Commercial Ethyl Glucuronide (EtG) and Ethyl Sulfate (EtS) Testing is Not Vulnerable to Incidental Alcohol Exposure in Pregnant Women.

PubMed

Ondersma, Steven J; Beatty, Jessica R; Rosano, Thomas G; Strickler, Ronald C; Graham, Amy E; Sokol, Robert J

2016-01-02

Ethyl Glucoronide (EtG) and Ethyl Sulfate (EtS) have shown promise as biomarkers for alcohol and may be sensitive enough for use with pregnant women in whom even low-level alcohol use is important. However, there have been reports of over-sensitivity of EtG and EtS to incidental exposure to sources such as alcohol-based hand sanitizer. Further, few studies have evaluated these biomarkers among pregnant women, in whom the dynamics of these metabolites may differ. This study evaluated whether commercial EtG-EtS testing was vulnerable to high levels of environmental exposure to alcohol in pregnant women. Two separate samples of five nurses-one pregnant and the other postpartum, all of whom reported high levels of alcohol-based hand sanitizer use-provided urine samples before and 4-8 hours after rinsing with alcohol-based mouthwash and using hand sanitizer. The five pregnant nurses provided urine samples before, during, and after an 8-hour nursing shift, during which they repeatedly cleansed with alcohol-based hand sanitizer (mean 33.8 uses). The five postpartum nurses used hand sanitizer repeatedly between baseline and follow-up urine samples. No urine samples were positive for EtG-EtS at baseline or follow-up, despite use of mouthwash and-in the pregnant sample-heavy use of hand sanitizer (mean of 33.8 uses) throughout the 8-hour shift. Current, commercially available EtG-EtS testing does not appear vulnerable to even heavy exposure to incidental sources of alcohol among pregnant and postpartum women.

Commercial Ethyl Glucuronide (EtG) and Ethyl Sulfate (EtS) Testing is not Vulnerable to Incidental Alcohol Exposure in Pregnant Women

PubMed Central

Beatty, Jessica R.; Rosano, Thomas G.; Strickler, Ronald C.; Graham, Amy E.; Sokol, Robert J.

2016-01-01

Background Ethyl Glucoronide (EtG) and Ethyl Sulfate (EtS) have shown promise as biomarkers for alcohol and may be sensitive enough for use with pregnant women in whom even low-level alcohol use is important. However, there have been reports of over-sensitivity of EtG and EtS to incidental exposure to sources such as alcohol-based hand sanitizer. Further, few studies have evaluated these biomarkers among pregnant women, in whom the dynamics of these metabolites may differ. Objectives This study evaluated whether commercial EtG-EtS testing was vulnerable to high levels of environmental exposure to alcohol in pregnant women. Methods Two separate samples of five nurses—one pregnant and the other postpartum, all of whom reported high levels of alcohol-based hand sanitizer use—provided urine samples before and 4–8 hours after rinsing with alcohol-based mouthwash and using hand sanitizer. The five pregnant nurses provided urine samples before, during, and after an 8-hour nursing shift, during which they repeatedly cleansed with alcohol-based hand sanitizer (mean 33.8 uses). The five postpartum nurses used hand sanitizer repeatedly between baseline and follow-up urine samples. Results No urine samples were positive for EtG-EtS at baseline or follow-up, despite use of mouthwash and—in the pregnant sample—heavy use of hand sanitizer (mean of 33.8 uses) throughout the 8-hour shift. Conclusions/Importance Current, commercially available EtG-EtS testing does not appear vulnerable to even heavy exposure to incidental sources of alcohol among pregnant and postpartum women. PMID:26771303

Determination of ethyl glucuronide in hair: a rapid sample pretreatment involving simultaneous milling and extraction.

PubMed

Mönch, Bettina; Becker, Roland; Nehls, Irene

2014-01-01

A combination of simultaneous milling and extraction known as micropulverized extraction was developed for the quantification of the alcohol marker ethyl glucuronide (EtG) in hair samples using a homogeneous reference material and a mixer mill. Best extraction results from 50 mg of hair were obtained with 2-mL plastic tubes containing two steel balls (∅ = 5 mm), 0.5 mL of water and with an oscillating frequency of 30 s(-1) over a period of 30 min. EtG was quantified employing a validated GC-MS procedure involving derivatization with pentafluoropropionic acid anhydride. This micropulverization procedure was compared with dry milling followed by separate aqueous extraction and with aqueous extraction after manual cutting to millimeter-size snippets. Micropulverization yielded 28.0 ± 1.70 pg/mg and was seen to be superior to manually cutting (23.0 ± 0.83 pg/mg) and equivalent to dry grinding (27.7 ± 1.71 pg/mg) with regard to completeness of EtG extraction. The option to process up to 20 samples simultaneously makes micropulverization especially valuable for the high throughput of urgent samples.

Value of ethyl glucuronide in plasma as a biomarker for recent alcohol consumption in the emergency room.

PubMed

Neumann, Tim; Helander, Anders; Dahl, Helen; Holzmann, Tilly; Neuner, Bruno; Weiss-Gerlach, Edith; Müller, Christian; Spies, Claudia

2008-01-01

This emergency department (ED) study compared the value of plasma ethyl glucuronide (EtG) testing with the information about alcohol consumption obtained using the standard alcohol biomarkers gamma-glutamyltransferase (GGT) and carbohydrate-deficient transferring (CDT) and the AUDIT questionnaire. Minimally injured and clinically non-intoxicated male patients (n = 81) admitted to an ED were screened regarding their alcohol consumption, using the computerized AUDIT questionnaire and a paper-and-pencil assessment including the type, amount and time of alcohol intake. Blood samples were collected for determination of ethanol, EtG (LC-MS) and GGT in plasma and %CDT in serum (Axis-Shield %CDT immunoassay). Out of the 81 patients, 23 (28%) were positive (>/=8 points) on the AUDIT questionnaire. Only 3 (4%) showed a detectable ethanol concentration (range 0.01-0.07 g/L) but 31 (38%) showed a detectable EtG (0.16-39.5 mg/L). In four patients, EtG was detectable in plasma for >48 h after estimated completed elimination of ethanol. EtG was not correlated with the long-term biomarkers %CDT or GGT, or the AUDIT results, but with the time since estimated completed ethanol elimination. EtG testing in blood was found useful in the ED as a way to detect recent drinking, even in cases of a negative ethanol test, and to confirm abstinence from alcohol. This sensitive and specific short-term biomarker provides valuable additional information about individual drinking habits and might also be helpful to identify an alcohol hangover.

Coloring, bleaching, and perming: influence on EtG content in hair.

PubMed

Kerekes, Isabelle; Yegles, Michel

2013-08-01

Hair analysis of ethyl glucuronide (EtG) has become, beside fatty acid ethyl ester, a valuable marker for the detection of moderate and chronic excessive alcohol consumption. So far, only few studies exist about the influence of cosmetic treatment on EtG content in hair. The aim of this study was to evaluate the effect of coloring, bleaching, and perming on the concentration of this alcohol marker in hair. Studies were also performed to evaluate the chemical stability of EtG in the presence of hydrogen peroxide and ammonium thioglycolate. Six air samples were treated in vitro by the different commercial cosmetics following the suppliers' instructions. After washing, pulverization, incubation in ultrasonic bath, and solid phase extraction, EtG was determined by GC/MS-NICI after solid phase extraction and heptafluorobutyric anhydride derivatization. The results showed that samples (n = 10) treated with the coloring product did not show any important change in the EtG results. In the bleaching study (n = 23), a mean decrease of 73.5% was observed. After incubation of a solution of EtG with hydrogen peroxide (15%), a decrease of 45% was shown supporting the hypothesis of a chemical degradation of EtG and a leaching out effect from the hair matrix. In the perm treatment study (n = 23), a mean decrease of 95.7% of EtG was found. Incubation of a solution of EtG with ammonium thioglycolate (5%) showed a total decrease of EtG supporting the hypothesis of a chemical degradation. Coloring treatment did not importantly influence EtG content in hair. However, an important decrease of EtG in hair could be found after bleaching and permanent wave treatment. This decrease seems to be because of a chemical degradation of EtG, after bleaching, and a leaching out effect from the matrix. After perming, it seems to be more of a chemical degradation of EtG. These data have to be considered for the correct interpretation of EtG amounts in hair.

Ethanol and ethyl glucuronide urine concentrations after ethanol-based hand antisepsis with and without permitted alcohol consumption.

PubMed

Gessner, Stephan; Below, Elke; Diedrich, Stephan; Wegner, Christian; Gessner, Wiebke; Kohlmann, Thomas; Heidecke, Claus-Dieter; Bockholdt, Britta; Kramer, Axel; Assadian, Ojan; Below, Harald

2016-09-01

During hand antisepsis, health care workers (HCWs) are exposed to alcohol by dermal contact and by inhalation. Concerns have been raised that high alcohol absorptions may adversely affect HCWs, particularly certain vulnerable individuals such as pregnant women or individuals with genetic deficiencies of aldehyde dehydrogenase. We investigated the kinetics of HCWs' urinary concentrations of ethanol and its metabolite ethyl glucuronide (EtG) during clinical work with and without previous consumption of alcoholic beverages by HCWs. The median ethanol concentration was 0.7 mg/L (interquartile range [IQR], 0.5-1.9 mg/L; maximum, 9.2 mg/L) during abstinence and 12.2 mg/L (IQR, 1.5-139.6 mg/L; maximum, 1,020.1 mg/L) during alcohol consumption. During abstinence, EtG reached concentrations of up to 958 ng/mL. When alcohol consumption was permitted, the median EtG concentration of all samples was 2,593 ng/mL (IQR, 890.8-3,576 ng/mL; maximum, 5,043 ng/mL). Although alcohol consumption was strongly correlated with both EtG and ethanol in urine, no significant correlation for the frequency of alcoholic hand antisepsis was observed in the linear mixed models. The use of ethanol-based handrub induces measurable ethanol and EtG concentrations in urine. Compared with consumption of alcoholic beverages or use of consumer products containing ethanol, the amount of ethanol absorption resulting from handrub applications is negligible. In practice, there is no evidence of any harmful effect of using ethanol-based handrubs as much as it is clinically necessary. Copyright © 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause Toll-like receptor 4 activation and enhanced pain

PubMed Central

Lewis, Susannah S.; Hutchinson, Mark R.; Zhang, Yingning; Hund, Dana K.; Maier, Steven F.; Rice, Kenner C.; Watkins, Linda R.

2013-01-01

We have previously observed that the non-opioid morphine metabolite, morphine-3-glucuronide, enhances pain via a toll-like receptor 4 (TLR4) dependent mechanism. The present studies were undertaken to determine whether TLR4-dependent pain enhancement generalizes to other classes of glucuronide metabolites. In silico modeling predicted that glucuronic acid alone and ethyl glucuronide, a minor but long-lasting ethanol metabolite, would dock to the same MD-2 portion of the TLR4 receptor complex previously characterized as the docking site for morphine-3-glucuronide. Glucuronic acid, ethyl glucuronide and ethanol all caused an increase in TLR4-dependent reporter protein expression in a cell line transfected with TLR4 and associated co-signaling molecules. Glucuronic acid-, ethyl glucuronide-, and ethanol-induced increases in TLR4 signaling were blocked by the TLR4 antagonists LPS-RS and (+)-naloxone. Glucuronic acid and ethyl glucuronide both caused allodynia following intrathecal injection in rats, which was blocked by intrathecal co-administration of the TLR4 antagonist LPS-RS. The finding that ethyl glucuronide can cause TLR4-dependent pain could have implications for human conditions such as hangover headache and alcohol withdrawal hyperalgesia, as well as suggesting that other classes of glucuronide metabolites could have similar effects. PMID:23348028

Systematic optimization of ethyl glucuronide extraction conditions from scalp hair by design of experiments and its potential effect on cut-off values appraisal.

PubMed

Alladio, Eugenio; Biosa, Giulia; Seganti, Fabrizio; Di Corcia, Daniele; Salomone, Alberto; Vincenti, Marco; Baumgartner, Markus R

2018-05-11

The quantitative determination of ethyl glucuronide (EtG) in hair samples is consistently used throughout the world to assess chronic excessive alcohol consumption. For administrative and legal purposes, the analytical results are compared with cut-off values recognized by regulatory authorities and scientific societies. However, it has been recently recognized that the analytical results depend on the hair sample pretreatment procedures, including the crumbling and extraction conditions. A systematic evaluation of the EtG extraction conditions from pulverized scalp hair was conducted by design of experiments (DoE) considering the extraction time, temperature, pH, and solvent composition as potential influencing factors. It was concluded that an overnight extraction at 60°C with pure water at neutral pH represents the most effective conditions to achieve high extraction yields. The absence of differential degradation of the internal standard (isotopically-labeled EtG) under such conditions was confirmed and the overall analytical method was validated according to SGWTOX and ISO17025 criteria. Twenty real hair samples with different EtG content were analyzed with three commonly accepted procedures: (a) hair manually cut in snippets and extracted at room temperature; (b) pulverized hair extracted at room temperature; (c) hair treated with the optimized method. Average increments of EtG concentration around 69% (from a to c) and 29% (from b to c) were recorded. In light of these results, the authors urge the scientific community to undertake an inter-laboratory study with the aim of defining more in detail the optimal hair EtG detection method and verifying the corresponding cut-off level for legal enforcements. This article is protected by copyright. All rights reserved.

A randomized controlled trial of ethyl glucuronide-based contingency management for outpatients with co-occurring alcohol use disorders and serious mental illness

PubMed Central

McDonell, Michael G.; Leickly, Emily; McPherson, Sterling; Skalisky, Jordan; Srebnik, Debra; Angelo, Frank; Vilardaga, Roger; Nepom, Jenny R.; Roll, John M.; Ries, Richard K.

2017-01-01

Objective To determine if a contingency management intervention using the ethyl glucuronide (EtG) alcohol biomarker resulted in increased alcohol abstinence in outpatients with co-occurring serious mental illnesses. Secondary objectives were to determine if contingency management was associated with changes in heavy drinking, treatment attendance, drug use, cigarette smoking, psychiatric symptoms, and HIV-risk behavior. Method Seventy-nine (37% female, 44% non-white) outpatients with serious mental illness and alcohol dependence receiving treatment as usual completed a 4-week observation period and were randomized to 12-weeks of contingency management for EtG-negative urine samples and addiction treatment attendance, or reinforcement only for study participation. Contingency management included the variable magnitude of reinforcement “prize draw” procedure contingent on EtG-negative samples (<150 ng/mL) three times a week and weekly gift cards for outpatient treatment attendance. Urine EtG, drug test, and self-report outcomes were assessed during the 12-week intervention and 3-month follow-up periods. Results Contingency management participants were 3.1 times (95% CI: 2.2, 4.5) more likely to submit an EtG-negative urine test during the 12-week intervention period, attaining nearly 1.5 weeks of additional abstinence relative to controls. Contingency management participants had significantly lower mean EtG levels, reported less drinking and fewer heavy drinking episodes, and were more likely to submit stimulant-negative urine and smoking-negative breath samples, relative to controls. Differences in self-reported alcohol use were maintained at the 3-month follow-up. Conclusions This is the first randomized trial utilizing an accurate and validated biomarker (EtG) to demonstrate the efficacy of contingency management for alcohol dependence in outpatients with serious mental illness. PMID:28135843

A Randomized Controlled Trial of Ethyl Glucuronide-Based Contingency Management for Outpatients With Co-Occurring Alcohol Use Disorders and Serious Mental Illness.

PubMed

McDonell, Michael G; Leickly, Emily; McPherson, Sterling; Skalisky, Jordan; Srebnik, Debra; Angelo, Frank; Vilardaga, Roger; Nepom, Jenny R; Roll, John M; Ries, Richard K

2017-04-01

The authors examined whether a contingency management intervention using the ethyl glucuronide (EtG) alcohol biomarker resulted in increased alcohol abstinence in outpatients with co-occurring serious mental illnesses. Secondary objectives were to determine whether contingency management was associated with changes in heavy drinking, treatment attendance, drug use, cigarette smoking, psychiatric symptoms, and HIV-risk behavior. Seventy-nine (37% female, 44% nonwhite) outpatients with serious mental illness and alcohol dependence receiving treatment as usual completed a 4-week observation period and were randomly assigned to 12 weeks of contingency management for EtG-negative urine samples and addiction treatment attendance, or reinforcement only for study participation. Contingency management included the variable magnitude of reinforcement "prize draw" procedure contingent on EtG-negative samples (<150 ng/mL) three times a week and weekly gift cards for outpatient treatment attendance. Urine EtG, drug test, and self-report outcomes were assessed during the 12-week intervention and 3-month follow-up periods. Contingency management participants were 3.1 times (95% CI=2.2-4.5) more likely to submit an EtG-negative urine test during the 12-week intervention period, attaining nearly 1.5 weeks of additional alcohol abstinence compared with controls. Contingency management participants had significantly lower mean EtG levels, reported less drinking and fewer heavy drinking episodes, and were more likely to submit stimulant-negative urine and smoking-negative breath samples, compared with controls. Differences in self-reported alcohol use were maintained at the 3-month follow-up. This is the first randomized trial utilizing an accurate and validated biomarker (EtG) to demonstrate the efficacy of contingency management for alcohol dependence in outpatients with serious mental illness.

Hair ethyl glucuronide concentrations in teetotalers: Should we re-evaluate the lower cut-off?

PubMed

Crunelle, Cleo L; Yegles, Michel; De Doncker, Mireille; Cappelle, Delphine; Covaci, Adrian; van Nuijs, Alexander L N; Neels, Hugo

2017-05-01

Ethyl glucuronide in hair (hEtG) can be used to assess the retrospective consumption of alcohol. A lower cut-off of 7pg/mg hair in the 0-3cm proximal scalp hair segment has been used for repeated alcohol consumption in the previous three months. While a concentration below this cut-off is stated not to contradict self reported abstinence, it is often used to assess whether an individual has remained abstinent in the period prior to hair sampling. Here, we address hEtG concentrations in alcohol consuming individuals and critically evaluate this cut-off value. Ten individuals remained abstinent from alcohol for 12 weeks. A lock of hair was cut before the start of the study, and the regrown hairs were cut after twelve weeks of abstinence. Hair EtG concentrations were measured both at baseline and after 12 weeks of abstinence. Study compliance was assessed by urine analysis every 2-3 days by liquid chromatography-tandem mass spectrometry with a lower limit of quantification (LLOQ) of 0.1μg/mL. HEtG concentrations were assessed in the first 3cm hair using gas chromatography-tandem mass spectrometry with an LLOQ of 0.2pg/mg. At the beginning of the study, participants had hEtG concentrations ranging between EtG from the pre-study period. Although the number of specimens was low, this study reports measurable h

Validation of HPLC-ESI-MS/MS Protocol to Analyze EtG in Hair for Assessment of Chronic Excessive Alcohol Use in Thailand in Conjunction with AUDIT.

