15% of the tested samples, and above 10 microg/kg in 63%. 3-MCPD was not occurred in 22% of the tested samples. The samples were analysed by gas chromatography-mass spectrometry (GC/MS).

  13. Exposure assessment of 3-monochloropropane-1, 2-diol esters from edible oils and fats in China.

    PubMed

    Li, Chang; Nie, Shao-Ping; Zhou, Yong-Qiang; Xie, Ming-Yong

    2015-01-01

    3-monochoropropane-1, 2-diol (3-MCPD) esters from edible oils are considered to be a possible risk factor for adverse effects in human. In the present study, the exposure assessment of 3-MCPD esters to Chinese population was performed. A total of 143 edible oil and fat samples collected from Chinese markets were determined for the concentrations of 3-MCPD esters. The concentration data together with the data of fats consumed were analyzed by the point evaluation and probabilistic assessment for the exposure assessment. The point evaluation showed that the mean daily intake (DI) of 3-MCPD esters were lower than the value of provisional maximum tolerable daily intake (PMTDI) of 3-MCPD (2 µg/kg BW/d). The mean DI values in different age groups obtained from probabilistic assessment were similar to the results of the point evaluation. However, in high percentiles (95th, 97.5th, 99th), the DI values in all age groups were undesirably higher than the value of PMTDI. Overall, the children and adolescents exposed more to 3-MCPD esters than the adults. Uncertainty was also analyzed for the exposure assessment. Decreasing the level of 3-MCPD esters in edible oils and consuming less oil were top priority to minimize the risk of 3-MCPD esters.

  14. Carcinogenicity study of 3-monochloropropane-1,2-diol in Sprague-Dawley rats.

    PubMed

    Cho, Wan-Seob; Han, Beom Seok; Nam, Ki Taek; Park, Kidae; Choi, Mina; Kim, Seung Hee; Jeong, Jayoung; Jang, Dong Deuk

    2008-09-01

    3-Monochloropropane-1,2-diol (alpha-chlorohydrin, 3-MCPD) is a well-known contaminant, which has been detected in a wide range of foods and ingredients, and is also a suspected cause of cancer. In this study, the carcinogenicity of 3-MCPD in SD rats was investigated. Groups of 50 male and 50 female rats were exposed for two years to drinking water containing 0, 25, 100 or 400ppm 3-MCPD. The body weights and water consumptions of the male and female rats given 400ppm 3-MCPD were significantly lower than those of the controls. The incidences of renal tubule adenomas or carcinomas and Leydig cell tumors occurred with dose-related positive trends in male rats. The incidences of renal tubule carcinomas and Leydig cell tumors were significantly increased in male rats given 400ppm 3-MCPD. The incidence of renal tubule adenomas showed a positive trend in female rats, which was significant in 400ppm 3-MCPD group. In conclusion, there was clear evidence of the carcinogenic activity of 3-MCPD in male SD rats, based on the increased incidences of renal tubule carcinomas and Leydig cell tumors. There was some evidence of the carcinogenic activity of 3-MCPD in female SD rats, based on the increased incidence of renal tubule adenomas.

  15. Novel approaches to analysis of 3-chloropropane-1,2-diol esters in vegetable oils.

    PubMed

    Moravcova, Eliska; Vaclavik, Lukas; Lacina, Ondrej; Hrbek, Vojtech; Riddellova, Katerina; Hajslova, Jana

    2012-03-01

    A sensitive and accurate method utilizing ultrahigh performance liquid chromatography (U-HPLC) coupled to high resolution mass spectrometry based on orbitrap technology (orbitrapMS) for the analysis of nine 3-chloropropane-1,2-diol (3-MCPD) diesters in vegetable oils was developed. To remove the interfering triacylglycerols that induce strong matrix effects, a clean-up step on silica gel column was used. The quantitative analysis was performed with the use of deuterium-labeled internal standards. The lowest calibration levels estimated for the respective analytes ranged from 2 to 5 μg kg(-1). Good recovery values (89-120%) and repeatability (RSD 5-9%) was obtained at spiking levels of 2 and 10 mg kg(-1). As an alternative, a novel ambient desorption ionization technique, direct analysis in real time (DART), hyphenated with orbitrapMS, was employed for no separation, high-throughput, semi-quantitative screening of 3-MCPD diesters in samples obtained by chromatographic fractionation. Additionally, the levels of 3-MCPD diesters measured in reallife vegetable oil samples (palm oil, sunflower oil, rapeseed oil) using both methods are reported. Relatively good agreement of the data generated by U-HPLC-orbitrapMS and DART-orbitrapMS were observed. With regard to a low ionization yield achieved for 3-MCPD monoesters, the methods presented in this paper were not yet applicable for the analysis of these contaminants at the naturally occurring levels.

  16. Antioxidants Inhibit Formation of 3-Monochloropropane-1,2-diol Esters in Model Reactions.

    PubMed

    Li, Chang; Jia, Hanbing; Shen, Mingyue; Wang, Yuting; Nie, Shaoping; Chen, Yi; Zhou, Yongqiang; Wang, Yuanxing; Xie, Mingyong

    2015-11-11

    The capacities of six antioxidants to inhibit the formation of 3-monochloropropane-1,2 diol (3-MCPD) esters were examined in this study. Inhibitory capacities of the antioxidants were investigated both in chemical models containing the precursors (tripalmitoyl glycerol, 1,2-dipalmitoyl-sn-glycerol, monopalmitoyl glycerol, and sodium chloride) of 3-MCPD esters and in oil models (rapeseed oil and sodium chloride). Six antioxidants, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), tert-butyl hydroquinone (TBHQ), propyl gallate (PG), L-ascorbyl palmitate (AP), and α-tocopherol (VE), were found to exhibit inhibiting capacities on 3-MCPD ester formation both in chemical models and in oil models. TBHQ provided the highest inhibitory capacity both in chemical models and in oil models; 44% of 3-MCPD ester formation was inhibited in the presence of TBHQ (66 mg/kg of oil) after heating of rapeseed oil at 230 °C for 30 min, followed by PG and AP. BHT, BHA, and VE appeared to have weaker inhibitory abilities in both models. VE exhibited the lowest inhibition rate; 22% of 3-MCPD esters were inhibited in the presence of VE (172 mg/kg of oil) after heating of rapeseed oil at 230 °C for 30 min. In addition, the inhibition rates of PG and VE decreased dramatically with an increase in temperature or heating time. The results suggested that some antioxidants, such as TBHQ, PG, and AP, could be the potential inhibitors of 3-MCPD esters in practice.

  17. Influence of dough ingredients on 3-chloropropane-1,2-diol (3-MCPD) formation in toast.

    PubMed

    Breitling-Utzmann, C M; Hrenn, H; Haase, N U; Unbehend, G M

    2005-02-01

    The influence of different dough ingredients such as fat, salt, sourdough, emulsifiers, and sugar on the formation of 3-chloropropane-1,2-diol (3-MCPD) during toast preparation under domestic conditions was investigated. In comparison with a fat-free recipe, addition of 1% peanut fat considerably increased 3-MCPD formation, but varying the fat (2-5%) or salt (1.6-2.4%) contents within technological acceptable limits did not show any significant differences. A baking agent, which is usually commercially applied by many toast bakers or industrial toast manufacturers, increased 3-MCPD formation in toasted bread slices. Considerable evidence was found that the baking agent's main component sucrose had the major part in increasing 3-MCPD levels. Emulsifiers containing monoacylglycerols moderately increased 3-MCPD levels, but the addition of lecithin did not have any significant influence. 3-MCPD levels showed a good correlation with the lightness (L* value) of the bread slices; their 3-MCPD content increased exponentially towards dark coloured toasts. The relation between 3-MCPD and 2-MCPD was an average of 3:1 in all samples. Dichloropropanols such as, for example, 1,3-dichloropropanol could not be detected.