PubMed

Thananchai, Thiwaphorn; Junkuy, Anongphan; Kittirattanapaiboon, Phunnapa; Sribanditmongkol, Pongruk

2016-06-01

Hair analysis for chronic excessive alcohol (ethanol) use has focused on ethyl glucuronide (EtG), a minor metabolite of ethanol. Preferred methods have involved high-performance liquid chromatography (HPLC) combined with tandem mass spectrometry (MS/MS) in line with an electrospray ionization (ESI) source. EtG analysis in hair has not yet been introduced to Thailand To validate an in-house HPLC-ESI-MS/MS hair analysis protocol for EtG and to apply it to a field sample of alcohol drinkers to assess different risk levels of alcohol consumption as measured by the Alcohol Use Disorders Identification Test (AUDIT). Validation procedures followed guidelines of the US Food and Drug Administration, the European Medicines Agency, and the Scientific Working Group for Forensic Toxicology. One hundred twenty subjects reported consuming alcohol during a 3-month period prior to enrollment. After taking the Thai-language version of AUDIT, subjects were divided on the basis of test scores into low, medium, and high-risk groups for chronic excessive alcohol use. The protocol satisfied the international standards for selectivity, specificity, accuracy, precision, and calibration curve. There was no significant matrix effect. Limits of detection and quantification (LOD/LOQ) were set at 15 pg of EtG per mg of hair. The protocol was not able to detect EtG in low-risk subjects (n = 38). Detection rates for medium-risk (n = 42) and high-risk subjects (n = 40) were 14.3% and 85%, respectively. The median of EtG concentration between these two groups were significantly different. Sensitivity and specificity were both more than 90% when EtG concentrations of high-risk subjects were compared with the 30 pg/mg cutoff recommended by the Society of Hair Testing (SoHT) for diagnosing chronic excessive alcohol consumption, based on an average ethanol daily intake greater than 60 g. The in-house protocol for EtG analysis in hair was validated according to international standards. The protocol is a

Segmental hair analysis to assess effectiveness of single-session motivational intervention to stop ethanol use during pregnancy.

PubMed

Joya, Xavier; Mazarico, Edurne; Ramis, Juan; Pacifici, Roberta; Salat-Batlle, Judith; Mortali, Claudia; García-Algar, Oscar; Pichini, Simona

2016-01-01

This study aimed to test the effectiveness of single-session motivational intervention to stop ethanol use during pregnancy using segmental hair analysis of ethyl glucuronide to objectively verify drinking behavior before and after intervention. 168 pregnant women attending Hospital del Mar (Barcelona, Spain) for antenatal visit were included in the study and randomly assigned to one of two conditions: single-session motivational intervention (MI; N=83) or single-session educational control condition (ECC; N=85). Ethyl glucuronide was measured in maternal hair divided into three segments of 3 cm each corresponding to the three different gestation trimesters by a validated liquid chromatography tandem mass spectrometry method. Concentrations of EtG<7 pg/mg, between 7 and 30 pg/mg and ≥30 pg/mg in each segment were used to assess total abstinence, repetitive moderate drinking and chronic excessive consumption in the previous three months. About a third of pregnant women self-reporting no ethanol consumption during gestation showed hair EtG values corresponding to ethanol drinking. Single-session MI helped in decreasing alcohol consumption during pregnancy as assessed by lower hair EtG concentrations in 2nd and 3rd trimesters. However, it did not significantly increase complete abstinence in pregnant women who previously showed hair EtG compatible with ethanol consumption. Pregnant women did not correctly self reported ethanol consumption during gestation, while hair EtG was essential to correctly identify drinking patterns. Single-session MI was not enough to stop ethanol use during pregnancy. Interventions at any visit during pregnancy are strongly recommended. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Glucuronidation of trans-resveratrol by human liver and intestinal microsomes and UGT isoforms.

PubMed

Brill, Shirley S; Furimsky, Anna M; Ho, Mark N; Furniss, Michael J; Li, Yi; Green, Adam G; Bradford, Wallace W; Green, Carol E; Kapetanovic, Izet M; Iyer, Lalitha V

2006-04-01

Resveratrol (trans-resveratrol, trans-3,5,4'-trihydroxystilbene) is a naturally occurring stilbene analogue found in high concentrations in red wine. There is considerable research interest to determine the therapeutic potential of resveratrol, as it has been shown to have tumour inhibitory and antioxidant properties. This study was performed to investigate the glucuronidation of resveratrol and possible drug interactions via glucuronidation. Two glucuronide conjugates, resveratrol 3-O-glucuronide and resveratrol 4'-O-glucuronide, were formed by human liver and intestinal microsomes. UGT1A1 and UGT1A9 were predominantly responsible for the formation of the 3-O-glucuronide (Km = 149 microM) and 4'-O-glucuronide (Km = 365 microM), respectively. The glucuronide conjugates were formed at higher levels (up to 10-fold) by intestinal rather than liver microsomes. Resveratrol was co-incubated with substrates of UGT1A1 (bilirubin and 7-ethyl-10-hydroxycamptothecin (SN-38)) and UGT1A9 (7-hydroxytrifluoromethyl coumarin (7-HFC)). No major changes were noted in bilirubin glucuronidation in the presence of resveratrol. Resveratrol significantly inhibited the glucuronidation of SN-38 (Ki = 6.2 +/- 2.1 microM) and 7-HFC (Ki = 0.6 +/- 0.2 microM). Hence, resveratrol has the potential to inhibit the glucuronidation of concomitantly administered therapeutic drugs or dietary components that are substrates of UGT1A1 and UGT1A9.

Meconium indicators of maternal alcohol abuse during pregnancy and association with patient characteristics.

PubMed

Goecke, Tamme W; Burger, Pascal; Fasching, Peter A; Bakdash, Abdulsallam; Engel, Anne; Häberle, Lothar; Voigt, Franziska; Faschingbauer, Florian; Raabe, Eva; Maass, Nicolai; Rothe, Michael; Beckmann, Matthias W; Pragst, Fritz; Kornhuber, Johannes

2014-01-01

Identification of women with moderate alcohol abuse during pregnancy is difficult. We correlated self-reported alcohol consumption during pregnancy and patient characteristics with objective alcohol indicators measured in fetal meconium. A total of 557 women singleton births and available psychological tests, obstetric data and meconium samples were included in statistical analysis. Alcohol metabolites (fatty acid ethyl esters (FAEEs) and ethyl glucuronide (EtG)), were determined from meconium and correlated with patient characteristics. We found that 21.2% of the 557 participants admitted low-to-moderate alcohol consumption during pregnancy. Of the parameters analyzed from meconium, only EtG showed an association with alcohol history (P < 0.01). This association was inverse in cases with EtG value above 120 ng/g. These values indicate women with most severe alcohol consumption, who obviously denied having consumed alcohol during pregnancy. No other associations between socioeconomic or psychological characteristics and the drinking status (via meconium alcohol metabolites) could be found. Women who drink higher doses of ethanol during pregnancy, according to metabolite measures in meconium, might be less likely to admit alcohol consumption. No profile of socioeconomic or psychological characteristics of those women positively tested via meconium could be established.

Dynamics of Secondary Large-Scale Structures in ETG Turbulence Simulations

NASA Astrophysics Data System (ADS)

Li, Jiquan; Y, Kishimoto; Dong, Jiaqi; N, Miyato; T, Matsumoto

2006-01-01

The dynamics of secondary large-scale structures in electron-temperature-gradient (ETG) turbulence is investigated based on gyrofluid simulations in sheared slab geometry. It is found that structural bifurcation to zonal flow dominated or streamer-like states depends on the spectral anisotropy of turbulent ETG fluctuation, which is governed by the magnetic shear. The turbulent electron transport is suppressed by enhanced zonal flows. However, it is still low even if the streamer is formed in ETG turbulence with strong shears. It is shown that the low transport may be related to the secondary excitation of poloidal long-wavelength mode due to the beat wave of the most unstable components or a modulation instability. This large-scale structure with a low frequency and a long wavelength may saturate, or at least contribute to the saturation of ETG fluctuations through a poloidal mode coupling. The result suggests a low fluctuation level in ETG turbulence.

Occupational Exposure to Alcohol-Based Hand Sanitizers: The Diagnostic Role of Alcohol Biomarkers in Hair.

PubMed

Salomone, A; Bozzo, A; Di Corcia, D; Gerace, E; Vincenti, M

2018-04-01

Ethyl glucuronide (EtG) and fatty acid ethyl esters (FAEEs) in hair are effective direct biomarkers of ethanol ingestion, whose analytical determination can be used to discriminate between chronic and occasional ethanol intake. Ethanol is a compound widely used in some workplaces (e.g., clinics, hospitals) and is present in considerable amounts in mouthwash for oral cleaning, medications, cosmetic products, hydro-alcoholic disinfectants and antiseptics for hands. This study examined the ethyl alcohol exposure derived from hand disinfectants (in gel form) by simulating the typical occupational situation of medical-health workers (healthcare workers, nurses, surgeons, etc.) who frequently wash their hands with antiseptic sanitizer. Two types of hand disinfectants with 62% w/w of ethanol content were daily applied to the hands of a teetotaler for 20 times a day, for 4 consecutive weeks, thus simulating a typical workplace situation and a cumulative dermal exposure to ethanol of ~1,100 g. Different matrices (head, chest and beard hair, urine) were regularly sampled and analyzed using a ultra high-performance liquid chromatography tandem massspectrometry validated method for EtG and a (HS)SPME-GC-MS validated technique for FAEEs. The data obtained showed that a significant dermal absorption and/or inhalation of ethanol occurred, and that the use of detergents produce urinary EtG concentrations both higher than the cut-offs normally used for clinical and forensic analyses (either 100 and 500 ng/mL, depending on the context). The concentrations of the ethanol metabolites in the keratin matrices were, respectively, below the cut-off of 7 pg/mg for EtG and below 0.5 ng/mg for FAAEs (0.35 ng/mg for ethyl palmitate). In conclusion, the regular use of alcohol-based hand sanitizers can affect the concentration of urinary EtG and lead to positive analytical results, particularly when specimens are obtained shortly after sustained use of ethanol-containing hand sanitizer. On the

Filling the gap between lab and clinical impact: An open randomized diagnostic trial comparing urinary ethylglucuronide and ethanol in alcohol dependent outpatients.

PubMed

Barrio, Pablo; Teixidor, Lídia; Ortega, Lluisa; Lligoña, Anna; Rico, Nayra; Bedini, José Luis; Vieta, Eduard; Gual, Antoni

2018-02-01

Efforts aimed at reducing alcohol-related harm include early detection of risky drinkers as well as detection of early relapse in patients with alcohol dependence. Ethyl glucuronide (EtG) has been proven to be a reliable biomarker for the detection of recent drinking; however, no randomized, diagnostic trial to date has tested its impact on drinking outcomes. The aim of this study was to assess, in a randomized design, the implications of EtG screening on alcohol outcomes, compared to screening with a low sensitivity biomarker such as ethanol. Alcohol dependent outpatients were randomized to either 24 weeks of continuous screening with EtG or ethanol. Patients were aware of screening methods and results. After 24 weeks, all participants were screened with EtG. Self-reports were also gathered. A logistic regression compared the rate of EtG positive results at study end between groups. Generalized estimating equations evaluated the descending monthly rate of EtG positive patients in the EtG group. A total of 162 patients were randomized. During the study period, the ethanol group showed less patients with positive screens (19/64 (29.7%) vs 58/98 (59%)). After 24 weeks, the EtG group showed a greater number of patients having a negative screening test compared to ethanol subjects when they were all screened with EtG (5/62 (8.1%) vs 13/39 (33.3%)). A significant decrease in the rate of EtG positive patients was found for the first three months of the study. Routine screening with EtG seems to reduce drinking and improve abstinence rates in alcohol dependent outpatients. Copyright © 2017 Elsevier B.V. All rights reserved.

Alcohol Consumption during Pregnancy: Analysis of Two Direct Metabolites of Ethanol in Meconium.

PubMed

Sanvisens, Arantza; Robert, Neus; Hernández, José María; Zuluaga, Paola; Farré, Magí; Coroleu, Wifredo; Serra, Montserrat; Tor, Jordi; Muga, Robert

2016-03-22

Alcohol consumption in young women is a widespread habit that may continue during pregnancy and induce alterations in the fetus. We aimed to characterize prevalence of alcohol consumption in parturient women and to assess fetal ethanol exposure in their newborns by analyzing two direct metabolites of ethanol in meconium. This is a cross-sectional study performed in September 2011 and March 2012 in a series of women admitted to an obstetric unit following childbirth. During admission, socio-demographic and substance use (alcohol, tobacco, cannabis, cocaine, and opiates) during pregnancy were assessed using a structured questionnaire and clinical charts. We also recorded the characteristics of pregnancy, childbirth, and neonates. The meconium analysis was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to detect the presence of ethyl glucuronide (EtG) and ethyl sulfate (EtS). Fifty-one parturient and 52 neonates were included and 48 meconium samples were suitable for EtG and EtS detection. The median age of women was 30 years (interquartile range (IQR): 26-34 years); EtG was present in all meconium samples and median concentration of EtG was 67.9 ng/g (IQR: 36.0-110.6 ng/g). With respect to EtS, it was undetectable (<0.01 ng/g) in the majority of samples (79.1%). Only three (6%) women reported alcohol consumption during pregnancy in face-to-face interviews. However, prevalence of fetal exposure to alcohol through the detection of EtG and EtS was 4.2% and 16.7%, respectively. Prevention of alcohol consumption during pregnancy and the detection of substance use with markers of fetal exposure are essential components of maternal and child health.

The determination of ethyl glucuronide in hair: Experiences from nine consecutive interlaboratory comparison rounds.

PubMed

Becker, R; Lô, I; Sporkert, F; Baumgartner, M

2018-07-01

The increasing request for hair ethyl glucuronide (HEtG) in alcohol consumption monitoring according to cut-off levels set by the Society of Hair Testing (SoHT) has triggered a proficiency testing program based on interlaboratory comparisons (ILC). Here, the outcome of nine consecutive ILC rounds organised by the SoHT on the determination of HEtG between 2011 and 2017 is summarised regarding interlaboratory reproducibility and the influence of procedural variants. Test samples prepared from cut hair (1mm) with authentic (in-vivo incorporated) and soaked (in-vitro incorporated) HEtG concentrations up to 80pg/mg were provided for 27-35 participating laboratories. Laboratory results were evaluated according to ISO 5725-5 and provided robust averages and relative reproducibility standard deviations typically between 20 and 35% in reasonable accordance with the prediction of the Horwitz model. Evaluation of results regarding the analytical techniques revealed no significant differences between gas and liquid chromatographic methods In contrast, a detailed evaluation of different sample preparations revealed significantly higher average values in case when pulverised hair is tested compared to cut hair. This observation was reinforced over the different ILC rounds and can be attributed to the increased acceptance and routine of hair pulverisation among laboratories. Further, the reproducibility standard deviations among laboratories performing pulverisation were on average in very good agreement with the prediction of the Horwitz model. Use of sonication showed no effect on the HEtG extraction yield. Copyright © 2018 Elsevier B.V. All rights reserved.

Ethylglucuronide in the urine as a marker of alcohol consumption during pregnancy: Comparison with four alcohol screening questionnaires.

PubMed

Ferraguti, Giampiero; Ciolli, Paola; Carito, Valentina; Battagliese, Gemma; Mancinelli, Rosanna; Ciafrè, Stefania; Tirassa, Paola; Ciccarelli, Rosaria; Cipriani, Alessia; Messina, Marisa Patrizia; Fiore, Marco; Ceccanti, Mauro

2017-06-05

Ethyl glucuronide (EtG) is an ethanol metabolite and EtG is used as a biomarker of alcohol drinking. EtG can be detected in the blood and in several biological matrices including urine, hair and nails. Alcohol consumption during pregnancy is a strong risk factor for fetus health so in the recent years different strategies to reveal alcohol use have been planning including the use of screening questionnaires as the AUDIT-C, T-ACE and TWEAK. The present study aims to investigate in pregnant women the specificity and predictive value of the AUDIT-C, T-ACE and TWEAK plus a food diary in use in Sapienza University Hospital compared with the results of urine EtG measurement. Seventy pregnant women were enrolled and examined. Urine samples were provided by pregnant women immediately after the interviews. EtG determinations were performed by Enzyme Immunoassay with a cut-off established at 100ng/mL. Data show that 34.28% of the enrolled pregnant women overcame the EtG cut off. No direct correlation was found between EtG data and the alcohol screening interviews showing lower levels of alcohol consumption, although T-ACE revealed the same at risk percentage. However, a significant concordance was observed with food diary data and T-ACE only in patients with higher EtG urinary concentration. This study provides clinical evidence that the diagnosis of maternal alcohol consumption during pregnancy only based on indirect methods, such as questionnaires and food diary, may significantly underestimate alcohol use. Copyright © 2017 Elsevier B.V. All rights reserved.

Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active

PubMed Central

Brown, Sarah M.; Holtzman, Michael; Kim, Thomas; Kharasch, Evan D.

2012-01-01

Background The long-lasting high affinity opioid buprenorphine has complex pharmacology including ceiling effects with respect to analgesia and respiratory depression. Plasma concentrations of the major buprenorphine metabolites norbuprenorphine, buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide approximate or exceed those of the parent drug. Buprenorphine glucuronide metabolites pharmacology is undefined. This investigation determined binding and pharmacological activity of the two glucuronide metabolites, and in comparison with buprenorphine and norbuprenorphine. Methods Competitive inhibition of radioligand binding to human mu, kappa, delta opioid and nociceptin receptors was used to determine glucuronide binding affinities for these receptors. Common opiate effects were assessed in vivo in Swiss Webster mice. Antinociception was assessed using a tail-flick assay, respiratory effects were measured using unrestrained whole-body plethysmography, and sedation was assessed by inhibition of locomotion measured by open-field testing. Results Buprenorphine-3-glucuronide had high affinity for human mu (Ki = 4.9±2.7 pM), delta (Ki = 270±0.4 nM), and nociceptin (Ki = 36±0.3 μM) but not kappa receptors. Norbuprenorphine-3-glucuronide had affinity for human kappa (Ki = 300±0.5 nM) and nociceptin (Ki= 18±0.2 μM) but not mu or delta receptors. At the dose tested, buprenorphine-3-glucuronide had a small antinociceptive effect. Neither glucuronide had significant effects on respiratory rate, but norbuprenorphine-3-glucuronide decreased tidal volume. Norbuprenorphine-3-glucuronide also caused sedation. Conclusions Both glucuronide metabolites of buprenorphine are biologically active at doses relevant to metabolite exposures which occur after buprenorphine. Activity of the glucuronides may contribute to the overall pharmacology of buprenorphine. PMID:22037640

Ethyl glucuronide concentration in hair for detecting heavy drinking and/or abstinence: a meta-analysis.

PubMed

Boscolo-Berto, Rafael; Viel, Guido; Montisci, Massimo; Terranova, Claudio; Favretto, Donata; Ferrara, Santo Davide

2013-05-01

In both clinical and forensic settings, hair analysis for ethyl glucuronide (HEtG) has been increasingly employed for diagnosing chronic excessive drinking and, more recently, for monitoring abstinence. This paper aims at meta-analysing published data on HEtG concentrations in teetotallers, social drinkers and heavy drinkers in order to evaluate the use of this marker in hair for identifying chronic excessive drinking and for monitoring abstinence. In May 2012, a systematic multi-database search retrieved 366 records related to HEtG and further screened for relevant publications in the field. Fifteen (4.1 %) records matched the selection criteria and were included in the meta-analysis. The mean and 95 % confidence intervals (CI) of HEtG concentrations in social drinkers (mean 7.5 pg/mg; 95 % CI 4.7-10.2 pg/mg; p < 0.001), heavy drinkers (mean 142.7 pg/mg; 95 % CI 99.9-185.5 pg/mg; p < 0.001) and deceased subjects with a known history of chronic excessive drinking (mean 586.1 pg/mg; 95 % CI 177.2-995.0 pg/mg; p < 0.01) were calculated. The ranges of mean values and 95 % confidence intervals for single studies involving teetotallers/social or social/heavy drinkers showed a partial overlap with a down-trespassing of both the 7 and 30 pg/mg thresholds for social and heavy drinkers, respectively. Although larger and well-designed population studies are required to draw any definitive conclusion, our data show that the cut-off of 30 pg/mg limits the false-negative effect in differentiating heavy from social drinkers, whereas the recently proposed 7 pg/mg cut-off value might only be used for suspecting an active alcohol use, and not for proving complete abstinence.

Alcohol, caffeine, and nicotine consumption in adolescents: hair analysis versus self-report.

PubMed

Bertol, Elisabetta; Vaiano, Fabio; Boscolo-Berto, Rafael; Fioravanti, Alessia; Palumbo, Diego; Catalani, Valeria; Mari, Francesco; Patussi, Valentino; Serpelloni, Giovanni

2017-05-01

Clinical reliability of self-reported data for alcohol, caffeine, and nicotine consumptions is lacking, particularly in adolescents. To compare a self-report questionnaire and hair analysis to assess the reliability and effectiveness of the self-report. A cross-sectional study on 14-15-year-old Italian students (n = 874, 38% males, 62% females) was performed comparing self-reported data to hair analysis. The latter quantified hair concentrations of caffeine, nicotine, cotinine, ethyl glucuronide (EtG), and fatty acid ethyl esters (FAEEs) using mass spectrometry. Concordance between self-report and hair testing ranged from good to poor across substances and levels of use: poor for heavy alcohol intake (EtG: k = 0.36, 20 positive cases by hair analysis, false negative by self-report, 2.3% of total sample; FAEE k = 0.31, 25 positive cases, 2.9% of total sample); fair to poor for active smokers (k = 0.40, 125 positive cases, 14.3% of total sample); and moderate for caffeine (k = 0.57, 56 positive cases, 6.4% of total sample). Epidemiological studies on alcohol, caffeine, and nicotine consumption in adolescents may benefit from the inclusion of toxicological analysis on hair samples to overcome the under-reporting phenomenon of questionnaires and detect more cases of problematic substance use.

Unreliable alcohol testing in a shipping safety programme.

PubMed

Helander, Anders; Hagelberg, Charlotte Asker; Beck, Olof; Petrini, Björn

2009-08-10

Within a maritime alcohol and drug testing programme, a case showing an unphysiological urine ethanol concentration (235 mmol/L, 10.8 g/L) was found. The sample contained low levels of the ethanol metabolites ethyl glucuronide (EtG) and ethyl sulphate (EtS) which confirmed prior drinking, but also tested positive for the fermenting yeast Candida albicans which suggested post-sampling ethanol formation. This and other questionable cases prompted investigation of the suitability of urine alcohol testing for the intended application. Besides the routine measurements of ethanol, illicit drugs and creatinine, randomly selected ethanol-positive and ethanol-negative urines collected within the maritime programme were checked for the presence of EtG and EtS and for fungal and bacterial growth. Data on sample handling and storage was also gathered. Ten of 15 (67%) ethanol-positive and 4 of 9 (44%) ethanol-negative urines contained yeast and/or bacteria. Among the ethanol-positive cases, 4 (27%) were obviously false positives because EtG and EtS were not detected. Microbial action as the reason for false-high ethanol concentrations was indicated in other cases. When 17 bacteria-infected but fungi-negative urines were supplemented with glucose and stored for 1 week at 21 degrees C, ethanol was formed in 2 specimens containing Escherichia coli and E. coli plus P. aeruginosa. In these samples, EtG was also formed on storage while EtS was not. The routines employed for urine collection and handling within this substance abuse programme caused many false-positive identifications of alcohol use with unintended medico-legal consequences. Unpreserved urines stored without cooling should not be used for alcohol testing, given the high risk for microbial interference.

Complete Genome Sequence of EtG, the First Phage Sequenced from Erwinia tracheiphila.

PubMed

Andrade-Domínguez, Andrés; Kolter, Roberto; Shapiro, Lori R

2018-02-22

Erwinia tracheiphila is the causal agent of bacterial wilt of cucurbits. Here, we report the genome sequence of the temperate phage EtG, which was isolated from an E. tracheiphila -infected cucumber plant. Phage EtG has a linear 30,413-bp double-stranded DNA genome with cohesive ends and 45 predicted open reading frames. Copyright © 2018 Andrade-Domínguez et al.

Hepatic disposition of the acyl glucuronide 1-O-gemfibrozil-beta-D-glucuronide: effects of clofibric acid, acetaminophen, and acetaminophen glucuronide.

PubMed

Sabordo, L; Sallustio, B C; Evans, A M; Nation, R L

2000-10-01

Glucuronidation of carboxylic acid compounds results in the formation of electrophilic acyl glucuronides. Because of their polarity, carrier-mediated hepatic transport systems play an important role in determining both intra- and extrahepatic exposure to these reactive conjugates. We have previously shown that the hepatic membrane transport of 1-O-gemfibrozil-beta-D-glucuronide (GG) is carrier-mediated and inhibited by the organic anion dibromosulfophthalein. In this study, we examined the influence of 200 microM acetaminophen, acetaminophen glucuronide, and clofibric acid on the disposition of GG (3 microM) in the recirculating isolated perfused rat liver preparation. GG was taken up by the liver, excreted into bile, and hydrolyzed within the liver to gemfibrozil, which appeared in perfusate but not in bile. Mean +/- S. D. hepatic clearance, apparent intrinsic clearance, hepatic extraction ratio, and biliary excretion half-life of GG were 10.4 +/- 1.4 ml/min, 94.1 +/- 17.9 ml/min, 0.346 +/- 0.046, and 30.9 +/- 4.9 min, respectively, and approximately 73% of GG was excreted into bile. At the termination of the experiment (t = 90 min), the ratio of GG concentrations in perfusate, liver, and bile was 1:35:3136. Acetaminophen and acetaminophen glucuronide had no effect on the hepatic disposition of GG, suggesting relatively low affinities of acetaminophen conjugates for hepatic transport systems or the involvement of multiple transport systems for glucuronide conjugates. In contrast, clofibric acid increased the hepatic clearance, extraction ratio, and apparent intrinsic clearance of GG (P <.05) while decreasing its biliary excretion half-life (P <.05), suggesting an interaction between GG and hepatically generated clofibric acid glucuronide at the level of hepatic transport. However, the transporter protein(s) involved remains to be identified.

Diethylstilbestrol can effectively accelerate estradiol-17-O-glucuronidation, while potently inhibiting estradiol-3-O-glucuronidation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Liangliang; Xiao, Ling; Xia, Yangliu

This in vitro study investigates the effects of diethylstilbestrol (DES), a widely used toxic synthetic estrogen, on estradiol-3- and 17-O- (E2-3/17-O) glucuronidation, via culturing human liver microsomes (HLMs) or recombinant UDP-glucuronosyltransferases (UGTs) with DES and E2. DES can potently inhibit E2-3-O-glucuronidation in HLM, a probe reaction for UGT1A1. Kinetic assays indicate that the inhibition follows a competitive inhibition mechanism, with the Ki value of 2.1 ± 0.3 μM, which is less than the possible in vivo level. In contrast to the inhibition on E2-3-O-glucuronidation, the acceleration is observed on E2-17-O-glucuronidation in HLM, in which cholestatic E2-17-O-glucuronide is generated. In themore » presence of DES (0–6.25 μM), K{sub m} values for E2-17-O-glucuronidation are located in the range of 7.2–7.4 μM, while V{sub max} values range from 0.38 to 1.54 nmol/min/mg. The mechanism behind the activation in HLM is further demonstrated by the fact that DES can efficiently elevate the activity of UGT1A4 in catalyzing E2-17-O-glucuronidation. The presence of DES (2 μM) can elevate V{sub max} from 0.016 to 0.81 nmol/min/mg, while lifting K{sub m} in a much lesser extent from 4.4 to 11 μM. Activation of E2-17-O-glucuronidation is well described by a two binding site model, with K{sub A}, α, and β values of 0.077 ± 0.18 μM, 3.3 ± 1.1 and 104 ± 56, respectively. However, diverse effects of DES towards E2-3/17-O-glucuronidation are not observed in liver microsomes from several common experimental animals. In summary, this study issues new potential toxic mechanisms for DES: potently inhibiting the activity of UGT1A1 and powerfully accelerating the formation of cholestatic E2-17-O-glucuronide by UGT1A4. - Highlights: • E2-3-O-glucuronidation in HLM is inhibited when co-incubated with DES. • E2-17-O-glucuronidation in HLM is stimulated when co-incubated with DES. • Acceleration of E2-17-O-glucuronidationin in HLM by DES is via

Interpretation of group-level factors from a large population dataset in the determination of ethyl glucuronide in hair.

PubMed

Salomone, Alberto; Pirro, Valentina; Lombardo, Tonia; Di Corcia, Daniele; Pellegrino, Sergio; Vincenti, Marco

2015-05-01

Ethyl glucuronide in hair (HEtG) is the most accredited marker to prove chronic alcohol abuse. In this study, we evaluate the comprehensive results of HEtG determination obtained during four years of activity (2009-2013) in our laboratory (Northwestern Italy) - across a large cohort of subjects (over 20 000 subjects mostly undergoing medical examination for driving re-licensing) - to provide a general perspective on HEtG analysis and dependence on group-level factors (e.g. age, gender, site and period of hair collection) that could bias the analytical results. HEtG was measured by liquid chromatography-tandem mass spectrometry. About 12% of the subjects presented HEtG concentrations over 30 pg/mg. Upon non-parametric hypothesis tests, distributions of HEtG in independent populations categorized by age proved statistically different, while no differences were found by considering gender, BMI, and site of sampling (head vs. chest hair). A 'seasonality' factor was evaluated by comparing periods of collection approximately representing the hair growth in winter, spring, summer and autumn, and a seasonal trend was observed showing the highest HEtG levels in winter (16.7%) and minimum levels in summer (8.3%). The experimental HEtG distributions confirm that chest hair sampling can be trusted as an alternative to scalp. Furthermore, among biological and external factors, age and season of sampling may significantly influence the measured HEtG concentration, and this potential source of bias should be taken into account when the results are interpreted. Copyright © 2014 John Wiley & Sons, Ltd.

Gyrokinetic Studies of Turbulence Reduction with Reverse Shear ETG Transport Barriers or Lithium Walls

NASA Astrophysics Data System (ADS)

Hammett, G. W.; Peterson, J. L.; Granstedt, E. M.; Bell, R.; Guttenfelder, W.; Kaye, S.; Leblanc, B.; Mikkelsen, D. R.; Smith, D. R.; Yuh, H. Y.; Candy, J.

2012-03-01

The National Spherical Torus Experiment (NSTX) can achieve high electron confinement regimes that are super-critically unstable to the electron temperature gradient (ETG) instability. These electron internal transport barriers (e-ITBs) occur when the magnetic shear becomes strongly negative. Using the gyrokinetic code GYRO, the first nonlinear ETG simulations of NSTX e-ITB plasmas demonstrate reduced turbulence consistent with this observation. This is qualitatively consistent with a secondary instability picture of reduced ETG turbulence at negative shear (Jenko and Dorland PRL 2002). Local simulations identify a strongly upshifted nonlinear critical gradient for thermal transport that depends on magnetic shear. Global simulations show that ETG-driven turbulence outside of the barrier is large enough to be experimentally relevant, but cannot propagate very far into the barrier. We also use GYRO to study turbulence in regimes that might be expected in the Lithium Torus eXperiment (LTX). While lithium has experimentally been shown to raise the edge temperature and improve performance, there can still be some turbulence from density-gradient-driven trapped electron modes, and a temperature pinch is found in some cases. (Supported by DOE.)

A utilitarian comparison of two alcohol use biomarkers with self-reported drinking history collected in antenatal clinics.

PubMed

May, Philip A; Hasken, Julie M; De Vries, Marlene M; Marais, Anna-Susan; Stegall, Julie M; Marsden, Daniel; Parry, Charles D H; Seedat, Soraya; Tabachnick, Barbara

2018-04-01

Alcohol use is reported accurately among pregnant women in some populations. Self-reported alcohol use via the AUDIT and 90-day recall for 193 women from antenatal clinics was compared to biomarker results: phosphatidylethanol (PEth) from bloodspots and ethyl glucuronide (EtG) in fingernails. AUDIT was positive for 67.9% of respondents, and 65.3% directly reported drinking. Individual biomarkers detected less drinking (PEth = 57.0%, EtG = 38.9%) than self-report. But 64.8% had drinking-positive values (>8 ng) on one or both biomarkers, which was not significantly different from self-report. Biomarkers indicated that 3.1% -6.8% of drinkers denied drinking. Combined biomarker sensitivity was 95% -80% and specificity 49% -76% for drinking in the previous 7-90 days. Combined biomarker results have their best yield (89.6%) and accuracy (78.8%) when measuring 90 day drinking. Women reported their alcohol use accurately, and the combined use of PEth and EtG is supported. Copyright © 2018 Elsevier Inc. All rights reserved.

Urinary Elimination of Bile Acid Glucuronides under Severe Cholestatic Situations: Contribution of Hepatic and Renal Glucuronidation Reactions.

PubMed

Perreault, Martin; Wunsch, Ewa; Białek, Andrzej; Trottier, Jocelyn; Verreault, Mélanie; Caron, Patrick; Poirier, Guy G; Milkiewicz, Piotr; Barbier, Olivier

2018-01-01

Biliary obstruction, a severe cholestatic complication, causes accumulation of toxic bile acids (BAs) in liver cells. Glucuronidation, catalyzed by UDP-glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic BAs. Using liquid chromatography coupled to tandem mass spectrometry, 11 BA glucuronide (-G) species were quantified in prebiliary and postbiliary stenting serum and urine samples from 17 patients with biliary obstruction. Stenting caused glucuronide- and fluid-specific changes in BA-G levels and BA-G/BA metabolic ratios. In vitro glucuronidation assays with human liver and kidney microsomes revealed that even if renal enzymes generally displayed lower K M values, the two tissues shared similar glucuronidation capacities for BAs. By contrast, major differences between the two tissues were observed when four human BA-conjugating UGTs 1A3, 1A4, 2B4, and 2B7 were analyzed for mRNA and protein levels. Notably, the BA-24G producing UGT1A3 enzyme, abundant in the liver, was not detected in kidney microsomes. In conclusion, the circulating and urinary BA-G profiles are hugely impacted under severe cholestasis. The similar BA-glucuronidating abilities of hepatic and renal extracts suggest that both the liver and kidney may contribute to the urine BA-G pool.

Urinary Elimination of Bile Acid Glucuronides under Severe Cholestatic Situations: Contribution of Hepatic and Renal Glucuronidation Reactions

PubMed Central

Perreault, Martin; Białek, Andrzej; Trottier, Jocelyn; Verreault, Mélanie; Caron, Patrick; Poirier, Guy G.