  18. Semi-aromatic polyesters based on a carbohydrate-derived rigid diol for engineering plastics.

    PubMed

    Wu, Jing; Eduard, Pieter; Thiyagarajan, Shanmugam; Noordover, Bart A J; van Es, Daan S; Koning, Cor E

    2015-01-01

    New carbohydrate-based polyesters were prepared from isoidide-2,5-dimethanol (extended isoidide, XII) through melt polymerization with dimethyl esters of terephthalic acid (TA) and furan-2,5-dicarboxylic acid (FDCA), yielding semi-crystalline prepolymers. Subsequent solid-state post-condensation (SSPC) gave high molecular weight (Mn =30 kg mol(-1) for FDCA) materials, the first examples of high Mn , semi-aromatic homopolyesters containing isohexide derivatives obtained via industrially relevant procedures. NMR spectroscopy showed that the stereo-configuration of XII was preserved under the applied conditions. The polyesters are thermally stable up to 380 °C. The TA- and FDCA-based polyesters have high Tg (105 °C and 94 °C, resp.) and Tm (284 °C and 250 °C, resp.) values. Its reactivity, stability, and ability to afford high Tg and Tm polyesters make XII a promising diol for the synthesis of engineering polymers.

  19. Hydrophilic diol monolith for the preparation of immuno-sorbents at reduced nonspecific interactions.

    PubMed

    Gunasena, Dilani N; El Rassi, Ziad

    2011-08-01

    A polar organic polymer monolith (M1) was introduced for performing immunoaffinity chromatography (IAC) at reduced nonspecific interactions. The M1 monolith was prepared by the in situ polymerization of glyceryl methacrylate (GMM) and pentaerythritol triacrylate (PETA). Through its surface diol groups, M1 provided the functionalities to immobilize antibodies. Anti-haptoglobin antibody was used as the model antibody to study the overall behavior of the immuno monolith M1 in terms of its binding to the antigen and to evaluate its nonspecific binding with other proteins, especially the high-abundance human serum proteins. To better assess the suitability of M1 for IAC, other immuno monoliths were prepared and compared with the immuno monolith M1. Two monoliths were of the traditional ones: copolymers of (i) glycidyl methacrylate and ethylene glycol dimethacrylate (EDMA) and (ii) GMM and EDMA, referred to as M2 and M3, respectively. A fourth monolith involving the copolymerization of N-(3-aminopropyl)methacrylamide hydrochloride and EDMA (M4) was introduced to allow the site-directed immobilization of antibodies. Owing to its hydroxyl groups, the M1 exhibited negligible nonspecific hydrophobic interactions with proteins. On the other hand, M4 exhibited extensive electrostatic interactions, while the M2 and to a lesser extent M3 exhibited hydrophobic interactions.

  20. Binding site for the adenosyl group of coenzyme B12 in diol dehydrase

    SciTech Connect

    Toraya, T.

    1985-11-01

    The binding of cob(II)alamin (CblII) and 5'-deoxyadenosine to diol dehydrase was studied spectroscopically and with (U-/sup 14/C)5'-deoxyadenosine. CblII was bound to this enzyme forming a tight 1:1 complex which was resistant to oxidation by O/sub 2/ even in the presence of CN-. An irreversible 1:1:1 ternary complex was formed between enzyme, CblII, and 5'-deoxyadenosine, when the enzyme was incubated first with the nucleoside and then with CblII. When this order of addition of the constituents was reversed, no 5'-deoxyadenosine was bound to the enzyme-CblII complex. Hydroxocobalamin could also bind to the enzyme together with the nucleoside, while other cob(III)alamins bearing a bulkier Co beta ligand displaced the nucleoside upon binding to the enzyme. The binding of (U-/sup 14/C)5'-deoxyadenosine was strongly inhibited by unlabeled 5'-deoxy-ara-adenosine, 4',5'-anhydroadenosine, adenosine, adenine, and 5',8-cyclic adenosine, in this order, but not by 5'-deoxyuridine. These results constitute direct evidence for the presence of the binding site for the adenosyl group of adenosylcobalamin, which is spatially limited to and highly specific for adenine nucleosides. The binding of 5'-deoxyadenosine to the apoenzyme was reversible.

  1. Formation of monochloropropane-1,2-diol and its esters in biscuits during baking.

    PubMed

    Mogol, Burçe Ataç; Pye, Céline; Anderson, Warwick; Crews, Colin; Gökmen, Vural

    2014-07-23

    The formation of free monochloropropane-1,2-diol (3-MCPD and 2-MCPD) and its esters (bound-MCPD) was investigated in biscuits baked with various time and temperature combinations. The effect of salt as a source of chloride on the formation of these processing contaminants was also determined. Kinetic examination of the data indicated that an increasing baking temperature led to an increase in the reaction rate constants for 3-MCPD, 2-MCPD, and bound-MCPD. The activation energies of formation of 3-MCPD and 2-MCPD were found to be 29 kJ mol(-1). Eliminating salt from the recipe decreased 3-MCPD and 2-MCPD formation rate constants in biscuits by 57.5 and 85.4%, respectively. In addition, there was no formation of bound-MCPD in biscuits during baking without salt. Therefore, lowering the thermal load or limiting the chloride concentration should be considered a means of reducing or eliminating the formation of these contaminants in biscuits. Different refined oils were also used in the recipe to test their effect on the occurrence of free MCPD and its esters in biscuits. Besides the baking process, the results also confirmed the role of refined oil in the final concentration of these contaminants in biscuits.

  2. Selective hydrodeoxygenation of cyclic vicinal diols to cyclic alcohols over tungsten oxide-palladium catalysts.

    PubMed

    Amada, Yasushi; Ota, Nobuhiko; Tamura, Masazumi; Nakagawa, Yoshinao; Tomishige, Keiichi

    2014-08-01

    Hydrodeoxygenation of cyclic vicinal diols such as 1,4-anhydroerythritol was conducted over catalysts containing both a noble metal and a group 5-7 transition-metal oxide. The combination of Pd and WOx allowed the removal of one of the two OH groups selectively. 3-Hydroxytetrahydrofuran was obtained from 1,4-anhydroerythritol in 72 and 74% yield over WOx -Pd/C and WOx -Pd/ZrO2 , respectively. The WOx -Pd/ZrO2 catalyst was reusable without significant loss of activity if the catalyst was calcined as a method of regeneration. Characterization of WOx -Pd/C with temperature-programmed reduction, X-ray diffraction, and transmission electron microscopy/energy-dispersive X-ray spectroscopy suggested that Pd metal particles approximately 9 nm in size were formed on amorphous tungsten oxide particles. A reaction mechanism was proposed on the basis of kinetics, reaction results with tungsten oxides under an atmosphere of Ar, and density functional theory calculations. A tetravalent tungsten center (W(IV) ) was formed by reduction of WO3 with the Pd catalyst and H2 , and this center served as the reductant for partial hydrodeoxygenation.