2018-01-01

Biliary obstruction, a severe cholestatic complication, causes accumulation of toxic bile acids (BAs) in liver cells. Glucuronidation, catalyzed by UDP-glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic BAs. Using liquid chromatography coupled to tandem mass spectrometry, 11 BA glucuronide (-G) species were quantified in prebiliary and postbiliary stenting serum and urine samples from 17 patients with biliary obstruction. Stenting caused glucuronide- and fluid-specific changes in BA-G levels and BA-G/BA metabolic ratios. In vitro glucuronidation assays with human liver and kidney microsomes revealed that even if renal enzymes generally displayed lower KM values, the two tissues shared similar glucuronidation capacities for BAs. By contrast, major differences between the two tissues were observed when four human BA-conjugating UGTs 1A3, 1A4, 2B4, and 2B7 were analyzed for mRNA and protein levels. Notably, the BA-24G producing UGT1A3 enzyme, abundant in the liver, was not detected in kidney microsomes. In conclusion, the circulating and urinary BA-G profiles are hugely impacted under severe cholestasis. The similar BA-glucuronidating abilities of hepatic and renal extracts suggest that both the liver and kidney may contribute to the urine BA-G pool. PMID:29850459

Disposition of Naringenin via Glucuronidation Pathway Is Affected by Compensating Efflux Transporters of Hydrophilic Glucuronides

PubMed Central

Xu, Haiyan; Kulkarni, Kaustubh H.; Singh, Rashim; Yang, Zhen; Wang, Stephen W.J.; Tam, Vincent H.; Hu, Ming

2010-01-01

The purposes of this study were to investigate how efflux transporters and UDP-glucuronosyltransferases (UGT) affect the disposition of naringenin. A rat intestinal perfusion model with bile duct cannulation was used along with rat intestinal and liver microsomes. In the intestinal perfusion model, both absorption and subsequent excretion of naringenin metabolites were rapid and site-dependent (p < 0.05). Naringenin was absorbed the most in colon and its glucuronides were excreted the most in duodenum. In metabolism studies, the intrinsic clearance value of naringenin glucuronidation was the highest in jejunum microsomes, followed by liver, ileal and colonic microsomes. The rapid metabolism in microsomes did not always translate into more efficient excretion in the rat perfusion model, however, because of presence of rate-limiting efflux transporters. When used separately, MK-571 (an inhibitor of multidrug resistance-related protein 2 or Mrp2) or dipyridamole (an inhibitor of breast cancer resistance protein or Bcrp1) did not affect excretion of naringenin glucuronides, but when used together, they significantly (p < 0.05) decreased intestinal and biliary excretion of naringenin glucuronides. In conclusion, efflux transporters Mrp2 and Bcrp1 are shown to compensate for each other and enable the intestinal excretion of flavonoid (i.e., naringenin) glucuronides. PMID:19736994

Utility of coloured hair for the detection of drugs and alcohol.

PubMed

Agius, Ronald

2014-06-01

The aim of this paper is to assess the utility of coloured hair for the detection of drugs and alcohol in a large statistically significant population. The positivity rate, the 1st, 5th, 50th, 95th, and 99th percentiles of five amphetamines, cannabinoids, cocaine, four opiates, methadone, buprenorphine, seven benzodiazepines, and ethyl glucuronide (EtG) in 9488 non-treated and 1026 cosmetically treated (dyed or bleached) authentic hair samples was compared. Analytical methods used were accredited for forensic purposes at the cut-offs defined by the German driving licence re-granting medical and psychological assessment (MPA) guidelines. Considering only the drug classes for which at least 10 positive samples were detected, the positivity rate in non-treated hair was highest for alcohol (4.50%; measured using EtG at concentrations ≥ 7 pg/mg hair), followed by THC (2.00%), cocaine (1.75%), and amphetamine (0.59%). While the 1st to 99th percentile range was significantly lower for drugs in treated, compared to non-treated hair, no significant change was observed for EtG. Additionally, no significant difference in the positivity rate was observed between treated hair and non-treated hair for both drugs and EtG. This study is the first attempt to evaluate the influence of cosmetic treatment, mainly dying, on the positivity rate for both drugs and EtG in hair samples submitted routinely for abstinence testing and the first to indicate that dyed and eventually bleached hair is not necessarily useless in detecting drugs and/or alcohol consumption, thus making coloured hair analysis still useful, often being the only possibility to prove such misuse. Copyright © 2014 John Wiley & Sons, Ltd.

Alcohol Biomarkers in Clinical and Forensic Contexts.

PubMed

Andresen-Streichert, Hilke; Müller, Alexander; Glahn, Alexander; Skopp, Gisela; Sterneck, Martina

2018-05-04

Biomarkers of alcohol consumption are important not only in forensic contexts, e.g., in child custody proceedings or as documentation of alcohol abstinence after temporary confiscation of a driver's license. They are increasingly being used in clinical medicine as well for verification of abstinence or to rule out the harmful use of alcohol. This review is based on pertinent publications that were retrieved by a selective literature search in PubMed concerning the direct and indirect alcohol markers discussed here, as well as on the authors' experience in laboratory analysis and clinical medicine. Alongside the direct demonstration of ethanol, the available markers of alcohol consumption include the classic indirect markers carbohydrate-deficient transferrin (CDT), gamma-glutamyltransferase (GGT), and mean corpuscular volume (MCV) as well as direct alcohol markers such as ethyl glucuronide (EtG) and ethyl sulfate (EtS) in serum and urine and EtG and fatty acid ethyl esters (FAEE) in hair. Phosphatidylethanol (PEth) is a promising parameter that com - plements the existing spectrum of tests with high specificity (48-89%) and sensi - tivity (88-100%). In routine clinical practice, the demonstration of positive alcohol markers often leads patients to admit previously denied alcohol use. This makes it possible to motivate the patient to undergo treatment for alcoholism. The available alcohol biomarkers vary in sensitivity and specificity with respect to the time period over which they indicate alcohol use and the minimum extent of alcohol use that they can detect. The appropriate marker or combination of markers should be chosen in each case according to the particular question that is to be answered by laboratory analysis.

Triterpenes and flavonol glucuronides from Oenothera cheiranthifolia.

PubMed

Nakanishi, Tsutomu; Inatomi, Yuka; Murata, Hiroko; Ishida, Syun-Suke; Fujino, Yuri; Miura, Kanako; Yasuno, Yoshito; Inada, Akira; Lang, Frank A; Murata, Jin

2007-02-01

A new ursane-type triterpene, named as cheiranthic acid (1), was isolated from the MeOH extract of whole plants of Oenothera cheiranthifolia (Onagraceae) along with an isomeric pair of known oleanane- and ursane-type triterpenes (arjunolic acid and asiatic acid) and three flavonol glucuronide analogues (quercetin 3-O-glucuronide, its n-butyl ester, and myricetin 3-O-glucuronide). Their structures were elucidated based on spectroscopic evidence.

Safety Assessment of Acyl Glucuronides-A Simplified Paradigm.

PubMed

Smith, Dennis A; Hammond, Timothy; Baillie, Thomas A

2018-06-01

While simple O - (ether-linked) and N -glucuronide drug conjugates generally are unreactive and considered benign from a safety perspective, the acyl glucuronides that derive from metabolism of carboxylic acid-containing xenobiotics can exhibit a degree of chemical reactivity that is dependent upon their molecular structure. As a result, concerns have arisen over the safety of acyl glucuronides as a class, several members of which have been implicated in the toxicity of their respective parent drugs. However, direct evidence in support of these claims remains sparse, and due to frequently encountered species differences in the systemic exposure to acyl glucuronides (both of the parent drug and oxidized derivatives thereof), coupled with their instability in aqueous media and potential to undergo chemical rearrangement (acyl migration), qualification of these conjugates by traditional safety assessment methods can be very challenging. In this Commentary, we discuss alternative (non-acyl glucuronide) mechanisms by which carboxylic acids may cause serious adverse reactions, and propose a novel, practical approach to compare systemic exposure to acyl glucuronide metabolites in humans to that in animal species used in preclinical safety assessment based on relative estimates of the total body burden of these circulating conjugates. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Glucuronidation and its impact on the bioactivity of [6]-shogaol.

PubMed

Wang, Pei; Zhao, Yantao; Zhu, Yingdong; Sang, Shengmin

2017-09-01

-shogaol (6S) from ginger has been reported to have diverse bioactivities and can be widely metabolized in animals and humans; however, the impact of glucuronidation on its bioactivity is still largely unknown. This study investigates the glucuronidation of 6S and its effect on cell cytotoxicity and Nrf2-inducing activities of 6S. The glucuronidated metabolite of 6S, 4-O-monoglucuronide 6S (6S-G), was synthesized and characterized for the first time. Glucuronidation of 6S in humans was studied using microsomes of the liver and intestine and recombinant UDP-glucuronosyltransferase (UGTs). The kinetics of 6S glucuronidation by human liver and intestinal microsomes followed the substrate inhibition kinetics model. The intrinsic glucuronidation clearance (CL int ) of 6S in human liver microsomes was higher than that in human intestine microsomes. Among the recombinant UGTs examined, UGT1A1, 1A3, 1A6, 1A8, 1A10, 2B7, 2B15, and 2B17 exhibited glucuronidation activity toward 6S, with UGT2B7 being the most potent one. Compared with 6S, the glucuronidation of 6S largely eliminated its cell cytotoxicity against human colon cancer cell lines HT-116 and HT-29, and its Nrf2-inducing activity. The findings from current study provide foundations for understanding the role of glucuronidation in biotransformation and biological activities of 6S. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Glucuronidation of deoxynivalenol (DON) by different animal species: identification of iso-DON glucuronides and iso-deepoxy-DON glucuronides as novel DON metabolites in pigs, rats, mice, and cows.

PubMed

Schwartz-Zimmermann, Heidi E; Hametner, Christian; Nagl, Veronika; Fiby, Iris; Macheiner, Lukas; Winkler, Janine; Dänicke, Sven; Clark, Erica; Pestka, James J; Berthiller, Franz

2017-12-01

The Fusarium mycotoxin deoxynivalenol (DON) is a frequent contaminant of cereal-based food and feed. Mammals metabolize DON by conjugation to glucuronic acid (GlcAc), the extent and regioselectivity of which is species-dependent. So far, only DON-3-glucuronide (DON-3-GlcAc) and DON-15-GlcAc have been unequivocally identified as mammalian DON glucuronides, and DON-7-GlcAc has been proposed as further DON metabolite. In the present work, qualitative HPLC-MS/MS analysis of urine samples of animals treated with DON (rats: 2 mg/kg bw, single bolus, gavage; mice: 1 mg/kg bw, single i.p. injection; pigs: 74 µg/kg bw, single bolus, gavage; cows: 5.2 mg DON/kg dry mass, oral for 13 weeks) revealed additional DON and deepoxy-DON (DOM) glucuronides. To elucidate their structures, DON and DOM were incubated with human (HLM) and rat liver microsomes (RLM). Besides the expected DON/DOM-3- and 15-GlcAc, minor amounts of four DON- and four DOM glucuronides were formed. Isolation and enzymatic hydrolysis of four of these compounds yielded iso-DON and iso-DOM, the identities of which were eventually confirmed by NMR. Incubation of iso-DON and iso-DOM with RLM and HLM yielded two main glucuronides for each parent compound, which were isolated and identified as iso-DON/DOM-3-GlcAc and iso-DON/DOM-8-GlcAc by NMR. Iso-DON-3-GlcAc, most likely misidentified as DON-7-GlcAc in the literature, proved to be a major DON metabolite in rats and a minor metabolite in pigs. In addition, iso-DON-8-GlcAc turned out to be one of the major DON metabolites in mice. DOM-3-GlcAc was the dominant DON metabolite in urine of cows and an important DON metabolite in rat urine. Iso-DOM-3-GlcAc was detected in urine of DON-treated rats and cows. Finally, DON-8,15-hemiketal-8-glucuronide, a previously described by-product of DON-3-GlcAc production by RLM, was identified in urine of DON-exposed mice and rats. The discovery of several novel DON-derived glucuronides in animal urine requires adaptation of

In silico prediction of acyl glucuronide reactivity

NASA Astrophysics Data System (ADS)

Potter, Tim; Lewis, Richard; Luker, Tim; Bonnert, Roger; Bernstein, Michael A.; Birkinshaw, Timothy N.; Thom, Stephen; Wenlock, Mark; Paine, Stuart

2011-11-01

Drugs and drug candidates containing a carboxylic acid moiety, including many widely used non-steroidal anti-inflammatory drugs (NSAIDs) are often metabolized to form acyl glucuronides (AGs). NSAIDs such as Ibuprofen are amongst the most widely used drugs on the market, whereas similar carboxylic acid drugs such as Suprofen have been withdrawn due to adverse events. Although the link between these AG metabolites and toxicity is not proven, there is circumstantial literature evidence to suggest that more reactive acyl glucuronides may, in some cases, present a greater risk of exhibiting toxic effects. We wished therefore to rank the reactivity of potential new carboxylate-containing drug candidates, and performed kinetic studies on synthetic acyl glucuronides to benchmark our key compounds. Driven by the desire to quickly rank the reactivity of compounds without the need for lengthy synthesis of the acyl glucuronide, a correlation was established between the degradation half-life of the acyl glucuronide and the half life for the hydrolysis of the more readily available methyl ester derivative. This finding enabled a considerable broadening of chemical property space to be investigated. The need for kinetic measurements was subsequently eliminated altogether by correlating the methyl ester hydrolysis half-life with the predicted 13C NMR chemical shift of the carbonyl carbon together with readily available steric descriptors in a PLS model. This completely in silico prediction of acyl glucuronide reactivity is applicable within the earliest stages of drug design with low cost and acceptable accuracy to guide intelligent molecular design. This reactivity data will be useful alongside the more complex additional pharmacokinetic exposure and distribution data that is generated later in the drug discovery process for assessing the overall toxicological risk of acidic drugs.

Evaluation of direct and indirect ethanol biomarkers using a likelihood ratio approach to identify chronic alcohol abusers for forensic purposes.

PubMed

Alladio, Eugenio; Martyna, Agnieszka; Salomone, Alberto; Pirro, Valentina; Vincenti, Marco; Zadora, Grzegorz

2017-02-01

The detection of direct ethanol metabolites, such as ethyl glucuronide (EtG) and fatty acid ethyl esters (FAEEs), in scalp hair is considered the optimal strategy to effectively recognize chronic alcohol misuses by means of specific cut-offs suggested by the Society of Hair Testing. However, several factors (e.g. hair treatments) may alter the correlation between alcohol intake and biomarkers concentrations, possibly introducing bias in the interpretative process and conclusions. 125 subjects with various drinking habits were subjected to blood and hair sampling to determine indirect (e.g. CDT) and direct alcohol biomarkers. The overall data were investigated using several multivariate statistical methods. A likelihood ratio (LR) approach was used for the first time to provide predictive models for the diagnosis of alcohol abuse, based on different combinations of direct and indirect alcohol biomarkers. LR strategies provide a more robust outcome than the plain comparison with cut-off values, where tiny changes in the analytical results can lead to dramatic divergence in the way they are interpreted. An LR model combining EtG and FAEEs hair concentrations proved to discriminate non-chronic from chronic consumers with ideal correct classification rates, whereas the contribution of indirect biomarkers proved to be negligible. Optimal results were observed using a novel approach that associates LR methods with multivariate statistics. In particular, the combination of LR approach with either Principal Component Analysis (PCA) or Linear Discriminant Analysis (LDA) proved successful in discriminating chronic from non-chronic alcohol drinkers. These LR models were subsequently tested on an independent dataset of 43 individuals, which confirmed their high efficiency. These models proved to be less prone to bias than EtG and FAEEs independently considered. In conclusion, LR models may represent an efficient strategy to sustain the diagnosis of chronic alcohol consumption

Biosynthesis of Drug Glucuronide Metabolites in the Budding Yeast Saccharomyces cerevisiae.

PubMed

Ikushiro, Shinichi; Nishikawa, Miyu; Masuyama, Yuuka; Shouji, Tadashi; Fujii, Miharu; Hamada, Masahiro; Nakajima, Noriyuki; Finel, Moshe; Yasuda, Kaori; Kamakura, Masaki; Sakaki, Toshiyuki

2016-07-05

Glucuronidation is one of the most common pathways in mammals for detoxification and elimination of hydrophobic xenobiotic compounds, including many drugs. Metabolites, however, can form active or toxic compounds, such as acyl glucuronides, and their safety assessment is often needed. The absence of efficient means for in vitro synthesis of correct glucuronide metabolites frequently limits such toxicological analyses. To overcome this hurdle we have developed a new approach, the essence of which is a coexpression system containing a human, or another mammalian UDP-glucuronosyltransferases (UGTs), as well as UDP-glucose-6-dehydrogenase (UGDH), within the budding yeast, Saccharomyces cerevisiae. The system was first tested using resting yeast cells coexpressing UGDH and human UGT1A6, 7-hydroxycoumarin as the substrate, in a reaction medium containing 8% glucose, serving as a source of UDP-glucuronic acid. Glucuronides were readily formed and recovered from the medium. Subsequently, by selecting suitable mammalian UGT enzyme for the coexpression system we could obtain the desired glucuronides of various compounds, including molecules with multiple conjugation sites and acyl glucuronides of several carboxylic acid containing drugs, namely, mefenamic acid, flufenamic acid, and zomepirac. In conclusion, a new and flexible yeast system with mammalian UGTs has been developed that exhibits a capacity for efficient production of various glucuronides, including acyl glucuronides.

Measurement of glucuronidation by isolated rat liver cells using [14C]fructose.

PubMed

Dawson, J; Knowles, R G; Pogson, C I

1992-03-03

We have developed a simple and sensitive method for the study of the relative rates of glucuronidation of compounds, in isolated liver cells, based on the incorporation of 14C from fructose into glucuronide conjugates. Liver cells from fasted rats are used to minimize any reduction of the specific activity by glycogenolysis. Although rates of glucuronidation are lower in isolated liver cells from fasted rats than in those from fed rats, because of a reduction in the concentration of UDP-glucuronic acid, it is possible to compare the rates of glucuronidation of different compounds. Radiolabelled glucuronides are separated from [14C]fructose and [14C]glucose, produced by the liver cells, by normal-phase HPLC on a polar amino-cyano column. The specific activity of the glucuronide was found to be approximately 50% of that of the [14C]fructose. Absolute amounts of glucuronide can be determined by measuring the specific activity of the [14C]glucose, also produced by liver cells from fructose, which reflects that of the glucose-6-phosphate and hence the UDP-glucuronic acid used for glucuronidation, although for the measurement of relative rates this would not be necessary. We have used this method to examine the kinetics of the glucuronidation of N-acetyl-p-aminophenol (acetaminophen), 4-nitrophenol and 1-naphthol in isolated rat liver cells. The method should be applicable to the study of the rates of glucuronidation of a range of aglycones and, unlike other methods, does not require glucuronide standards or radiolabelled aglycone.

Detection of pentachlorophenol and its glucuronide and sulfate conjugates in fish bile and exposure water

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stehly, G.R.; Hayton, W.L.

1988-08-01

The glucuronide and sulfate conjugates of pentachlorophenol (PCP) that were present in the bile and exposure water of goldfish (Carassius auratus) were used to develop methodology to quantify PCP and its metabolites. Reverse phase HPLC with radioactivity detection separated PCP and its metabolites, and was used to verify a method of quantification that used differential extraction and scintillation counting. Extractions of aqueous phase at pH 2 or 8, with butanol, ethyl acetate, or ether indicated that ether at pH 8 best separated PCP from its metabolites. The sulfate conjugate of PCP was the major metabolite produced when goldfish were exposedmore » to 125 micrograms UC-PCP/l. It was present primarily in the exposure water, but also appeared in the bile.« less

Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans

PubMed Central

Fujiwara, Ryoichi; Yoda, Emiko; Tukey, Robert H.

2018-01-01

More than 20% of clinically used drugs are glucuronidated by a microsomal enzyme UDP-glucuronosyltransferase (UGT). Inhibition or induction of UGT can result in an increase or decrease in blood drug concentration. To avoid drug-drug interactions and adverse drug reactions in individuals, therefore, it is important to understand whether UGTs are involved in metabolism of drugs and drug candidates. While most of glucuronides are inactive metabolites, acyl-glucuronides that are formed from compounds with a carboxylic acid group can be highly toxic. Animals such as mice and rats are widely used to predict drug metabolism and drug-induced toxicity in humans. However, there are marked species differences in the expression and function of drug-metabolizing enzymes including UGTs. To overcome the species differences, mice in which certain drug-metabolizing enzymes are humanized have been recently developed. Humanized UGT1 (hUGT1) mice were created in 2010 by crossing Ugt1-null mice with human UGT1 transgenic mice in a C57BL/6 background. hUGT1 mice can be promising tools to predict human drug glucuronidation and acyl-glucuronide-associated toxicity. In this review article, studies of drug metabolism and toxicity in the hUGT1 mice are summarized. We further discuss research and strategic directions to advance the understanding of drug glucuronidation in humans. PMID:29079228

Direct detection of glucuronide metabolites of lidocaine in sheep urine.

PubMed

Doran, Gregory S; Smith, Alistair K; Rothwell, Jim T; Edwards, Scott H

2018-02-15

The anaesthetic lidocaine is metabolised quickly to produce a series of metabolites, including several hydroxylated metabolites, which are further metabolised by addition of a glucuronic acid moiety. Analysis of these glucuronide metabolites in urine is performed indirectly by cleaving the glucuronic acid group using β-glucuronidase. However, direct analysis of intact glucuronide conjugates is a more straightforward approach as it negates the need for long hydrolysis incubations, and minimises the oxidation of sensitive hydrolysis products, while also distinguishing between the two forms of hydroxylated metabolites. A method was developed to identify three intact glucuronides of lidocaine in sheep urine using LC-MS/MS, which was further confirmed by the synthesis of glucuronide derivatives of 3OH-MEGX and 4OH-LIDO. Direct analysis of urine allowed the detection of the glucuronide metabolites of hydroxylidocaine (OH-LIDO), hydroxyl-monoethylglycinexylidide (OH-MEGX), and hydroxy-2,6-xylidine (OH-XYL). Analysis of urine before and after β-glucuronidase digestion showed that the efficiency of hydrolysis of these glucuronide metabolites may be underestimated in some studies. Analysis of urine in the current study from three different sheep with similar glucuronide metabolite concentrations resulted in different hydrolysis efficiencies, which may have been a result of different levels of substrate binding by matrix components, preventing enzyme cleavage. The use of direct analysis of intact glucuronides has the benefit of being less influenced by these matrix effects, while also allowing analysis of unstable metabolites like 4OH-XYL, which rapidly oxidises after hydrolysis. Additionally, direct analysis is less expensive and less time consuming, while providing more information about the status of hydroxylated metabolites in urine. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

Detection and identification of 2-nitro-morphine and 2-nitro-morphine-6-glucuronide in nitrite adulterated urine specimens containing morphine and its glucuronides.

PubMed

Luong, Susan; Fu, Shanlin

2014-03-01

In vitro urine adulteration is a well-documented practice adopted by individuals aiming to evade detection of drug use, when required to undergo mandatory sports and workplace drug testing. Potassium nitrite is an effective urine adulterant due to its oxidizing potential, and has been shown to mask the presence of many drugs of abuse. However, limited research has been conducted to understand its mechanism of action, and to explore the possibility of the drugs undergoing direct oxidation to form stable reaction products. In this study, opiates including morphine, codeine, morphine-3-glucuronide and morphine-6-glucuronide were exposed to potassium nitrite in water and urine to mimic the process of nitrite adulteration. It was found that two stable reaction products were detected by liquid chromatography-mass spectrometry (LC-MS) when morphine and morphine-6-glucuronide were exposed to nitrite. Isolation and elucidation using spectrometric and spectroscopic techniques revealed that they were 2-nitro-morphine and 2-nitro-morphine-6-glucuronide, respectively. These reaction products were also formed when an authentic morphine-positive urine specimen was fortified with nitrite. 2-Nitro-morphine was found to be stable enough to undergo the enzymatic hydrolysis procedure and also detectable by gas chromatography-mass spectrometry (GC-MS) after forming a trimethylsilyl derivative. On the contrary, morphine-3-glucuronide did not appear to be chemically manipulated when exposed to potassium nitrite in urine. These reaction products are not endogenously produced, are relatively stable and can be monitored with both LC-MS and GC-MS confirmatory techniques. As a result, these findings have revealed the possibility for the use of 2-nitro-morphine and 2-nitro-morphine-6-glucuronide as markers for the indirect monitoring of morphine and morphine-6-glucuronide in urine specimens adulterated with nitrite. Copyright © 2013 John Wiley & Sons, Ltd.

Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans.

PubMed

Fujiwara, Ryoichi; Yoda, Emiko; Tukey, Robert H

2018-02-01

More than 20% of clinically used drugs are glucuronidated by a microsomal enzyme UDP-glucuronosyltransferase (UGT). Inhibition or induction of UGT can result in an increase or decrease in blood drug concentration. To avoid drug-drug interactions and adverse drug reactions in individuals, therefore, it is important to understand whether UGTs are involved in metabolism of drugs and drug candidates. While most of glucuronides are inactive metabolites, acyl-glucuronides that are formed from compounds with a carboxylic acid group can be highly toxic. Animals such as mice and rats are widely used to predict drug metabolism and drug-induced toxicity in humans. However, there are marked species differences in the expression and function of drug-metabolizing enzymes including UGTs. To overcome the species differences, mice in which certain drug-metabolizing enzymes are humanized have been recently developed. Humanized UGT1 (hUGT1) mice were created in 2010 by crossing Ugt1-null mice with human UGT1 transgenic mice in a C57BL/6 background. hUGT1 mice can be promising tools to predict human drug glucuronidation and acyl-glucuronide-associated toxicity. In this review article, studies of drug metabolism and toxicity in the hUGT1 mice are summarized. We further discuss research and strategic directions to advance the understanding of drug glucuronidation in humans. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

VizieR Online Data Catalog: Virgo cluster ETGs: GC and galaxy diffuse light (Li+, 2015)

NASA Astrophysics Data System (ADS)

Li, B.; Peng, E. W.; Zhang, H.-X.; Blakeslee, J. P.; Cote, P.; Ferrarese, L.; Jordan, A.; Liu, C.; Mei, S.; Puzia, T. H.; Takamiya, M.; Trancho, G.; West, M. J.

2017-09-01

We selected four intermediate-luminosity ETGs from the ACS Virgo Cluster Survey (ACSVCS; Cote et al. 2004, J/ApJS/153/223), a homogeneous Hubble Space Telescope survey of 100 ETGs in the nearby Virgo cluster of galaxies using the Advanced Camera for Surveys (ACS; Ford et al. 1998SPIE.3356..234F). We observed these galaxies with the Gemini Multi-Object Spectrographs (GMOS, Hook et al. 2004PASP..116..425H), twin instruments on the Gemini North and Gemini South telescopes. Our target galaxies have sizes (Re~10-18") that fit well within the GMOS field of view (5.5 arcmin2), providing coverage out to 10-16Re. Each galaxy contained ~50 targetable GCs with V<23 mag. VCC 1231, VCC 1062, and VCC 2000 data were taken with GMOS-South, whereas data for VCC 685 was taken with GMOS-North. (3 data files).

In Vitro Stability of Free and Glucuronidated Cannabinoids in Urine Following Controlled Smoked Cannabis

PubMed Central

Desrosiers, Nathalie A.; Lee, Dayong; Scheidweiler, Karl B.; Concheiro-Guisan, Marta; Gorelick, David A.; Huestis, Marilyn A.

2014-01-01

Analyte stability is an important factor in urine test interpretation, yet cannabinoid stability data are limited. A comprehensive study of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol, cannabinol, THC-glucuronide, and THCCOOH-glucuronide stabilities in authentic urine was completed. Urine samples after ad libitum cannabis smoking were pooled to prepare low and high pools for each study participant; baseline concentrations were measured within 24h at room temperature (RT), 4°C and −20°C. Stability at RT, 4°C and −20°C was evaluated by Friedman tests for up to 1 year. THCCOOH, THC-glucuronide, and THCCOOH-glucuronide were quantified in baseline pools. RT THCCOOH baseline concentrations were significantly higher than −20°C, but not 4°C baseline concentrations. After 1 week at RT, THCCOOH increased, THCCOOH-glucuronide decreased, but THC-glucuronide was unchanged. In RT low pool, total THCCOOH (THCCOOH+THCCOOH-glucuronide) was significantly lower after 1 week. At 4°C, THCCOOH was stable 2 weeks, THCCOOH-glucuronide 1 month and THC-glucuronide for at least 6 months. THCCOOH was stable frozen for 1 year, but 6 months high pool results were significantly higher than baseline; THC-glucuronide and THCCOOH-glucuronide were stable for 6 months. Total THCCOOH was stable 6 months at 4°C, and frozen 6 months (low) and 1 year (high). THC, cannabidiol and cannabinol were never detected in urine; although not detected initially, 11-OH-THC was detected in 2 low and 3 high pools after one week at RT. Substantial THCCOOH-glucuronide deconjugation was observed at RT and 4°C. Analysis should be conducted within 3 months if non-hydrolyzed THCCOOH or THCCOOH-glucuronide quantification is required. PMID:24292435

Studies on the disturbance of glucuronide formation in infectious hepatitis

PubMed Central

Vest, M. F.; Fritz, E.

1961-01-01

The ability of the liver to form glucuronides was measured in 10 patients with infectious hepatitis. One test was done at the onset and another about four weeks later after the clinical symptoms had disappeared. N-acetyl-p-aminophenol (N.A.P.A.) or acetanilide was administered in doses ranging from 10 to 20 mg. per kg. body weight, either orally or by intravenous injection. N.A.P.A. is conjugated by the liver at the hydroxyl group and excreted in the urine as sulphuric and glucuronic acid conjugates. Total conjugated p-aminophenol, free N.A.P.A., and N.A.P.A. glucuronide were estimated in the urine of our patients. In the blood the disappearance of N.A.P.A. (free form) and the formation of N.A.P.A. glucuronide were traced. During the acute phase of hepatitis the excretion of total conjugated p-aminophenol and of N.A.P.A. glucuronide in the urine is lower than after recovery from the disease. Likewise free N.A.P.A. disappears more slowly from the circulation and the peak concentration of N.A.P.A. glucuronide in the serum remains lower at the onset of hepatitis than after clinical cure. These results indicate that glucuronide formation during the acute stage of infectious hepatitis is depressed, as are other transformation mechanisms, i.e., of hippuric acid. PMID:13925655

Chemoenzymatic Synthesis, Characterization, and Scale-Up of Milk Thistle Flavonolignan Glucuronides

PubMed Central

Gufford, Brandon T.; Graf, Tyler N.; Paguigan, Noemi D.; Oberlies, Nicholas H.

2015-01-01

Plant-based therapeutics, including herbal products, continue to represent a growing facet of the contemporary health care market. Mechanistic descriptions of the pharmacokinetics and pharmacodynamics of constituents composing these products remain nascent, particularly for metabolites produced following herbal product ingestion. Generation and characterization of authentic metabolite standards are essential to improve the quantitative mechanistic understanding of herbal product disposition in both in vitro and in vivo systems. Using the model herbal product, milk thistle, the objective of this work was to biosynthesize multimilligram quantities of glucuronides of select constituents (flavonolignans) to fill multiple knowledge gaps in the understanding of herbal product disposition and action. A partnership between clinical pharmacology and natural products chemistry expertise was leveraged to optimize reaction conditions for efficient glucuronide formation and evaluate alternate enzyme and reagent sources to improve cost effectiveness. Optimized reaction conditions used at least one-fourth the amount of microsomal protein (from bovine liver) and cofactor (UDP glucuronic acid) compared with typical conditions using human-derived subcellular fractions, providing substantial cost savings. Glucuronidation was flavonolignan-dependent. Silybin A, silybin B, isosilybin A, and isosilybin B generated five, four, four, and three monoglucuronides, respectively. Large-scale synthesis (40 mg of starting material) generated three glucuronides of silybin A: silybin A-7-O-β-d-glucuronide (15.7 mg), silybin A-5-O-β-d-glucuronide (1.6 mg), and silybin A-4´´-O-β-d-glucuronide (11.1 mg). This optimized, cost-efficient method lays the foundation for a systematic approach to synthesize and characterize herbal product constituent glucuronides, enabling an improved understanding of mechanisms underlying herbal product disposition and action. PMID:26316643

Metabolism of isotretinoin. Biliary excretion of isotretinoin glucuronide in the rat.

PubMed

Meloche, S; Besner, J G

1986-01-01

The biliary metabolites of isotretinoin were examined after iv administration of 4-20-mg/kg doses to vitamin A-normal bile duct-cannulated rats. Analysis of bile by reverse phase high performance liquid chromatography showed that injection of isotretinoin is followed by a rapid excretion of metabolites in bile. Isotretinoin glucuronide was identified as the major metabolite in bile. A specific high performance liquid chromatography method based on the assay of generated isotretinoin in beta-glucuronidase-treated bile was developed for the determination of isotretinoin glucuronide in bile samples. The excretion rate of isotretinoin glucuronide increased rapidly to reach a maximum 55 min after dosing and then declined exponentially. After 330 min of collection, biliary excretion of isotretinoin glucuronide was almost complete, and the metabolite accounted for 34.8-37.9% of the dose. These results indicate that conjugation with glucuronic acid represents a major pathway for the metabolism of pharmacological doses of isotretinoin. The maximum excretion rate of isotretinoin glucuronide in bile increased in a linear manner with the dose of isotretinoin, and no delay was observed after the larger doses. These data suggest that glucuronidation and biliary excretion are not saturated at high pharmacological doses of isotretinoin.

Pilot Investigation of a Phosphatidylethanol-Based Contingency Management Intervention Targeting Alcohol Use

PubMed Central

McDonell, Michael G.; Skalisky, Jordan; Leickly, Emily; Orr, Michael F.; Roll, John; McPherson, Sterling; Hill-Kapturczak, Nathalie; Javors, Martin

2018-01-01

Phosphatidylethanol (PEth) can be detected in blood from 14 to as many as 28 days after alcohol consumption, depending on the amount and frequency of alcohol consumed. PEth may have utility for verifying abstinence in a contingency management (CM) intervention for alcohol use, particularly in settings where frequent verification of abstinence is impossible or impractical. Five nontreatment-seeking heavy drinkers (40% men) participated in an 11-week, ABA-phased within-subject experiment for which they submitted blood spots for PEth measurement, urine samples for ethyl glucuronide (EtG) testing, and self-report drinking data weekly. Participants received reinforcers for submitting samples throughout the A phases. During the B phase (CM phase), they received additional reinforcers when their PEth level was reduced from the previous week and was verified by a negative EtG (<150 ng/ml) urine test and self-report. PEth, EtG, and self-report outcomes were compared between A phases (Weeks 1–3, 8–11) and B phases (Weeks 4–7). During the A phases, 23% of PEth results indicated alcohol abstinence, whereas 53% of PEth samples submitted during the CM (B phase) indicated alcohol abstinence. Participants were more likely to submit EtG-negative urine samples and report lower levels of drinking and heavy drinking during the B phase, relative to the A phases. We also explored the ability of PEth to detect self-reported drinking. The combined PEth homologs (16:0/18:1 and 16:0/18:2) predicted self-reported drinking with area under the curve from 0.81 (1 week) to 0.80 (3 weeks). Results support the initial feasibility of a Peth-based CM intervention. PMID:28714726

Chemoenzymatic Synthesis, Characterization, and Scale-Up of Milk Thistle Flavonolignan Glucuronides.

PubMed

Gufford, Brandon T; Graf, Tyler N; Paguigan, Noemi D; Oberlies, Nicholas H; Paine, Mary F

2015-11-01

Plant-based therapeutics, including herbal products, continue to represent a growing facet of the contemporary health care market. Mechanistic descriptions of the pharmacokinetics and pharmacodynamics of constituents composing these products remain nascent, particularly for metabolites produced following herbal product ingestion. Generation and characterization of authentic metabolite standards are essential to improve the quantitative mechanistic understanding of herbal product disposition in both in vitro and in vivo systems. Using the model herbal product, milk thistle, the objective of this work was to biosynthesize multimilligram quantities of glucuronides of select constituents (flavonolignans) to fill multiple knowledge gaps in the understanding of herbal product disposition and action. A partnership between clinical pharmacology and natural products chemistry expertise was leveraged to optimize reaction conditions for efficient glucuronide formation and evaluate alternate enzyme and reagent sources to improve cost effectiveness. Optimized reaction conditions used at least one-fourth the amount of microsomal protein (from bovine liver) and cofactor (UDP glucuronic acid) compared with typical conditions using human-derived subcellular fractions, providing substantial cost savings. Glucuronidation was flavonolignan-dependent. Silybin A, silybin B, isosilybin A, and isosilybin B generated five, four, four, and three monoglucuronides, respectively. Large-scale synthesis (40 mg of starting material) generated three glucuronides of silybin A: silybin A-7-O-β-D-glucuronide (15.7 mg), silybin A-5-O-β-D-glucuronide (1.6 mg), and silybin A-4´´-O-β-D-glucuronide (11.1 mg). This optimized, cost-efficient method lays the foundation for a systematic approach to synthesize and characterize herbal product constituent glucuronides, enabling an improved understanding of mechanisms underlying herbal product disposition and action. Copyright © 2015 by The American Society

Genetic polymorphism of UDP-glucuronosyltransferase (UGT2B15) and glucuronidation of paracetamol in healthy population.