  3. Ion-pair supercritical fluid chromatography of metoprolol and related amino alcohols on diol silica.

    PubMed

    Gyllenhaal, Olle; Edström, Lena; Persson, Bengt-Arne

    2006-11-17

    In this paper, a chromatographic system based on carbon dioxide with methanol as mobile phase, and diol silica as stationary phase has been investigated for metoprolol and related amino alcohols by addition of strong acids to systems with triethylamine base as primary additive. Standard conditions used were 10% of methanol, containing 24 mM of acid and 18 mM of triethylamine, in carbon dioxide with a flow rate of 1.5 ml min(-1). The column dimensions were 125 mm x 4 mm I.D. and kept at 40 degrees C with a back pressure of 150 bar. Effects on selectivity were stronger with trifluoroacetic acid than with ethanesulfonic acid. From a large set of related analytes, it was shown that selectivity changes were significant when the structure close to the nitrogen of the amino alcohol analyte differed. The stability of the column in the short time perspective was examined and it showed negligible changes. For a diastereoisomeric pair, not resolved in a basic system with triethylamine nor by addition of ethanesulfonic acid, resolution improved to about 2.1 with trifluoroacetic acid. The described approach offers a way to tune the selectivity of SFC systems when amines are analyzed without the need to change stationary phase for the chromatographic separation.

  4. USE OF MULTIPHOTON LASER SCANNING MICROSCOPY TO IMAGE BENZO[A]PYRENE AND METABOLITES IN FISH EARLY LIFE STAGES

    EPA Science Inventory

    Multiphoton laser scanning micrsocopy holds promise as a tool to study the tissue distribution of environmental chemical contaminants during fish early life stage development. One such chemical for which this is possible is benzo[a]pyrene (BaP), a polyaromatic hydrocarbon that a...

  5. Species-specific testicular and hepatic microsomal metabolism of benzo(a)pyrene, an ubiquitous toxicant and endocrine disruptor

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Information on the metabolism of the environmental toxicant, benzo(a)pyrene (BaP) in the male reproductive system is crucial for understanding BaP-induced infertility. Microsomes were isolated from the liver and testes of rat, mouse, hamster, ram, boar, bull, and monkey and incubated with BaP. Post-...

  6. Effects on specific promoter DNA methylation in zebrafish embryos and larvae following benzo[a]pyrene exposure

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Benzo[a]pyrene (BaP) is an established reproductive and developmental toxicant. BaP exposure in humans and animals has been linked to infertility and multigenerational health consequences. DNA methylation is the most studied epigenetic mechanism that regulates gene expression, and mapping of methyla...

  7. Electrochemical detection of benzo(a)pyrene and related DNA damage using DNA/hemin/nafion-graphene biosensor.

    PubMed

    Ni, Yongnian; Wang, Pingping; Song, Haiyan; Lin, Xiaoyun; Kokot, Serge

    2014-04-22

    A novel electrochemical biosensor, DNA/hemin/nafion-graphene/GCE, was constructed for the analysis of the benzo(a)pyrene PAH, which can produce DNA damage induced by a benzo(a)pyrene (BaP) enzyme-catalytic product. This biosensor was assembled layer-by-layer, and was characterized with the use of cyclic voltammetry, electrochemical impedance spectroscopy (EIS) and atomic force microscopy. Ultimately, it was demonstrated that the hemin/nafion-graphene/GCE was a viable platform for the immobilization of DNA. This DNA biosensor was treated separately in benzo(a)pyrene, hydrogen peroxide (H2O2) and in their mixture, respectively, and differential pulse voltammetry (DPV) analysis showed that an oxidation peak was apparent after the electrode was immersed in H2O2. Such experiments indicated that in the presence of H2O2, hemin could mimic cytochrome P450 to metabolize benzo(a)pyrene, and a voltammogram of its metabolite was recorded. The DNA damage induced by this metabolite was also detected by electrochemical impedance and ultraviolet spectroscopy. Finally, a novel, indirect DPV analytical method for BaP in aqueous solution was developed based on the linear metabolite versus BaP concentration plot; this method provided a new, indirect, quantitative estimate of DNA damage.

  8. ADDITIVITY OF IN VIVO MUTATION INDUCTION BY CUMULATIVE EXPOSURES TO BENZO[A]PYRENE OR DIBENZO[A,L]PYRENE

    EPA Science Inventory

    Dibenzo[a,l]pyrene (DB[a,l]P) and benzo[a]pyrene (B[a]P) are polycyclic aromatic hydrocarbons (PAH) found in cigarette smoke condensate, coal combustion processes and in some environmental pollutants. In this study, we investigated the effect of dosing regimen on the mutagenicity...

  9. USE OF MULTIPHOTON LASER SCANNING MICROSCOPY TO IMAGE BENZO[A]PYRENE AND METABOLITES IN FISH EGGS

    EPA Science Inventory

    Multiphoton laser scanning microscopy (MPLSM) is a promising tool to study the tissue distribution of environmental chemical contaminants during fish early life stages. One such chemical for which this is possible is benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon that a...

  10. Detoxication of benzo[a]pyrene-7,8-dione by sulfotransferases (SULTs) in human lung cells.

    PubMed

    Zhang, Li; Huang, Meng; Blair, Ian A; Penning, Trevor M

    2012-08-24

    Polycyclic aromatic hydrocarbons (PAH) are environmental and tobacco carcinogens. Human aldo-keto reductases catalyze the metabolic activation of proximate carcinogenic PAH trans-dihydrodiols to yield electrophilic and redox-active o-quinones. Benzo[a]pyrene-7,8-dione a representative PAH o-quinone is reduced back to the corresponding catechol to generate a futile redox-cycle. We investigated whether sulfonation of PAH catechols by human sulfotransferases (SULT) could intercept the catechol in human lung cells. RT-PCR identified SULT1A1, -1A3, and -1E1 as the isozymes expressed in four human lung cell lines. The corresponding recombinant SULTs were examined for their substrate specificity. Benzo[a]pyrene-7,8-dione was reduced to benzo[a]pyrene-7,8-catechol by dithiothreitol under anaerobic conditions and then further sulfonated by the SULTs in the presence of 3'-[(35)S]phosphoadenosine 5'-phosphosulfate as the sulfonate group donor. The human SULTs catalyzed the sulfonation of benzo[a]pyrene-7,8-catechol and generated two isomeric benzo[a]pyrene-7,8-catechol O-monosulfate products that were identified by reversed phase HPLC and by LC-MS/MS. The various SULT isoforms produced the two isomers in different proportions. Two-dimensional (1)H and (13)C NMR assigned the two regioisomers of benzo[a]pyrene-7,8-catechol monosulfate as 8-hydroxy-benzo[a]pyrene-7-O-sulfate (M1) and 7-hydroxy-benzo[a]pyrene-8-O-sulfate (M2), respectively. The kinetic profiles of three SULTs were different. SULT1A1 gave the highest catalytic efficiency (k(cat)/K(m)) and yielded a single isomeric product corresponding to M1. By contrast, SULT1E1 showed distinct substrate inhibition and formed both M1 and M2. Based on expression levels, catalytic efficiency, and the fact that the lung cells only produce M1, it is concluded that the major isoform that can intercept benzo[a]pyrene-7,8-catechol is SULT1A1.

  11. Biological activities of dihydrodiols derived from two polycyclic hydrocarbons in rodent test systems.

    PubMed Central

    Chouroulinkov, I.; Gentil, A.; Tierney, B.; Grover, P. L.; Sims, P.

    1979-01-01

    Comparisons have been made between (a) the initiation of tumours in mouse skin, (b) the induction of hyperplasia and the suppression of sebaceous glands in mouse skin and (c) the induction of s.c. tumours in rats, by either benzo[a]pyrene or 7-methylbenz[a]anthracene and their related K-region and non-K-region dihydrodiols. Whilst the 3,4-dihydrodiol derived from 7-methylbenz[a]anthracene is more active than the hydrocarbon in initiating tumours in mouse skin (subsequently promoted by a phorbol ester) the 7,8-dihydrodiol of benzo[a]pyrene is very much less active than benzo[a]pyrene itself in the induction of hyperplasia or the suppression of sebaceous glands in mouse skin or in the induction of s.c. sarcomas in rats. Since much other evidence suggests that the 3,4-dihydrodiol of 7-methylbenz[a]anthracene and the 7,8-dihydrodiol of benzo[a]pyrene are the dihydrodiols involved, via the related vicinal diol-epoxides, in the metabolic activation of these hydrocarbons, mouse skin initiation-promotion experiments may be more useful for the identification of such diols than the other two in vivo tests for biological activity used here. PMID:444395

  12. Prenatal Exposure to Benzo(a)pyrene Impairs Later-Life Cortical Neuronal Function

    PubMed Central

    McCallister, Monique M.; Maguire, Mark; Ramesh, Aramandla; Aimin, Qiao; Liu, Sheng; Khoshbouei, Habibeh; Aschner, Michael; Ebner, Ford F.; Hood, Darryl B.

    2009-01-01

    Prenatal exposure to environmental contaminants, such as Benzo(a)pyrene [B(a)P] has been shown to impair brain development. The overarching hypothesis of our work is that glutamate receptor subunit expression is crucial for cortical evoked responses and that prenatal B(a)P exposure modulates the temporal developmental expression of glutamatergic receptor subunits in the somatosensory cortex. To characterize prenatal B(a)P exposure on the development of cortical function, pregnant Long Evans rats were exposed to low-level B(a)P (300μg/kg BW) by oral gavage on gestational days 14 to 17. At this exposure dose, there was no significant effect of B(a)P on 1) the number of pups born per litter, 2) the pre-weaning growth curves and 3) initial and final brain to body weight ratios. Control and B(a)P-exposed offspring were profiled for B(a)P metabolites in plasma and whole brain during the pre-weaning period. No detectable levels of metabolites were found in the control offspring. However, a time-dependent decrease in total metabolite concentration was observed in B(a)P-exposed offspring. On PND100-120, cerebrocortical mRNA expression was determined for the glutamatergic NMDA receptor subunit (NR2B) in control and B(a)P-exposed offspring. Neural activity was also recorded from neurons in primary somatic sensory (barrel) cortex. Semiquantitative PCR from B(a)P-exposed offspring revealed a significant 50% reduction in NR2B mRNA expression in B(a)P-exposed offspring relative to controls. Recordings from B(a)P-exposed offspring revealed that N-methyl-D-aspartate (NMDA) receptor -dependent neuronal activity in barrel cortex evoked by whisker stimulation was also significantly reduced (70%) as compared to controls. Analysis showed that the greatest deficit in cortical neuronal responses occurred in the shorter latency epochs from 5-20ms post-stimulus. The results suggest that in utero exposure to benzo(a)pyrene results in diminished mRNA expression of the NMDA NR2B receptor

  13. 40 CFR 63.1427 - Process vent requirements for processes using extended cookout as an epoxide emission reduction...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... constant, 1/hr. t = Time, hours. Note: This equation assumes a first order reaction with respect to epoxide... concentration in the vapor space using Raoult's Law or another appropriate phase equilibrium equation and...

  14. 40 CFR 63.1427 - Process vent requirements for processes using extended cookout as an epoxide emission reduction...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... constant, 1/hr. t = Time, hours. Note: This equation assumes a first order reaction with respect to epoxide... concentration in the vapor space using Raoult's Law or another appropriate phase equilibrium equation and...

  15. A mechanistic study into the epoxidation of carboxylic acid and alkene in a mono, di-acylglycerol lipase.

    PubMed

    Wang, Xuping; Tang, Qingyun; Popowicz, Grzegorz Maria; Yang, Bo; Wang, Yonghua

    2015-05-01

    More and more industrial chemistry reactions rely on green technologies. Enzymes are finding increasing use in diverse chemical processes. Epoxidized vegetable oils have recently found applications as plasticizers and additives for PVC production. We report here an unusual activity of the Malassezia globosa lipase (SMG1) that is able to catalyze epoxidation of alkenes. SMG1 catalyzes formation of peroxides from long chain carboxylic acids that subsequently react with double bonds of alkenes to produce epoxides. The SMG1 is selective towards carboxylic acids and active also as a mutant lacking hydrolase activity. Moreover we present previously unobserved mechanism of catalysis that does not rely on acyl-substrate complex nor tetrahedral intermediate. Since SMG1 lipase is activated by allosteric change upon binding to the lipophilic-hydrophilic phase interface we reason that it can be used to drive the epoxidation in the lipophilic phase exclusively.

  16. Epoxide pathways improve model predictions of isoprene markers and reveal key role of acidity in aerosol formation

    EPA Science Inventory

    Isoprene significantly contributes to organic aerosol in the southeastern United States where biogenic hydrocarbons mix with anthropogenic emissions. In this work, the Community Multiscale Air Quality model is updated to predict isoprene aerosol from epoxides produced under both ...

  17. First HPLC-UV method for rapid and simultaneous quantification of phenobarbital, primidone, phenytoin, carbamazepine, carbamazepine-10,11-epoxide, 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine, lamotrigine, oxcarbazepine and licarbazepine in human plasma.