PubMed

Mehboob, Huma; Iqbal, Tahira; Jamil, Amer; Khaliq, Tanweer

2016-05-01

Inter individual variability in polymorphic UDP-glucuronosyltransferase (UGT2B15) has been associated with varied glucuronidation level. The present project was designed to determine the genetic polymorphism of UDP-glucuronosyltransferase (UGT2B15) and glucuronidation of paracetamol in healthy (male=59 and female=50) population. The association between genotype (UGT2B15) and phenotype (paracetamol glucuronidation) has been evaluated. According to trimodal model, genotypes and phenotypes were categorized as fast, intermediate and slow glucuronidators. Presence of wild type allele illustrated a UGT2B15 genotype as fast glucuronidator. The glucuronidation status was investigated by HPLC analysis of paracetamol. Ratio of paracetamol glucuronide to paracetamol was determined with two antimodes at glucuronidation ratio of 0.3 and 1.8. In our study, 7% and 12% of population was distributed as slow glucuronidators by phenotype and genotype, respectively and association between phenotype and genotype was good for analysis of glucuronidation status as displayed by kappa value (0.792).

Challenges and Opportunities with Predicting in Vivo Phase II Metabolism via Glucuronidation from in Vitro Data

PubMed Central

Ge, Shufan; Tu, Yifan; Hu, Ming

2017-01-01

Glucuronidation is the most important phase II metabolic pathway which is responsible for the clearance of many endogenous and exogenous compounds. To better understand the elimination process for compounds undergoing glucuronidation and identify compounds with desirable in vivo pharmacokinetic properties, many efforts have been made to predict in vivo glucuronidation using in vitro data. In this article, we reviewed typical approaches used in previous predictions. The problems and challenges in prediction of glucuronidation were discussed. Besides that different incubation conditions can affect the prediction accuracy, other factors including efflux / uptake transporters, enterohepatic recycling, and deglucuronidation reactions also contribute to the disposition of glucuronides and make the prediction more difficult. PBPK modeling, which can describe more complicated process in vivo, is a promising prediction strategy which may greatly improve the prediction of glucuronidation and potential DDIs involving glucuronidation. Based on previous studies, we proposed a transport-glucuronidation classification system, which was built based on the kinetics of both glucuronidation and transport of the glucuronide. This system could be a very useful tool to achieve better in vivo predictions. PMID:28966903

Identification of hydroxyropivacaine glucuronide in equine urine by ESI+/MS/MS.

PubMed Central

Harkins, J D; Karpiesiuk, W; Tobin, T; Dirikolu, L; Lehner, A F

2000-01-01

Ropivacaine is a local anesthetic that has a high potential for abuse in racing horses. It can be recovered from urine collected after administration as a hydroxylated metabolite following beta-glucuronidase treatment of the urine. Based on these findings, it has been inferred that ropivacaine is present in equine urine as a glucuronide metabolite; however, these metabolites have never been directly identified. Using ESI+/MS/MS, the presence of a [M+H]+ molecular ion of m/z 467 was demonstrated in urine corresponding to the calculated mass of a hydroxyropivacaine glucuronide +1. The abundance of this ion diminished after glucuronidase treatment with concomitant appearance of a m/z 291 peak, which is consistent with its hydrolysis to hydroxyropivacaine. In further work, the m/z 467 material was fragmented in the MS/MS system, yielding fragments interpretable as hydroxyropivacaine glucuronide. These data are consistent with the presence of a hydroxyropivacaine glucuronide in equine urine and constitute the first direct demonstration of a specific glucuronide metabolite in equine urine. PMID:10935884

Species-Associated Differences in the Inhibition of Propofol Glucuronidation by Magnolol

PubMed Central

Yang, Lu; Zhu, Liangliang; Ge, Guangbo; Xiao, Ling; Wu, Yan; Liang, Sicheng; Cao, Yunfeng; Yang, Ling; Wang, Dong

2014-01-01

Magnolol, a major active constituent in herbal medicine, potently inhibits propofol glucuronidation in human liver microsomes, with inhibition constants in the nanomolar range. This study was conducted to investigate magnolol-induced inhibition of propofol glucuronidation in liver microsomes from Swiss–Hauschka mice, Sprague–Dawley rats, Chinese Bama pigs, and cynomolgus macaques. Results indicated that magnolol (10 μM) inhibited propofol glucuronidation in liver microsomes from Bama pigs and cynomolgus macaques but not in those from mice or rats. Data from liver microsomes from Bama pigs indicated a competitive inhibition mechanism, with a Ki of 1.7 μM. In contrast to that of pig liver microsomes, the inhibition of microsomes from cynomolgus macaques followed a noncompetitive mechanism, with a Ki of 3.4 μM. In summary, this study indicates that magnolol-induced inhibition of propofol glucuronidation varies substantially among species, and the Ki values determined by using liver microsomes from various experimental animal species far exceed that for human liver microsomes. The inhibition of propofol glucuronidation by magnolol in liver microsomes from all animal species tested was significantly lower than the inhibition previously demonstrated in human liver microsomes. Hepatic microsomes from Swiss–Hauschka mice, Sprague–Dawley rats, Chinese Bama pigs, and cynomolgus macaques are not effective models of the inhibition of glucuronidation induced by magnolol in humans. PMID:25199099

Species-associated differences in the inhibition of propofol glucuronidation by magnolol.

PubMed

Yang, Lu; Zhu, Liangliang; Ge, Guangbo; Xiao, Ling; Wu, Yan; Liang, Sicheng; Cao, Yunfeng; Yang, Ling; Wang, Dong

2014-07-01

Magnolol, a major active constituent in herbal medicine, potently inhibits propofol glucuronidation in human liver microsomes, with inhibition constants in the nanomolar range. This study was conducted to investigate magnolol-induced inhibition of propofol glucuronidation in liver microsomes from Swiss-Hauschka mice, Sprague-Dawley rats, Chinese Bama pigs, and cynomolgus macaques. Results indicated that magnolol (10 μM) inhibited propofol glucuronidation in liver microsomes from Bama pigs and cynomolgus macaques but not in those from mice or rats. Data from liver microsomes from Bama pigs indicated a competitive inhibition mechanism, with a Ki of 1.7 μM. In contrast to that of pig liver microsomes, the inhibition of microsomes from cynomolgus macaques followed a noncompetitive mechanism, with a Ki of 3.4 μM. In summary, this study indicates that magnolol-induced inhibition of propofol glucuronidation varies substantially among species, and the Ki values determined by using liver microsomes from various experimental animal species far exceed that for human liver microsomes. The inhibition of propofol glucuronidation by magnolol in liver microsomes from all animal species tested was significantly lower than the inhibition previously demonstrated in human liver microsomes. Hepatic microsomes from Swiss-Hauschka mice, Sprague-Dawley rats, Chinese Bama pigs, and cynomolgus macaques are not effective models of the inhibition of glucuronidation induced by magnolol in humans.

Disposition of flavonoids via recycling: Direct biliary excretion of enterically or extrahepatically derived flavonoid glucuronides.

PubMed

Zeng, Min; Sun, Rongjin; Basu, Sumit; Ma, Yong; Ge, Shufan; Yin, Taijun; Gao, Song; Zhang, Jun; Hu, Ming

2016-05-01

Enterohepatic recycling is often thought to involve mostly phase II metabolites generated in the liver. This study aims to determine if direct biliary excretion of extrahepatically generated glucuronides would also enable recycling. Conventional and modified intestinal perfusion models along with intestinal and liver microsomes were used to determine the contribution of extrahepatically derived glucuronides. Glucuronidation of four flavonoids (genistein, biochanin A, apigenin, and chrysin at 2.5-20 μM) were generally more rapid in the hepatic than intestinal microsomes. Furthermore, when aglycones (at 10 μM each) were perfused, larger (1.7-9 fold) amounts of glucuronides were found in the bile than in the luminal perfusate. However, higher concentrations of glucuronides were not found in jugular vein than portal vein, and apigenin glucuronide actually displayed a significantly lower concentration in jugular vein (<1 nM) than portal vein (≈4 nM). A direct portal infusion of four flavonoid glucuronides (5.9-10.4 μM perfused at 2 mL/h) showed that the vast majority (>65%) of the glucuronides (except for biochanin A glucuronide) administered were efficiently excreted into the bile. Direct biliary excretion of extrahepatically generated flavonoid glucuronides is a highly efficient clearance mechanism, which should enable enterohepatic recycling of flavonoids without hepatic conjugating enzymes. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Identification of human UDP-glucuronosyltransferases involved in N-carbamoyl glucuronidation of lorcaserin.

PubMed

Sadeque, Abu J M; Usmani, Khawja A; Palamar, Safet; Cerny, Matthew A; Chen, Weichao G

2012-04-01

Lorcaserin, a selective serotonin 5-HT(2C) receptor agonist, is a weight management agent in clinical development. Lorcaserin N-carbamoyl glucuronidation governs the predominant excretory pathway of lorcaserin in humans. Human UDP-glucuronosyltransferases (UGTs) responsible for lorcaserin N-carbamoyl glucuronidation are identified herein. Lorcaserin N-carbamoyl glucuronide formation was characterized by the following approaches: metabolic screening using human tissues (liver, kidney, intestine, and lung) and recombinant enzymes, kinetic analyses, and inhibition studies. Whereas microsomes from all human tissues studied herein were found to be catalytically active for lorcaserin N-carbamoyl glucuronidation, liver microsomes were the most efficient. With recombinant UGT enzymes, lorcaserin N-carbamoyl glucuronidation was predominantly catalyzed by three UGT2Bs (UGT2B7, UGT2B15, and UGT2B17), whereas two UGT1As (UGT1A6 and UGT1A9) played a minor role. UGT2B15 was most efficient, with an apparent K(m) value of 51.6 ± 1.9 μM and V(max) value of 237.4 ± 2.8 pmol/mg protein/min. The rank order of catalytic efficiency of human UGT enzymes for lorcaserin N-carbamoyl glucuronidation was UGT2B15 > UGT2B7 > UGT2B17 > UGT1A9 > UGT1A6. Inhibition of lorcaserin N-carbamoyl glucuronidation activities of UGT2B7, UGT2B15, and UGT2B17 in human liver microsomes by mefenamic acid, bisphenol A, and eugenol further substantiated the involvement of these UGT2B isoforms. In conclusion, multiple human UGT enzymes catalyze N-carbamoyl glucuronidation of lorcaserin; therefore, it is unlikely that inhibition of any one of these UGT activities will lead to significant inhibition of the lorcaserin N-carbamoyl glucuronidation pathway. Thus, the potential for drug-drug interaction by concomitant administration of a drug(s) that is metabolized by any of these UGTs is remote.

Direct radioimmunoassay of urinary estrogen and pregnanediol glucuronides during the menstrual cycle

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stanczyk, F.Z.; Miyakawa, I.; Goebelsmann, U.

Assays measuring immunoreactive estrone glucuronide (E/sub 1/G), estradiol-3-glucuronide (E/sub 2/-3G), estradiol-17..beta..-glucuronide (E/sub 2/-17G), estriol-3-glucuronide (E/sub 3/-3G), estriol-16..cap alpha..-glucuronide (E/sub 3/-16G), and pregnanediol-3..cap alpha..-glucuronide (Pd-3G) directly in diluted urine were developed and validated. These estrogen and pregnanediol glucuronide fractions were measured in aliquots of 24-hour and overnight samples of urine collected daily from seven women for one menstrual cycle. Urinary hormone excretion was correlated with daily serum estradiol (E/sub 2/), progesterone (P), and lutenizing hormonee (LH) levels. A sharp midcycle LH peak preceded by a preovulatory rise in serum E/sub 2/ and followed by luteal phase serum P levels were notedmore » in each of the seven apparently ovulatory cycles. Twenty-four-hour and overnight urinary excretion patterns of estrogen glucuronides were similar to those of serum E/sub 2/. Of the five estrogen glucuronide fractions tested, excretion of E/sub 2/-17G exhibited the earliest and steepest ascending slope of the preovulatory estrogen surge and correlated best with serum E/sub 2/ levels. Urinary excretion of E/sub 1/-G, E/sub 2/-3G, and E/sub 3/-16G also showed an early and steep preovulatory rise and preceded that of E/sub 3/-3G, whereas urinary excretion of E/sub 3/-3G exhibited the poorest correlation with serum E/sub 2/ concentrations. The urinary excretion of Pd-3G rose parallel to serum P levels and was markedly elevated 2 to 3 days after the midcycle LH peak in both 24-hour and overnight collections of urine. These results indicate that among the urinary estrogen conjugate fractions tested, E/sub 2/-17G is the one that most suitably predicts ovulation.« less

[Enantioselectivity in the excretion of glucuronides of carprofen in man, dogs and horses].

PubMed

Delatour, P; Garnier, F; Maire, R

1996-10-01

After administration of the racemic drug, the stereoselective quantification of the enantiomers of free and conjugated carprofen was performed in human plasma and in plasma, urine and bile of dogs and horses. In humans, the plasma profile of free carprofen and its glucuronides is not stereoselective and the glucuronides excreted in urine are close to a racemate. In dogs and horses on the contrary, the R(-) enantiomer of the free drug is predominant in plasma, while urine and/or bile concentrations of the glucuronides are high in comparison to plasma with a strong selectivity for the S(+) enantiomer. Because glucuronidation of carprofen, as a carboxylic compound, is known to be the major metabolic pathway in most species, interspecies discrepancies in the stereoselective disposition of carprofen seem to be mainly related to the stereoselectivity in the excretion of the glucuronides. Finally, the high plasma concentrations of carprofen glucuronides in human in comparison to other animal species suggest that the former could be specifically subjected to immunological side effects in the time course of treatments by this type of compounds.

Glucuronidation of 6 alpha-hydroxy bile acids by human liver microsomes.

PubMed Central

Radomińska-Pyrek, A; Zimniak, P; Irshaid, Y M; Lester, R; Tephly, T R; St Pyrek, J

1987-01-01

The glucuronidation of 6-hydroxylated bile acids by human liver microsomes has been studied in vitro; for comparison, several major bile acids lacking a 6-hydroxyl group were also investigated. Glucuronidation rates for 6 alpha-hydroxylated bile acids were 10-20 times higher than those of substrates lacking a hydroxyl group in position 6. The highest rates measured were for hyodeoxy- and hyocholic acids, and kinetic analyses were carried out using these substrates. Rigorous product identification by high-field proton nuclear magnetic resonance and by electron impact mass spectrometry of methyl ester/peracetate derivatives revealed that 6-O-beta-D-glucuronides were the exclusive products formed in these enzymatic reactions. These results, together with literature data, indicate that 6 alpha-hydroxylation followed by 6-O-glucuronidation constitutes an alternative route of excretion of toxic hydrophobic bile acids. PMID:3110212

Identification and characterization of human UDP-glucuronosyltransferases responsible for the in-vitro glucuronidation of arctigenin.

PubMed

Xin, Hong; Xia, Yang-Liu; Hou, Jie; Wang, Ping; He, Wei; Yang, Ling; Ge, Guang-Bo; Xu, Wei

2015-12-01

This study aimed to characterize the glucuronidation pathway of arctigenin (AR) in human liver microsomes (HLM) and human intestine microsomes (HIM). HLM and HIM incubation systems were employed to catalyse the formation of AR glucuronide. The glucuronidation activity of commercially recombinant UGT isoforms towards AR was screened. A combination of chemical inhibition assay and kinetic analysis was used to determine the UGT isoforms involved in the glucuronidation of AR in HLM and HIM. AR could be extensively metabolized to one mono-glucuronide in HLM and HIM. The mono-glucuronide was biosynthesized and characterized as 4'-O-glucuronide. UGT1A1, 1A3, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7 and 2B17 participated in the formation of 4'-O-G, while UGT2B17 demonstrated the highest catalytic activity in this biotransformation. Both kinetic analysis and chemical inhibition assays demonstrated that UGT1A9, UGT2B7 and UGT2B17 played important roles in AR-4'-O-glucuronidation in HLM. Furthermore, HIM demonstrated moderate efficiency for AR-4'-O-glucuronidation, implying that AR may undergo a first-pass metabolism during the absorption process. UGT1A9, UGT2B7 and UGT2B17 were the major isoforms responsible for the 4'-O-glucuronidation of AR in HLM, while UGT2B7 and UGT2B17 were the major contributors to this biotransformation in HIM. © 2015 Royal Pharmaceutical Society.

Autism and Phthalate Metabolite Glucuronidation

ERIC Educational Resources Information Center

Stein, T. Peter; Schluter, Margaret D.; Steer, Robert A.; Ming, Xue

2013-01-01

Exposure to environmental chemicals may precipitate autism spectrum disorders (ASD) in genetically susceptible children. Differences in the efficiency of the glucuronidation process may substantially modulate substrate concentrations and effects. To determine whether the efficiency of this pathway is compromised in children with ASD, we measured…

Characterization of in vitro glucuronidation clearance of a range of drugs in human kidney microsomes: comparison with liver and intestinal glucuronidation and impact of albumin.

PubMed

Gill, Katherine L; Houston, J Brian; Galetin, Aleksandra

2012-04-01

Previous studies have shown the importance of the addition of albumin for characterization of hepatic glucuronidation in vitro; however, no reports exist on the effects of albumin on renal or intestinal microsomal glucuronidation assays. This study characterized glucuronidation clearance (CL(int, UGT)) in human kidney, liver, and intestinal microsomes in the presence and absence of bovine serum albumin (BSA) for seven drugs with differential UDP-glucuronosyltransferase (UGT) 1A9 and UGT2B7 specificity, namely, diclofenac, ezetimibe, gemfibrozil, mycophenolic acid, naloxone, propofol, and telmisartan. The impact of renal CL(int, UGT) on accuracy of in vitro-in vivo extrapolation (IVIVE) of glucuronidation clearance was investigated. Inclusion of 1% BSA for acidic drugs and 2% for bases/neutral drugs in incubations was found to be suitable for characterization of CL(int, UGT) in different tissues. Although BSA increased CL(int, UGT) in all tissues, the extent was tissue- and drug-dependent. Scaled CL(int, UGT) in the presence of BSA ranged from 2.22 to 207, 0.439 to 24.4, and 0.292 to 23.8 ml · min(-1) · g tissue(-1) in liver, kidney, and intestinal microsomes. Renal CL(int, UGT) (per gram of tissue) was up to 2-fold higher in comparison with that for liver for UGT1A9 substrates; in contrast, CL(int, UGT) for UGT2B7 substrates represented approximately one-third of hepatic estimates. Scaled renal CL(int, UGT) (in the presence of BSA) was up to 30-fold higher than intestinal glucuronidation for the drugs investigated. Use of in vitro data obtained in the presence of BSA and inclusion of renal clearance improved the IVIVE of glucuronidation clearance, with 50% of drugs predicted within 2-fold of observed values. Characterization and consideration of kidney CL(int, UGT) is particularly important for UGT1A9 substrates.

Characterization of In Vitro Glucuronidation Clearance of a Range of Drugs in Human Kidney Microsomes: Comparison with Liver and Intestinal Glucuronidation and Impact of Albumin

PubMed Central

Gill, Katherine L.; Houston, J. Brian

2012-01-01

Previous studies have shown the importance of the addition of albumin for characterization of hepatic glucuronidation in vitro; however, no reports exist on the effects of albumin on renal or intestinal microsomal glucuronidation assays. This study characterized glucuronidation clearance (CLint, UGT) in human kidney, liver, and intestinal microsomes in the presence and absence of bovine serum albumin (BSA) for seven drugs with differential UDP-glucuronosyltransferase (UGT) 1A9 and UGT2B7 specificity, namely, diclofenac, ezetimibe, gemfibrozil, mycophenolic acid, naloxone, propofol, and telmisartan. The impact of renal CLint, UGT on accuracy of in vitro-in vivo extrapolation (IVIVE) of glucuronidation clearance was investigated. Inclusion of 1% BSA for acidic drugs and 2% for bases/neutral drugs in incubations was found to be suitable for characterization of CLint, UGT in different tissues. Although BSA increased CLint, UGT in all tissues, the extent was tissue- and drug-dependent. Scaled CLint, UGT in the presence of BSA ranged from 2.22 to 207, 0.439 to 24.4, and 0.292 to 23.8 ml · min−1 · g tissue−1 in liver, kidney, and intestinal microsomes. Renal CLint, UGT (per gram of tissue) was up to 2-fold higher in comparison with that for liver for UGT1A9 substrates; in contrast, CLint, UGT for UGT2B7 substrates represented approximately one-third of hepatic estimates. Scaled renal CLint, UGT (in the presence of BSA) was up to 30-fold higher than intestinal glucuronidation for the drugs investigated. Use of in vitro data obtained in the presence of BSA and inclusion of renal clearance improved the IVIVE of glucuronidation clearance, with 50% of drugs predicted within 2-fold of observed values. Characterization and consideration of kidney CLint, UGT is particularly important for UGT1A9 substrates. PMID:22275465

Repaglinide-gemfibrozil drug interaction: inhibition of repaglinide glucuronidation as a potential additional contributing mechanism

PubMed Central

Gan, Jinping; Chen, Weiqi; Shen, Hong; Gao, Ling; Hong, Yang; Tian, Yuan; Li, Wenying; Zhang, Yueping; Tang, Yuwei; Zhang, Hongjian; Humphreys, William Griffith; Rodrigues, A David

2010-01-01

AIM To further explore the mechanism underlying the interaction between repaglinide and gemfibrozil, alone or in combination with itraconazole. METHODS Repaglinide metabolism was assessed in vitro (human liver subcellular fractions, fresh human hepatocytes, and recombinant enzymes) and the resulting incubates were analyzed, by liquid chromatography-mass spectrometry (LC-MS) and radioactivity counting, to identify and quantify the different metabolites therein. Chemical inhibitors, in addition to a trapping agent, were also employed to elucidate the importance of each metabolic pathway. Finally, a panel of human liver microsomes (genotyped for UGT1A1*28 allele status) was used to determine the importance of UGT1A1 in the direct glucuronidation of repaglinide. RESULTS The results of the present study demonstrate that repaglinide can undergo direct glucuronidation, a pathway that can possibly contribute to the interaction with gemfibrozil. For example, [3H]-repaglinide formed glucuronide and oxidative metabolites (M2 and M4) when incubated with primary human hepatocytes. Gemfibrozil effectively inhibited (∼78%) both glucuronide and M4 formation, but had a minor effect on M2 formation. Concomitantly, the overall turnover of repaglinide was also inhibited (∼80%), and was completely abolished when gemfibrozil was co-incubated with itraconazole. These observations are in qualitative agreement with the in vivo findings. UGT1A1 plays a significant role in the glucuronidation of repaglinide. In addition, gemfibrozil and its glucuronide inhibit repaglinide glucuronidation and the inhibition by gemfibrozil glucuronide is time-dependent. CONCLUSIONS Inhibition of UGT enzymes, especially UGT1A1, by gemfibrozil and its glucuronide is an additional mechanism to consider when rationalizing the interaction between repaglinide and gemfibrozil. PMID:21175442

Structure-Dependent Deconjugation of Flavonoid Glucuronides by Human β-Glucuronidase - In Vitro and In Silico Analyses.

PubMed

Untergehrer, Monika; Bücherl, Daniel; Wittmann, Hans-Joachim; Strasser, Andrea; Heilmann, Jörg; Jürgenliemk, Guido

2015-08-01

Flavonoid glycosides are extensively metabolized to glucuronidated compounds after oral intake. Recently, a cleavage of quercetin glucuronides by β-glucuronidase has been found. To characterize the deglucuronidation reaction and its structural prerequisites among the flavonoid subtypes more precisely, four flavonol glucuronides with varying glucuronidation positions, five flavone 7-O-glucuronides with varying A- and B-ring substitution as well as one flavanone- and one isoflavone-7-O-glucuronide were analyzed in a human monocytic cell line. Investigation of the deglucuronidation rates by HPLC revealed a significant influence of the glucuronidation position on enzyme activity for flavonols. Across the flavonoid subtypes, the C-ring saturation also showed a significant influence on deglucuronidation, whereas A- and B-ring variations within the flavone-7-O-glucuronides did not affect the enzymes' activity. Results were compared to computational binding studies on human β-glucuronidase. Additionally, molecular modeling and dynamic studies were performed to obtain detailed insight into the binding and cleavage mode of the substrate at the active site of the human β-glucuronidase. Georg Thieme Verlag KG Stuttgart · New York.

Repaglinide-gemfibrozil drug interaction: inhibition of repaglinide glucuronidation as a potential additional contributing mechanism.

PubMed

Gan, Jinping; Chen, Weiqi; Shen, Hong; Gao, Ling; Hong, Yang; Tian, Yuan; Li, Wenying; Zhang, Yueping; Tang, Yuwei; Zhang, Hongjian; Humphreys, William Griffith; Rodrigues, A David

2010-12-01

To further explore the mechanism underlying the interaction between repaglinide and gemfibrozil, alone or in combination with itraconazole. Repaglinide metabolism was assessed in vitro (human liver subcellular fractions, fresh human hepatocytes, and recombinant enzymes) and the resulting incubates were analyzed, by liquid chromatography-mass spectrometry (LC-MS) and radioactivity counting, to identify and quantify the different metabolites therein. Chemical inhibitors, in addition to a trapping agent, were also employed to elucidate the importance of each metabolic pathway. Finally, a panel of human liver microsomes (genotyped for UGT1A1*28 allele status) was used to determine the importance of UGT1A1 in the direct glucuronidation of repaglinide. The results of the present study demonstrate that repaglinide can undergo direct glucuronidation, a pathway that can possibly contribute to the interaction with gemfibrozil. For example, [³H]-repaglinide formed glucuronide and oxidative metabolites (M2 and M4) when incubated with primary human hepatocytes. Gemfibrozil effectively inhibited (∼78%) both glucuronide and M4 formation, but had a minor effect on M2 formation. Concomitantly, the overall turnover of repaglinide was also inhibited (∼80%), and was completely abolished when gemfibrozil was co-incubated with itraconazole. These observations are in qualitative agreement with the in vivo findings. UGT1A1 plays a significant role in the glucuronidation of repaglinide. In addition, gemfibrozil and its glucuronide inhibit repaglinide glucuronidation and the inhibition by gemfibrozil glucuronide is time-dependent. Inhibition of UGT enzymes, especially UGT1A1, by gemfibrozil and its glucuronide is an additional mechanism to consider when rationalizing the interaction between repaglinide and gemfibrozil. © 2010 The Authors. British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society.

Resveratrol-3-O-glucuronide and resveratrol-4'-O-glucuronide reduce DNA strand breakage but not apoptosis in Jurkat T cells treated with camptothecin.

PubMed

Zunino, Susan J; Storms, David H

2017-08-01

Resveratrol has been reported to inhibit or induce DNA damage, depending upon the type of cell and the experimental conditions. Dietary resveratrol is present in the body predominantly as metabolites and limited data is available concerning the activities of these metabolic products. In the present study, physiologically obtainable levels of the resveratrol metabolites resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide and resveratrol-3-O-sulfate were evaluated for their ability to protect Jurkat T cells against DNA damage induced by the topoisomerase I inhibitors camptothecin and topotecan. The cells were pretreated for 24 h with 10 µM resveratrol aglycone or each resveratrol metabolite prior to the induction of DNA damage with camptothecin or topotecan. In separate experiments, the cells were co-treated with resveratrol or its metabolites, and a topoisomerase I inhibitor. The detection of histone 2AX phosphorylation and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) were used to determine DNA damage, and apoptosis was measured using an antibody against cleaved poly ADP-ribose polymerase. It was identified that pretreatment of the cells with resveratrol-3-O-glucuronide and resveratrol-4'-O-glucuronide reduced the mean fluorescence intensity of staining for DNA strand breaks following treatment with camptothecin, while the percentage of cells undergoing apoptosis was unchanged. However, pretreatment of the cells with resveratrol aglycone increased the DNA damage and apoptosis induced by the drugs. These results suggest that the glucuronide metabolites of resveratrol partially protected the cells from DNA damage, but did not influence the induction of cell death by camptothecin and topotecan. These data suggest that resveratrol aglycone treatment may be beneficial for treating types of cancer that have direct contact with resveratrol prior to its metabolism, including gastrointestinal cancers, which are routinely treated with

Glucuronidation of Drugs and Drug-Induced Toxicity in Humanized UDP-Glucuronosyltransferase 1 Mice

PubMed Central

Kutsuno, Yuki; Itoh, Tomoo; Tukey, Robert H.

2014-01-01

UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that catalyze glucuronidation of various drugs. Although experimental rodents are used in preclinical studies to predict glucuronidation and toxicity of drugs in humans, species differences in glucuronidation and drug-induced toxicity have been reported. Humanized UGT1 mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice) were recently developed. In this study, acyl-glucuronidations of etodolac, diclofenac, and ibuprofen in liver microsomes of hUGT1 mice were examined and compared with those of humans and regular mice. The kinetics of etodolac, diclofenac, and ibuprofen acyl-glucuronidation in hUGT1 mice were almost comparable to those in humans, rather than in mice. We further investigated the hepatotoxicity of ibuprofen in hUGT1 mice and regular mice by measuring serum alanine amino transferase (ALT) levels. Because ALT levels were increased at 6 hours after dosing in hUGT1 mice and at 24 hours after dosing in regular mice, the onset pattern of ibuprofen-induced liver toxicity in hUGT1 mice was different from that in regular mice. These data suggest that hUGT1 mice can be valuable tools for understanding glucuronidations of drugs and drug-induced toxicity in humans. PMID:24764149

Resveratrol-3-O-glucuronide and resveratrol-4′-O-glucuronide reduce DNA strand breakage but not apoptosis in Jurkat T cells treated with camptothecin

PubMed Central

Zunino, Susan J.; Storms, David H.

2017-01-01

Resveratrol has been reported to inhibit or induce DNA damage, depending upon the type of cell and the experimental conditions. Dietary resveratrol is present in the body predominantly as metabolites and limited data is available concerning the activities of these metabolic products. In the present study, physiologically obtainable levels of the resveratrol metabolites resveratrol-3-O-glucuronide, resveratrol-4′-O-glucuronide and resveratrol-3-O-sulfate were evaluated for their ability to protect Jurkat T cells against DNA damage induced by the topoisomerase I inhibitors camptothecin and topotecan. The cells were pretreated for 24 h with 10 µM resveratrol aglycone or each resveratrol metabolite prior to the induction of DNA damage with camptothecin or topotecan. In separate experiments, the cells were co-treated with resveratrol or its metabolites, and a topoisomerase I inhibitor. The detection of histone 2AX phosphorylation and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) were used to determine DNA damage, and apoptosis was measured using an antibody against cleaved poly ADP-ribose polymerase. It was identified that pretreatment of the cells with resveratrol-3-O-glucuronide and resveratrol-4′-O-glucuronide reduced the mean fluorescence intensity of staining for DNA strand breaks following treatment with camptothecin, while the percentage of cells undergoing apoptosis was unchanged. However, pretreatment of the cells with resveratrol aglycone increased the DNA damage and apoptosis induced by the drugs. These results suggest that the glucuronide metabolites of resveratrol partially protected the cells from DNA damage, but did not influence the induction of cell death by camptothecin and topotecan. These data suggest that resveratrol aglycone treatment may be beneficial for treating types of cancer that have direct contact with resveratrol prior to its metabolism, including gastrointestinal cancers, which are routinely treated with

Characterization of raloxifene glucuronidation. Potential role of UGT1A8 genotype on raloxifene metabolism in vivo

PubMed Central

Sun, Dongxiao; Jones, Nathan R; Manni, Andrea; Lazarus, Philip

2014-01-01

Raloxifene is a 2nd-generation selective estrogen receptor modulator used for the prevention and treatment of osteoporosis and the prevention of breast cancer in postmenopausal women. Raloxifene is extensively metabolized by glucuronidation to form raloxifene-6-glucuronide (ral-6-Gluc) and raloxifene-4′-glucuronide (ral-4′-Gluc). The goal of the present study was to determine whether functional polymorphisms in active UGTs could play a role in altered raloxifene glucuronidation in vivo. Using homogenates from HEK293 UGT-overexpressing cell lines, raloxifene was shown to be glucuronidated primarily by the hepatic UGTs 1A1 and 1A9 and the extra-hepatic UGTs 1A8 and 1A10; no detectable raloxifene glucuronidation activity was found for UGT2B enzymes. Functional UGT1A1 transcriptional promoter genotypes were significantly (ptrend=0.005) associated with ral-6-Gluc formation in human liver microsomes, and, consistent with the decreased raloxifene glucuronidation activities observed in vitro with cell line over-expressing UGT1A8 variants, the UGT1A8*2 variant was significantly (p=0.023) correlated with total raloxifene glucuronide formation in human jejunum homogenates. While ral-4′-Gluc exhibited 1/100th the anti-estrogenic activity of raloxifene itself as measured by binding to the estrogen receptor, raloxifene glucuronides comprised ∼99% of the circulating raloxifene dose in raloxifene-treated subjects, with ral-4′-Gluc comprising ∼70% of raloxifene glucuronides. Plasma ral-6-Gluc (ptrend=0.0025), ral-4′-Gluc (ptrend=0.001), and total raloxifene glucuronides (ptrend=0.001) were increased in raloxifene-treated subjects who were predicted slow metabolizers [UGT1A8 (*1/*3)] vs intermediate metabolizers [UGT1A8 (*1/*1) or UGT1A8 (*1/*2)] vs fast metabolizers [UGT1A8 (*2/*2). These data suggest that raloxifene metabolism may be dependent on UGT1A8 genotype and that UGT1A8 genotype may play an important role in overall response to raloxifene. PMID:23682072

In Vitro Stability of Free and Glucuronidated Cannabinoids in Blood and Plasma Following Controlled Smoked Cannabis

PubMed Central

Karschner, Erin L.; Desrosiers, Nathalie A.; Gorelick, David A.; Huestis, Marilyn A.

2013-01-01

BACKGROUND Blood and plasma cannabinoid stability is important for test interpretation and is best studied in authentic rather than fortified samples. METHODS Low and high blood and plasma pools were created for each of 10 participants after they smoked a cannabis cigarette. The stabilities of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol (CBD), cannabinol (CBN), THC-glucuronide, and THCCOOH-glucuronide were determined after 1 week at room temperature; 1, 2, 4, 12, and 26 (±2) weeks at 4 °C; and 1, 2, 4, 12, 26 (±2), and 52 (±4) weeks at −20 °C. Stability was assessed by Friedman test. RESULTS Numbers of THC-glucuronide and CBD-positive blood samples were insufficient to assess stability. In blood, 11-OH-THC and CBN were stable for 1 week at room temperature, whereas THC and THCCOOH-glucuronide decreased and THCCOOH increased. In blood, THC, THCCOOH-glucuronide, THCCOOH, 11-OH-THC, and CBN were stable for 12, 4, 4, 12, and 26 weeks, respectively, at 4 °C and 12, 12, 26, 26, and 52 weeks at −20 °C. In plasma, THC-glucuronide, THC, CBN, and CBD were stable for 1 week at room temperature, whereas THCCOOH-glucuronide and 11-OH-THC decreased and THCCOOH increased. In plasma, THC-glucuronide, THC, THCCOOH-glucuronide, THCCOOH, 11-OH-THC, CBN, and CBD were stable for 26, 26, 2, 2, 26, 12, and 26 weeks, respectively, at 4 °C and 52, 52, 26, 26, 52, 52, and 52 weeks, respectively, at −20 °C. CONCLUSIONS Blood and plasma samples should be stored at −20 °C for no more than 3 and 6 months, respectively, to assure accurate cannabinoid quantitative results. PMID:23519966

Effect of the β-glucuronidase inhibitor saccharolactone on glucuronidation by human tissue microsomes and recombinant UDP-glucuronosyltransferases (UGTs)

PubMed Central

Oleson, Lauren; Court, Michael H.

2009-01-01

Glucuronidation studies using microsomes and recombinant UDP-glucuronosyltransferases (rUGTs) can be complicated by the presence of endogenous β-glucuronidases leading to underestimation of glucuronide formation rates. Saccharolactone is the most frequently used β-glucuronidase inhibitor, although as of yet it is not clear whether this reagent should be routinely added to glucuronidation incubations. Here we determined the effect of saccharolactone on eight different UGT probe activities using pooled human liver microsomes (pHLMs) and rUGTs. Despite the use of buffered incubation solutions it was necessary to adjust the pH of saccharolactone solutions to avoid effects (enhancement or inhibition) of lowered pH on UGT activity. Saccharolactone at concentrations ranging from 1 to 20 mM failed to show enhancement of any of the glucuronidation activities evaluated that could be considered consistent with inhibition of β-glucuronidase. However, for most activities, higher saccharolactone concentrations resulted in a modest degree of inhibition. The greatest inhibitory effect was observed for 5-hydroxytryptamine and estradiol glucuronidation by pHLMs with 35% decrease at 20 mM saccharolactone concentration. Endogenous β-glucuronidase activities were also measured using various human tissue microsomes and rUGTs with estradiol-3-glucuronide and estradiol-17-glucuronide as substrates. Glucuronide hydrolysis was observed for pHLMs, lung microsomes, and insect-cell expressed rUGTs, but not for kidney or intestinal microsomes, or HEK293 microsomes. However, the extent of hydrolysis was relatively small representing only 9 to 19% of the glucuronide formation rate measured in the same preparations. Consequently, these data do not support the routine inclusion of saccharolactone in glucuronidation incubations and, if used, saccharolactone concentrations should be titrated to achieve activity enhancement without inhibition. PMID:18718121

In Vitro Glucuronidation and Sulfation of ε-Viniferin, a Resveratrol Dimer, in Humans and Rats.