    PubMed

    Serralheiro, Ana; Alves, Gilberto; Fortuna, Ana; Rocha, Marília; Falcão, Amílcar

    2013-04-15

    A sensitive and fast high-performance liquid chromatographic method coupled with ultraviolet detection is herein reported for the simultaneous determination of human plasma concentration of six antiepileptic drugs frequently used in clinical practice [phenobarbital (PB), primidone (PRM), phenytoin (PHT), carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC)] and some of their main metabolites, carbamazepine-10,11-epoxide (CBZ-E), 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine (trans-diol) and licarbazepine (Lic). Sample preparation consisted of a deproteinization step with methanol followed by a solid-phase extraction procedure. Chromatographic separation was achieved in approximately 15 min on a reversed-phase C18 column using a mobile phase composed by water-methanol-acetonitrile-triethylamine (68.7:25:6:0.3, v/v/v/v; pH 6.5) pumped isocratically at 1.0 mL/min. The detector was set at 237 nm. Calibration curves were linear with regression coefficients greater than 0.992 over the concentration ranges 0.25-100 μg/mL for PB, 0.4-50 μg/mL for PRM, 0.5-50 μg/mL for PHT, 0.1-50 μg/mL for CBZ, LTG and CBZ-E, 0.1-25 μg/mL for OXC, 0.25-10 μg/mL for trans-diol and 0.15-80 μg/mL for Lic. Inter- and intra-day imprecision did not exceed 12.15% and inaccuracy was within ±14.91%. Absolute mean recoveries ranged from 78.49 to 101.04% and no interferences were observed at the retention times of the analytes and internal standard (ketoprofen). This bioanalytical method was successfully applied to real plasma samples from epileptic patients and it seems to be a suitable tool for routine therapeutic drug monitoring and also to support other clinical pharmacokinetic-based studies.

  18. Inactivation mechanism of glycerol dehydration by diol dehydratase from combined quantum mechanical/molecular mechanical calculations.

    PubMed

    Doitomi, Kazuki; Kamachi, Takashi; Toraya, Tetsuo; Yoshizawa, Kazunari

    2012-11-13

    Inactivation of diol dehydratase during the glycerol dehydration reaction is studied on the basis of quantum mechanical/molecular mechanical calculations. Glycerol is not a chiral compound but contains a prochiral carbon atom. Once it is bound to the active site, the enzyme adopts two binding conformations. One is predominantly responsible for the product-forming reaction (G(R) conformation), and the other primarily contributes to inactivation (G(S) conformation). Reactant radical is converted into a product and byproduct in the product-forming reaction and inactivation, respectively. The OH group migrates from C2 to C1 in the product-forming reaction, whereas the transfer of a hydrogen from the 3-OH group of glycerol to C1 takes place during the inactivation. The activation barrier of the hydrogen transfer does not depend on the substrate-binding conformation. On the other hand, the activation barrier of OH group migration is sensitive to conformation and is 4.5 kcal/mol lower in the G(R) conformation than in the G(S) conformation. In the OH group migration, Glu170 plays a critical role in stabilizing the reactant radical in the G(S) conformation. Moreover, the hydrogen bonding interaction between Ser301 and the 3-OH group of glycerol lowers the activation barrier in G(R)-TS2. As a result, the difference in energy between the hydrogen transfer and the OH group migration is reduced in the G(S) conformation, which shows that the inactivation is favored in the G(S) conformation.

  19. Digestive determinants of benzo[a]pyrene and phenanthrene bioaccumulation by a deposit-feeding polychaete

    SciTech Connect

    Penry, D.L.; Weston, D.P.

    1998-11-01

    The uptake of hydrophobic contaminants from ingested sediment can contribute significantly to body burdens of deposit feeders, and feeding behavior and digestive physiology can play important roles in bioaccumulation. The authors examined the uptake of polycyclic aromatic hydrocarbons (PAHs) by the deposit-feeding polychaete Abarenicola pacifica in experiments in which worms were first acclimated to low or high organic carbon sediments with 0.08 or 0.45% total organic carbon, respectively and then transferred to low or high organic carbon test sediments contaminated with radiolabeled phenanthrene or benzo[a]pyrene. Ingestion rate was measurements are essential in many types of bioaccumulation studies because differences in ingestion rates between sediment types may confound some traditional measures of bioavailability. Physiological acclimation to the low or high organic carbon sediments did not appear to affect PAH uptake from the test sediments, but acclimation did affect biotransformation capabilities, particularly for phenanthrene.

  20. Asbestos-catalyzed oxidation of benzo(a)pyrene by superoxide-peroxidized microsomes

    SciTech Connect

    Byczkowski, J.Z.; Gessner, T.

    1987-08-01

    Asbestos and benzo(a)pyrene (B(a)P) are ubiquitous in our environment and both are recognized as causal factors for cancer in man and animals. In vitro studies showed a synergism in morphological transformation of mammalian cells treated with asbestos and B(a)P. It has been shown that asbestos can mediate lipid peroxidation and that iron cations might be involved in the catalytic activity of asbestos fibers. A previous study of B(a)P metabolism by microsomes showed that peroxidative conditions change the balance between activation and deactivation of B(a)P and demonstrated that catalytically active iron can play a role in this process. The present investigation examines the effect of asbestos on oxidation of B(a)P by superoxide - peroxidized microsomes in vitro.

  1. Movements of benzo(a)pyrene across the hemochorial placenta of the guinea pig

    SciTech Connect

    Kelman, B.J.; Springer, D.L.

    1982-01-01

    In an effort to determine fetal exposure resulting from maternally administered benzo(a)pyrene (BaP), the clearance of radiolabeled BaP from mother to fetus was measured across the hemochorial placenta of the guinea pig at 60 days of gestation. Using techniques previously reported for other toxic materials, the fetal circulation of the placenta was isolated. BaP injected into the maternal circulation, and the concentration of BaP determined in the perfusate. The clearance of BaP from mother to fetus was high following intravenous injection. Clearances appeared to be a function of umbilical blood flow, and ranged from 0.59 to 2.40 ml/min at an umbilical flow of 2.5 ml/min. Since clearances of BaP approximated those obtained for tritiated water, it is apparent that circulating BaP gains easy access to the fetus.

  2. Liquid chromatographic determination of benzo(a)pyrene in total particulate matter of cigarette smoke

    SciTech Connect

    Tomkins, B.A.; Jenkins, R.A.; Griest, W.H.; Reagan, R.R.; Holladay, S.K.

    1985-09-01

    The benzo(a)pyrene (BaP) delivery of reference and commercially available tobacco cigarettes, as well as reference and placebo marijuana cigarettes, is determined using a sequential liquid chromatographic/liquid chromatographic procedure. The total particulate matter of sample cigarette smoke is collected using a Cambridge filter pad, which is ultrasonically extracted with acetone. The resulting extract is filtered, then fractionated using semipreparative-scale normal phase liquid chromatography (LC). Quantitative determination is achieved using analytical-scale reverse phase LC equipped with a fluorescence detector. The method is precise (+/- 10-15% relative standard deviation) and yields 85% or better BaP recovery at the ng/cig. level. A single pad may be analyzed in 8 person-hours, while a more typical lot of 12 pads (6 pads each for 2 cigarette brands) may be analyzed in 10 person-days.

  3. Octanol-water partition coefficient of benzo(a)pyrene: measurement, calculation, and environmental implications

    SciTech Connect

    Mallon, B.J.; Harrison, F.L.

    1984-03-01

    Benzo(a)pyrene (BaP) is a potent carcinogen produced in significant quantities during pyrolysis of such substances as coal, wood, and cigarettes. Several researchers have shown that the lipophilic storage and soil sediment accumulation of many organic solutes is proportional to the partitioning between octanol-1 and water. The octanol-water partition coefficient (P) is defined as P = C/sub o//C/sub w/, where C/sub o/ and C/sub w/ are the concentration of the solute in n-octanol and water. Considerable data are available demonstrating that P values measured in the laboratory can be used to predict the environmental behavior of organic pollutants. Literature searches reveal that calculated, but not measured, log P values are reported for BaP. This laboratory study was initiated to define better the log P of BaP.

  4. Live cell imaging of the intracellular compartmentalization of the contaminate benzo[a]pyrene.

    PubMed

    Ali, Rizwan; Trump, Saskia; Lehmann, Irina; Hanke, Thomas

    2015-05-01

    This study investigates the cellular response of murine hepatoma cells to the polycyclic aromatic hydrocarbon benzo[a]pyrene (B[a]P) using two-photon and confocal laser scanning microscopy. The intracellular distribution of B[a]P and the B[a]P/AhR complex was visualized time- and concentration-dependent for up to 48 h of exposure. B[a]P was predominantly found in lipid droplets, endoplasmic reticulum and lysosomes, where B[a]P is collected and forms large aggregates. Changes in mitochondrial membrane potential and bleb formation due to high B[a]P concentrations were observed. The imaging data presented in this study provide new insights into the systemic cellular regulation following B[a]P exposure.

  5. Chlorophyll catalyse the photo-transformation of carcinogenic benzo[a]pyrene in water

    PubMed Central

    Luo, Lijuan; Lai, Xueying; Chen, Baowei; Lin, Li; Fang, Ling; Tam, Nora F. Y.; Luan, Tiangang

    2015-01-01

    Algal blooms cause great damage to water quality and aquaculture. However, this study showed that dead algal cells and chlorophyll could accelerate the photo-transformation of benzo[a]pyrene (BaP), a ubiquitous and persistent pollutant with potently mutagenic and carcinogenic toxicities, under visible light irradiation. Chlorophyll was found to be the major active substance in dead algal cells, and generated a high level of singlet oxygen to catalyse the photo-transformation of BaP. According to various BaP metabolites formed, the degradation mechanism was proposed as that chlorophyll in dead algal cells photo-oxidized BaP to quinones via photocatalytic generation of singlet oxygen. The results provided a good insight into the role of chlorophyll in the photo-transformation of organic contaminants and could be a possible remediation strategy of organic pollutants in natural environment. PMID:26239357

  6. Chlorophyll catalyse the photo-transformation of carcinogenic benzo[a]pyrene in water

    NASA Astrophysics Data System (ADS)

    Luo, Lijuan; Lai, Xueying; Chen, Baowei; Lin, Li; Fang, Ling; Tam, Nora F. Y.; Luan, Tiangang

    2015-08-01

    Algal blooms cause great damage to water quality and aquaculture. However, this study showed that dead algal cells and chlorophyll could accelerate the photo-transformation of benzo[a]pyrene (BaP), a ubiquitous and persistent pollutant with potently mutagenic and carcinogenic toxicities, under visible light irradiation. Chlorophyll was found to be the major active substance in dead algal cells, and generated a high level of singlet oxygen to catalyse the photo-transformation of BaP. According to various BaP metabolites formed, the degradation mechanism was proposed as that chlorophyll in dead algal cells photo-oxidized BaP to quinones via photocatalytic generation of singlet oxygen. The results provided a good insight into the role of chlorophyll in the photo-transformation of organic contaminants and could be a possible remediation strategy of organic pollutants in natural environment.

  7. In Vivo Anti-Tumor Activity and Toxicological Evaluations of Perillaldehyde 8,9-Epoxide, a Derivative of Perillyl Alcohol

    PubMed Central

    Andrade, Luciana Nalone; Amaral, Ricardo Guimarães; Dória, Grace Anne Azevedo; Fonseca, Cecília Santos; da Silva, Tayane Kayane Mariano; Albuquerque Júnior, Ricardo Luiz Cavalcante; Thomazzi, Sara Maria; do Nascimento, Lázaro Gomes; Carvalho, Adriana Andrade; de Sousa, Damião Pergentino

    2016-01-01

    Recent studies have revealed the high cytotoxicity of p-menthane derivatives against human tumor cells. In this study, the substance perillaldehyde 8,9-epoxide, a p-menthane class derivative obtained from (S)-(−)-perillyl alcohol, was selected in order to assess antitumor activity against experimental sarcoma 180 tumors. Toxicological effects related to the liver, spleen, kidneys and hematology were evaluated in mice submitted to treatment. The tumor growth inhibition rate was 38.4%, 58.7%, 35.3%, 45.4% and 68.1% at doses of 100 and 200 mg/kg/day for perillaldehyde 8,9-epoxide, perillyl alcohol and 25 mg/kg/day for 5-FU intraperitoneal treatments, respectively. No toxicologically significant effect was found in liver and kidney parameters analyzed in Sarcoma 180-inoculated mice treated with perillaldehyde 8,9-epoxide. Histopathological analyses of the liver, spleen, and kidneys were free from any morphological changes in the organs of the animals treated with perillaldehyde 8,9-epoxide. In conclusion, the data suggest that perillaldehyde 8,9-epoxide possesses significant antitumor activity without systemic toxicity for the tested parameters. By comparison, there was no statistical difference for the antitumor activity between perillaldehyde 8,9-epoxide and perillyl alcohol. PMID:26742032

  8. Theoretical determination of molecular structure and conformation. 18. On the formation of epoxides during the ozonolysis of alkenes

    SciTech Connect

    Cremer, D.; Bock, C.W.

    1986-06-11

    The reaction of carbonyl oxide (CH/sub 2/OO) and ethylene has been investigated by ab initio techniques. According to theoretical results, carbonyl oxide can act as an oxygen-transfer agent, thus leading to epoxide and aldehyde: C/sub 2/H/sub 4/ + CH/sub 2/OO ..-->.. CH/sub 2/OCH/sub 2/ + CH/sub 2/O. The calculated transition-state energies of the various epoxidation modes are 4-8 kcal/mol, which are comparable to activation energies of cycloaddition (cycloreversion) reactions encountered in the ozonolysis of alkenes. Epoxidation of alkene by carbonyl oxide is best described as a S/sub N/2 reaction on the terminal oxygen atom of carbonyl oxide. The preferred collision mode of the O-transfer reaction can be rationalized on the basis of frontier orbital interactions. Apart from epoxidation, carbonyl oxide can add to ethylene, yielding 1,2-dioxolane. The energy requirements of the cycloaddition are equivalent to those of the epoxidation. However, 1,2-dioxolanes will only be observed under normal ozonolysis conditions if the excess energy generated in the cycloaddition reaction is readily dissipated. Otherwise, 1,2-dioxolanes will immediately decompose, again yielding, among other products, epoxides.

  9. Benzo[a]pyrene in urban environments of eastern Moscow: pollution levels and critical loads

    NASA Astrophysics Data System (ADS)

    Kasimov, Nikolay S.; Kosheleva, Natalia E.; Nikiforova, Elena M.; Vlasov, Dmitry V.

    2017-02-01

    Polycyclic aromatic hydrocarbons (PAHs), particularly benzo[a]pyrene (BaP), are toxic compounds emitted from various anthropogenic sources. Understanding the BaP concentrations, dynamics and decomposition in soil is required to assess the critical loads of BaP in urban environments. This study is the first attempt to evaluate all major input and output components of benzo[a]pyrene (BaP) balance and to calculate the permissible load on the urban environment in different land-use zones in the Eastern district of Moscow. BaP contamination of the snow cover in the Eastern district of Moscow was related to daily BaP fallout from the atmosphere. In 2010, the mean content of the pollutant in the snow dust was 1942 ng g-1, whereas the average intensity of its fallout was 7.13 ng m-2 per day. Across the territory, BaP winter fallout intensities varied from 0.3 to 1100 ng m-2 per day. The average BaP content in the surface (0-10 cm) soil horizons was 409 ng g-1, which is 83 times higher than the local background value and 20 times higher than the maximum permissible concentration (MPC) accepted in Russia. The variations in soil and snow BaP concentrations among different land-use zones were examined. A significant contribution of BaP from the atmosphere to urban soils was identified. Based on the measurements of BaP atmospheric fallout and BaP reserves in the soils, the critical loads of BaP for the land-use zones in the Eastern district were calculated for different values of degradation intensity and different exposure times. It was established that at an annual degradation intensity of 1-10 %, ecologically safe BaP levels in the soils of all land-use zones, excluding the agricultural zone, will only be reached after many decades or centuries.

  10. Predicting lung dosimetry of inhaled particleborne benzo[a]pyrene using physiologically based pharmacokinetic modeling

    PubMed Central

    Campbell, Jerry; Franzen, Allison; Van Landingham, Cynthia; Lumpkin, Michael; Crowell, Susan; Meredith, Clive; Loccisano, Anne; Gentry, Robinan; Clewell, Harvey

    2016-01-01

    Abstract Benzo[a]pyrene (BaP) is a by-product of incomplete combustion of fossil fuels and plant/wood products, including tobacco. A physiologically based pharmacokinetic (PBPK) model for BaP for the rat was extended to simulate inhalation exposures to BaP in rats and humans including particle deposition and dissolution of absorbed BaP and renal elimination of 3-hydroxy benzo[a]pyrene (3-OH BaP) in humans. The clearance of particle-associated BaP from lung based on existing data in rats and dogs suggest that the process is bi-phasic. An initial rapid clearance was represented by BaP released from particles followed by a slower first-order clearance that follows particle kinetics. Parameter values for BaP-particle dissociation were estimated using inhalation data from isolated/ventilated/perfused rat lungs and optimized in the extended inhalation model using available rat data. Simulations of acute inhalation exposures in rats identified specific data needs including systemic elimination of BaP metabolites, diffusion-limited transfer rates of BaP from lung tissue to blood and the quantitative role of macrophage-mediated and ciliated clearance mechanisms. The updated BaP model provides very good prediction of the urinary 3-OH BaP concentrations and the relative difference between measured 3-OH BaP in nonsmokers versus smokers. This PBPK model for inhaled BaP is a preliminary tool for quantifying lung BaP dosimetry in rat and humans and was used to prioritize data needs that would provide significant model refinement and robust internal dosimetry capabilities. PMID:27569524

  11. Epoxidation of 1-Octene with hydrogen peroxide aqueous catalyzed by titania supported sulfonated coal

    NASA Astrophysics Data System (ADS)

    Nurhadi, Mukhamad

    2017-02-01

    Titania supported sulfonated coal was created as heterogeneous catalyst for epoxidation of 1-octene with aqueous hydrogen peroxide as oxidant at room temperature. The catalysts were prepared from coal that was sulfonated with H2SO4 (97%) and impregnated 7.2%wt with titanium(IV) isopropoxide (Ti(PrO)4). All catalysts coal (C), CS, Ti(7.2)-CS and Ti(7.2)-CSC were characterized by FTIR. The catalytic performance was tested for epoxidation of 1-octene with H2O2 aqueous as oxidant. It is found that Ti(7.2)-CS possessed the best catalytic performance and it gave the highest 1,2 epoxyoctene 322 µmol.

  12. Block Copolymerization of Lactide and an Epoxide Facilitated by a Redox Switchable Iron-Based Catalyst.

    PubMed

    Biernesser, Ashley B; Delle Chiaie, Kayla R; Curley, Julia B; Byers, Jeffery A

    2016-04-18

    A cationic iron(III) complex was active for the polymerization of various epoxides, whereas the analogous neutral iron(II) complex was inactive. Cyclohexene oxide polymerization could be "switched off" upon in situ reduction of the iron(III) catalyst and "switched on" upon in situ oxidation, which is orthogonal to what was observed previously for lactide polymerization. Conducting copolymerization reactions in the presence of both monomers resulted in block copolymers whose identity can be controlled by the oxidation state of the catalyst: selective lactide polymerization was observed in the iron(II) oxidation state and selective epoxide polymerization was observed in the iron(III) oxidation state. Evidence for the formation of block copolymers was obtained from solubility differences, GPC, and DOSY-NMR studies.

  13. From epoxidized linseed oil to bioresin: an overall approach of epoxy/anhydride cross-linking.

    PubMed

    Pin, Jean-Mathieu; Sbirrazzuoli, Nicolas; Mija, Alice

    2015-04-13

    Biorenewable resources can be used as green monomers to design tailored structures for formulations that can play an important role as functional materials. The choice of optimal structures depends on the targeted properties and applications. This work focuses on the elaboration of biobased materials with toughened mechanical properties based on epoxidized linseed oil. This result was obtained by an overall approach of cross-linking process, that is, starting with the optimal choice of hardeners and finally favoring the side reactions of polymerization. Therefore, the anionic alternating copolymerization of epoxide with mono- and dianhydrides was investigated to tailor the parameters that led to maximal conversions and properties. The obtained highly cross-linked networks perform well, as demonstrated by good impact strengths, high glass transition temperatures, and excellent thermal stability, which opens up the possibility of using these emergent materials for industrial applications.

  14. Ladder Polyether Synthesis via Epoxide-Opening Cascades Directed by a Disappearing Trimethylsilyl Group

    PubMed Central

    Heffron, Timothy P.; Simpson, Graham L.; Merino, Estibaliz; Jamison, Timothy F.

    2010-01-01

    Epoxide-opening cascades offer the potential to construct complex polyether natural products expeditiously and in a manner that emulates the biogenesis proposed for these compounds. Herein we provide a full account of our development of a strategy that addresses several important challenges of such cascades. The centerpiece of the method is a trimethylsilyl (SiMe3) group that serves several purposes and leaves no trace of itself by the time the cascade has come to an end. The main function of the SiMe3 group is to dictate the regioselectivity of epoxide opening. This strategy is the only general method of effecting endo-selective cascades under basic conditions. PMID:20302314

  15. CO2 copolymers from epoxides: catalyst activity, product selectivity, and stereochemistry control.

    PubMed

    Lu, Xiao-Bing; Ren, Wei-Min; Wu, Guang-Peng

    2012-10-16

    The use of carbon dioxide as a carbon source for the synthesis of organic chemicals can contribute to a more sustainable chemical industry. Because CO(2) is such a thermodynamically stable molecule, few effective catalysts are available to facilitate this transformation. Currently, the major industrial processes that convert CO(2) into viable products generate urea and hydroxybenzoic acid. One of the most promising new technologies for the use of this abundant, inexpensive, and nontoxic renewable resource is the alternating copolymerization of CO(2) and epoxides to provide biodegradable polycarbonates, which are highly valuable polymeric materials. Because this process often generates byproducts, such as polyether or ether linkages randomly dispersed within the polycarbonate chains and/or the more thermodynamically stable cyclic carbonates, the choice of catalyst is critical for selectively obtaining the expected product. In this Account, we outline our efforts to develop highly active Co(III)-based catalysts for the selective production of polycarbonates from the alternating copolymerization of CO(2) with epoxides. Binary systems consisting of simple (salen)Co(III)X and a nucleophilic cocatalyst exhibited high activity under mild conditions even at 0.1 MPa CO(2) pressure and afforded copolymers with >99% carbonate linkages and a high regiochemical control (∼95% head-to-tail content). Discrete, one-component (salen)Co(III)X complexes bearing an appended quaternary ammonium salt or sterically hindered Lewis base showed excellent activity in the selectively alternating copolymerization of CO(2) with both aliphatic epoxides and cyclohexene oxide at high temperatures with low catalyst loading and/or low pressures of CO(2). Binary or one-component catalysts based on unsymmetric multichiral Co(III) complexes facilitated the efficient enantioselective copolymerization of CO(2) with epoxides, providing aliphatic polycarbonates with >99% head-to-tail content. These

  16. Synthesis of cyclic sulfites from epoxides and sulfur dioxide with silica-immobilized homogeneous catalysts.

    PubMed

    Takenaka, Yasumasa; Kiyosu, Takahiro; Mori, Goro; Choi, Jun-Chul; Fukaya, Norihisa; Sakakura, Toshiyasu; Yasuda, Hiroyuki

    2012-01-09

    Quaternary ammonium- and amino-functionalized silica catalysts have been prepared for the selective synthesis of cyclic sulfites from epoxides and sulfur dioxide, demonstrating the effects of immobilizing the homogeneous catalysts on silica. The cycloaddition of sulfur dioxide to various epoxides was conducted under solvent-free conditions at 100 °C. The quaternary ammonium- and amino-functionalized silica catalysts produced cyclic sulfites in high yields (79-96 %) that are comparable to those produced by the homogeneous catalysts. The functionalized silica catalysts could be separated from the product solution by filtration, thereby avoiding the catalytic decomposition of the cyclic sulfite products upon distillation of the product solution. Heterogenization of a homogeneous catalyst by immobilization can, therefore, improve the efficiency of the purification of crude reaction products. Despite a decrease in catalytic activity after each recycling step, the heterogeneous pyridine-functionalized silica catalyst provided high yields after as many as five recycling processes.

  17. Retinoids inhibit 2,3,7,8-tetrachlorodibenzo-p-dioxine-induced activity of benzo[a]pyrene metabolizing enzymes in human diploid fibroblasts.

    PubMed

    Kohl, F V; Rüdiger, H W

    1980-09-01

    Retinoids are known to inhibit the substrate mediated enzyme induction of benzo[a]pyrene metabolizing enzymes. Consequently, the effect of two retinoids on the induction of benzo[a]pyrene metabolizing enzymes by the more potent inductor 2,3,7,8-tetrachlorodibenzo-p-dioxine (TCDD) was investigated. The studies were performed with human diploid fibroblasts in culture. Vitamin A palmitate and all-trans-retinoic-acid were found to prevent the TCDD induced increase of benzo[a]pyrene metabolism in a dose-dependent manner. The fact that this effect was immediately reversible makes it unlikely that it was due to non-specific toxic effects. The data suggest that retinoids cause a preferential inhibition of the de novo synthesis of benzo[a]pyrene metabolizing enzymes.

  18. Effect of ingested benzo(a)pyrene and cadmium on tissue accumulation, hydroxylase activity, and intestinal morphology of the black sea bass, Centropristis striata

    SciTech Connect

    Fair, P.H.; Fortner, A.R.

    1987-02-01

    Black sea bass, Centropristis striata, were fed shrimp containing (/sup 14/C)benzo(a)pyrene (200 ppb) in the presence and absence of cadmium (10 ppm) for 10 days. Concentrations of cadmium in muscle tissue were significantly higher when both cadmium and benzo(a)pyrene were ingested simultaneously by the fish. Results indicate that selected tissue concentrations of total benzo(a)pyrene compounds (parent and metabolites) were not affected by the presence of cadmium. The bile contained the majority of benzo(a)pyrene found for all treatments. Ingestion of both contaminants had no effect on hepatic benzo(a)pyrene hydroxylase activity. Histological evidence from the feeding study demonstrated the presence of subcellular inclusions in the intestinal columnar cells and the combined effects of both contaminants appeared greater than either alone.

  19. Biodegradation of benzo[a]pyrene by the mixed culture of Bacillus cereus and Bacillus vireti isolated from the petrochemical industry.

    PubMed

    Mohandass, Ramya; Rout, Pallabi; Jiwal, Sonia; Sasikala, Chitrambalam

    2012-11-01

    Polycyclic aromatic hydrocarbons are a group of compounds that pose threat to humans and animal life. Methods to reduce the amount of PAHs in the environment are continuously being sought. The bacterial consortium capable of utilizing benzo(a)pyrene as the sole source of carbon and energy was isolated from petrochemical soil. The isolates were identified as Bacillus cereus and Bacillus viretibased on morphological characterization, and 16S rDNA gene sequence analysis. About 58.98% of benzo(a)pyrene at concentration of 500 mg l(-1) in mineral salts medium were removed by bacterial consortium. GC mass spectral analysis showed the presence of metabolite cis-4-(7-hydroxypyren-8-yl)-2-oxobut-3enoic acid. The results indicate that the bacterial consortium is a new bacterial resource for biodegrading benzo(a)pyrene and might be used for bioremediation of sites heavily contaminated by benzo[a]pyrene and its derivatives.

  20. A diatomaceous origin for long-chain diols and mid-chain hydroxy methyl alkanoates widely occurring in quaternary marine sediments: indicators for high-nutrient conditions

    NASA Astrophysics Data System (ADS)

    Sinninghe Damsté, Jaap S.; Rampen, Sebastiaan; Irene, W.; Rijpstra, C.; Abbas, Ben; Muyzer, Gerard; Schouten, Stefan

    2003-04-01

    For the first time a biological source for the long-chain alkyl 1,14-diols and 12-hydroxy methyl alkanoates, lipids widely occurring in the marine water column and sediments, has been identified. Cultures of Proboscia indica and Proboscia alata, rhizosolenoid diatoms belonging to the widespread diatom genus Proboscia, contain C 28, C 28:1, C 30, and C 30:1 alkyl 1,14-diols, and C 27 and C 29 12-hydroxy methyl alkanoates as major neutral lipids. These components form a substantial fraction of lipid fractions from sediment traps or sediments, especially in areas with an elevated primary production such as upwelling regions. Examination of literature data reveals that as much as 20 to 35% of the total lipid flux in the Arabian Sea is derived from Proboscia diatoms during the start of the upwelling season. Their rapid transfer to the water-sediment interface may explain why corresponding 1,14-keto-ols, inferred oxidation products of diols, are hardly formed. These interpretations are supported by compound-specific carbon isotopic analysis of long-chain keto-ols and diols in surface sediments of the Arabian Sea. The data indicate that long-chain alkyl 1,14-diols and 12-hydroxy methyl alkanoates can be applied as indicators for high-nutrient conditions in the photic zone.