PubMed

Courtois, Arnaud; Jourdes, Michael; Dupin, Adeline; Lapèze, Caroline; Renouf, Elodie; Biais, Benoît; Teissedre, Pierre-Louis; Mérillon, Jean-Michel; Richard, Tristan; Krisa, Stéphanie

2017-05-03

ε-Viniferin is a resveratrol dimer that possesses antioxidant or anti-inflammatory activities. However little is known about the metabolism of this oligostilbene. This study was thus undertaken as a first approach to identify and characterize the metabolites of ε-viniferin and to describe the kinetic profile of their appearance in humans and rats. The glucuronides and sulfates of ε-viniferin were first obtained by chemical hemi-synthesis and were fully characterized by UPLC-MS and NMR spectroscopy. Then, ε-viniferin was incubated with human or rat S9 liver fractions that led to the formation of four glucuronoconjugates and four sulfoconjugates. In both species, ε-viniferin was subjected to an intense metabolism as 70 to 80% of the molecule was converted to glucuronides and sulfates. In humans, the hepatic clearance of ε-viniferin (V max /K m ) for glucuronidation and sulfation were 4.98 and 6.35 µL/min/mg protein, respectively, whereas, in rats, the hepatic clearance for glucuronidation was 20.08 vs. 2.59 µL/min/mg protein for sulfation. In humans, three major metabolites were observed: two glucuronides and one sulfate. By contrast, only one major glucuronide was observed in rats. This strong hepatic clearance of ε-viniferin in human and rat could explain its poor bioavailability and could help to characterize its active metabolites.

Isolation, purification, and structural characterization of flunixin glucuronide in the urine of greyhound dogs.

PubMed

Brady, T C; Kind, A J; Hyde, W H; Favrow, M; Hill, D W

1998-04-01

A urinary metabolite of flunixin in greyhound dogs was isolated and purified by a gradient-elution solid-phase extraction technique. The purified metabolite was shown to be hydrolyzed to free flunixin by strong base and by beta-glucuronidase, suggesting the presence of a C1-beta-glucuronide ester of flunixin. The metabolite was further characterized by positive-ion, tandem MS with electrospray ionization. Mass spectral data showed the presence of a protonated molecular ion (M+1) at m/z 473, which was consistent with the molecular weight of protonated flunixin glucuronide, and a product ion at m/z 297, which was consistent with the molecular weight of protonated flunixin. Collisionally induced dissociation of the m/z 297 product ion showed a fragmentation pattern consistent with that of standard flunixin. These data support the contention that this metabolite of flunixin in greyhound urine is the C1-beta-glucuronide of flunixin. Acyl glucuronide metabolites of some organic acid drugs have been shown to bind covalently to tissue proteins in vitro, in vivo, and ex vivo. The presence of this metabolite may, therefore, have pharmacokinetic and pharmacodynamic implications for flunixin in greyhound dogs, as well as in other animal species in which the acyl glucuronide of flunixin is a metabolite.

Simultaneous Quantification of Free and Glucuronidated Cannabinoids in Human Urine by Liquid Chromatography-Tandem Mass Spectrometry

PubMed Central

Scheidweiler, Karl B.; Desrosiers, Nathalie A.; Huestis, Marilyn A.

2012-01-01

Background Cannabis is the most commonly abused drug of abuse and is commonly quantified during urine drug testing. We conducted a controlled drug administration studies investigating efficacy of urinary cannabinoid glucuronide metabolites for documenting recency of cannabis intake and for determining stability of urinary cannabinoids. Methods A liquid chromatography tandem mass spectrometry method was developed and validated quantifying Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol, cannabinol, THC-glucuronide and THCCOOH-glucuronide in 0.5 ml human urine via supported-liquid extraction. Chromatography was performed on an Ultra Biphenyl column with a gradient of 10 mmol/l ammonium acetate, pH 6.15 and 15% methanol in acetonitrile at 0. 4ml/min. Analytes were monitored by positive and negative mode electrospray ionization and multiple reaction monitoring mass spectrometry. Results Linear ranges were 0.5–50 ng/ml for THC-glucuronide, 1–100 ng/ml for THCCOOH, 11-OH-THC and cannabidiol, 2–100 ng/ml for THC and cannabinol, and 5–500 ng/ml for THCCOOH-glucuronide (R2>0.99). Mean extraction efficiencies were 34–73% with analytical recovery (bias) 80.5–118.0% and total imprecision 3.0–10.2% coefficient of variation. Conclusion This method simultaneously quantifies urinary cannabinoids and phase II glucuronide metabolites, and enables evaluation of urinary cannabinoid glucuronides for documenting recency of cannabis intake and cannabinoid stability. The assay is applicable for routine urine cannabinoid testing. PMID:22771478

Studies to further investigate the inhibition of human liver microsomal CYP2C8 by the acyl-β-glucuronide of gemfibrozil.

PubMed

Jenkins, S M; Zvyaga, T; Johnson, S R; Hurley, J; Wagner, A; Burrell, R; Turley, W; Leet, J E; Philip, T; Rodrigues, A D

2011-12-01

In previous studies, gemfibrozil acyl-β-glucuronide, but not gemfibrozil, was found to be a mechanism-based inhibitor of cytochrome P450 2C8. To better understand whether this inhibition is specific for gemfibrozil acyl-β-glucuronide or whether other glucuronide conjugates are potential substrates for inhibition of this enzyme, we evaluated several pharmaceutical compounds (as their acyl glucuronides) as direct-acting and metabolism-dependent inhibitors of CYP2C8 in human liver microsomes. Of 11 compounds that were evaluated as their acyl glucuronide conjugates, only gemfibrozil acyl-β-glucuronide exhibited mechanism-based inhibition, indicating that CYP2C8 mechanism-based inhibition is very specific to certain glucuronide conjugates. Structural analogs of gemfibrozil were synthesized, and their glucuronide conjugates were prepared to further examine the mechanism of inhibition. When the aromatic methyl groups on the gemfibrozil moiety were substituted with trifluoromethyls, the resulting glucuronide conjugate was a weaker inhibitor of CYP2C8 and mechanism-based inhibition was abolished. However, the glucuronide conjugates of monomethyl gemfibrozil analogs were mechanism-based inhibitors of CYP2C8, although not as potent as gemfibrozil acyl-β-glucuronide itself. The ortho-monomethyl analog was a more potent inhibitor than the meta-monomethyl analog, indicating that CYP2C8 favors the ortho position for oxidation and potential inhibition. Molecular modeling of gemfibrozil acyl-β-glucuronide in the CYP2C8 active site is consistent with the ortho-methyl position being the favored site of covalent attachment to the heme. Moreover, hydrogen bonding to four residues (Ser100, Ser103, Gln214, and Asn217) is implicated.

Human hydroxylated metabolites of BDE-47 and BDE-99 are glucuronidated and sulfated in vitro.

PubMed

Erratico, Claudio; Zheng, Xiaobo; Ryden, Andreas; Marsh, Goran; Maho, Walid; Covaci, Adrian

2015-07-16

Polybrominated diphenyl ethers (PBDEs) were used worldwide as additive flame retardants and are classified as persistent, bioaccumulable and toxic environmental pollutants. In humans, the hydroxylated metabolites of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) formed in vitro have also been detected in vivo. To further characterize the metabolism of BDE-47 and BDE-99 and to identify candidate markers for monitoring the human exposure to PBDEs using non-invasive approaches, glucuronidation and sulfation of hydroxylated metabolites of BDE-47 and BDE-99 were investigated using human liver microsomes and cytoplasm, respectively. The formed Phase II metabolites were analyzed by liquid chromatography-tandem mass spectrometry using a novel approach to develop analytical methods in absence of authentic standards. All available standards for hydroxylated metabolites of BDE-47 and BDE-99 were glucuronidated and sulfated, showing that glucuronidation and sulfation are part of the metabolism pathway of BDE-47 and BDE-99 in vitro. The major glucuronidated and sulfated analogs of hydroxylated metabolites of BDE-47 were (a) 2,4-DBP-Gluc and 5-Gluc-BDE-47, and (b) 2'-Sulf-BDE-28, 4-Sulf-BDE-42 and 3-Sulf-BDE-47, respectively. The major glucuronidated and sulfated analogs of hydroxylated metabolites of BDE-99 were (a) 2,4,5-TBP-Gluc and 6'-Gluc-BDE-99, and (b) 3'-Sulf-BDE-99 and 5'-Sulf-BDE-99, respectively. Apparent Km values associated with the formation of sulfated metabolites of BDE-47 and BDE-99 were ten times lower than those of the corresponding glucuronidated metabolites, suggesting that sulfated rather than glucuronidated metabolites of OH-PBDEs might be used as markers of human exposure to PBDEs using a non-invasive approach based on urine sample collection. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Bisphenol-A glucuronidation in human liver and breast: identification of UDP-glucuronosyltransferases (UGTs) and influence of genetic polymorphisms.

PubMed

Street, Christina M; Zhu, Zhaohui; Finel, Moshe; Court, Michael H

2017-01-01

1. Bisphenol-A is a ubiquitous environmental contaminant that is primarily metabolized by glucuronidation and associated with various human diseases including breast cancer. Here we identified UDP-glucuronosyltransferases (UGTs) and genetic polymorphisms responsible for interindividual variability in bisphenol-A glucuronidation in human liver and breast. 2. Hepatic UGTs showing the highest bisphenol-A glucuronidation activity included UGT2B15 and UGT1A9. Relative activity factor normalization indicated that UGT2B15 contributes >80% of activity at bisphenol-A concentrations under 5 μM, while UGT1A9 contributes up to 50% of activity at higher concentrations. 3. Bisphenol-A glucuronidation by liver microsomes (46 donors) ranged from 0.25 to 4.3 nmoles/min/mg protein. Two-fold higher glucuronidation (p = 0.018) was observed in UGT1A9 *22/*22 livers compared with *1/*1 and *1/*22 livers. However, no associations were observed for UGT2B15*2 or UGT1A1*28 genotypes. 4. Bisphenol-A glucuronidation by breast microsomes (15 donors) ranged from <0.2 to 56 fmoles/min/mg protein. Breast mRNA expression of UGTs capable of glucuronidating bisphenol-A was highest for UGT1A1, followed by UGT2B4, UGT1A9, UGT1A10, UGT2B7 and UGT2B15. Bisphenol-A glucuronidation was over 10-fold lower in breast tissues with the UGT1A1*28 allele compared with tissues without this allele (p = 0.006). 5. UGT2B15 and UGT1A9 contribute to glucuronidation variability in liver, while UGT1A1 is important in breast.

The Contribution of Common UGT2B10 and CYP2A6 Alleles to Variation in Nicotine Glucuronidation among European Americans

PubMed Central

Bloom, A. Joseph; von Weymarn, Linda B.; Martinez, Maribel; Bierut, Laura J.; Goate, Alison; Murphy, Sharon E.

2014-01-01

UDP-glucuronosytransferase-2B10 (UGT2B10) is the primary catalyst of nicotine glucuronidation. To develop a predictive genetic model of nicotine metabolism, the conversion of deuterated (D2)-nicotine to D2-nicotine-glucuronide, D2-cotinine, D2-cotinine-glucuronide, and D2-trans-3'-hydroxycotinine were quantified in 188 European Americans, and the contribution of UGT2B10 genotype to variability in first-pass nicotine glucuronidation assessed, following a procedure previously applied to nicotine C-oxidation. The proportion of total nicotine converted to nicotine-glucuronide (D2-nicotine-glucuronide/ (D2-nicotine +D2-nicotine-glucuronide +D2-cotinine +D2-cotinine-glucuronide +D2-trans-3'-hydroxycotinine)) was the primary phenotype. The variant, rs61750900T (D67Y) (minor allele frequency (MAF) = 10%), is confirmed to abolish nicotine glucuronidation activity. Another variant, rs112561475G (N397D) (MAF = 2%), is significantly associated with enhanced glucuronidation. rs112561475G is the ancestral allele of a well-conserved amino acid, indicating that the majority of human UGT2B10 alleles are derived hypomorphic alleles. CYP2A6 and UGT2B10 genotype explain 53% of the variance in oral nicotine glucuronidation in this sample. CYP2A6 and UGT2B10 genetic variants are also significantly associated with un-deuterated (D0) nicotine glucuronidation in subjects smoking ad libitum. We find no evidence for further common variation markedly influencing hepatic UGT2B10 expression in European Americans. PMID:24192532

Bilirubin glucuronidation revisited: proper assay conditions to estimate enzyme kinetics with recombinant UGT1A1.

PubMed

Zhou, Jin; Tracy, Timothy S; Remmel, Rory P

2010-11-01

Bilirubin, an end product of heme catabolism, is primarily eliminated via glucuronic acid conjugation by UGT1A1. Impaired bilirubin conjugation, caused by inhibition of UGT1A1, can result in clinical consequences, including jaundice and kernicterus. Thus, evaluation of the ability of new drug candidates to inhibit UGT1A1-catalyzed bilirubin glucuronidation in vitro has become common practice. However, the instability of bilirubin and its glucuronides presents substantial technical challenges to conduct in vitro bilirubin glucuronidation assays. Furthermore, because bilirubin can be diglucuronidated through a sequential reaction, establishment of initial rate conditions can be problematic. To address these issues, a robust high-performance liquid chromatography assay to measure both bilirubin mono- and diglucuronide conjugates was developed, and the incubation conditions for bilirubin glucuronidation by human embryonic kidney 293-expressed UGT1A1 were carefully characterized. Our results indicated that bilirubin glucuronidation should be assessed at very low protein concentrations (0.05 mg/ml protein) and over a short incubation time (5 min) to assure initial rate conditions. Under these conditions, bilirubin total glucuronide formation exhibited a hyperbolic (Michaelis-Menten) kinetic profile with a K(m) of ∼0.2 μM. In addition, under these initial rate conditions, the relative proportions between the total monoglucuronide and the diglucuronide product were constant across the range of bilirubin concentration evaluated (0.05-2 μM), with the monoglucuronide being the predominant species (∼70%). In conclusion, establishment of appropriate incubation conditions (i.e., very low protein concentrations and short incubation times) is necessary to properly characterize the kinetics of bilirubin glucuronidation in a recombinant UGT1A1 system.

Comparison of the effects of curcumin and curcumin glucuronide in human hepatocellular carcinoma HepG2 cells.

PubMed

Shoji, Motomu; Nakagawa, Kiyotaka; Watanabe, Akio; Tsuduki, Tsuyoshi; Yamada, Teiko; Kuwahara, Shigefumi; Kimura, Fumiko; Miyazawa, Teruo

2014-05-15

Curcumin is a yellow pigment found in turmeric (Curcuma Longa L.), and is reported, in recent studies, to have several pharmacological effects, including anti-oxidant, anti-inflammatory, anti-tumour and lipid-lowering properties. However, as most curcumin is conjugated when absorbed through the intestine, free curcumin is present at extremely low levels inside the body. Therefore, curcumin metabolites have been presumed to be responsible for the curcumin bioactivity. In this study, we first confirmed that curcumin glucuronide is the major metabolite of curcumin found in the plasma after oral administration of curcumin in rats. Next, we synthesised curcumin glucuronide and compared the effects of curcumin and curcumin glucuronide on gene expression in a human hepatoma cell line (HepG2). We found that the effects of curcumin glucuronide are weaker than those of curcumin and that this difference is related to relative absorption rates of curcumin and curcumin glucuronide into HepG2 cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

Mitochondrial Dysfunction Leads to Deconjugation of Quercetin Glucuronides in Inflammatory Macrophages

PubMed Central

Miki, Satomi; Shiba, Yuko; Minekawa, Shoko; Nishikawa, Tomomi; Mukai, Rie; Terao, Junji; Kawai, Yoshichika

2013-01-01

Dietary flavonoids, such as quercetin, have long been recognized to protect blood vessels from atherogenic inflammation by yet unknown mechanisms. We have previously discovered the specific localization of quercetin-3-O-glucuronide (Q3GA), a phase II metabolite of quercetin, in macrophage cells in the human atherosclerotic lesions, but the biological significance is poorly understood. We have now demonstrated the molecular basis of the interaction between quercetin glucuronides and macrophages, leading to deconjugation of the glucuronides into the active aglycone. In vitro experiments showed that Q3GA was bound to the cell surface proteins of macrophages through anion binding and was readily deconjugated into the aglycone. It is of interest that the macrophage-mediated deconjugation of Q3GA was significantly enhanced upon inflammatory activation by lipopolysaccharide (LPS). Zymography and immunoblotting analysis revealed that β-glucuronidase is the major enzyme responsible for the deglucuronidation, whereas the secretion rate was not affected after LPS treatment. We found that extracellular acidification, which is required for the activity of β-glucuronidase, was significantly induced upon LPS treatment and was due to the increased lactate secretion associated with mitochondrial dysfunction. In addition, the β-glucuronidase secretion, which is triggered by intracellular calcium ions, was also induced by mitochondria dysfunction characterized using antimycin-A (a mitochondrial inhibitor) and siRNA-knockdown of Atg7 (an essential gene for autophagy). The deconjugated aglycone, quercetin, acts as an anti-inflammatory agent in the stimulated macrophages by inhibiting the c-Jun N-terminal kinase activation, whereas Q3GA acts only in the presence of extracellular β-glucuronidase activity. Finally, we demonstrated the deconjugation of quercetin glucuronides including the sulfoglucuronides in vivo in the spleen of mice challenged with LPS. These results showed that

Biotransformation of Bisphenol AF to Its Major Glucuronide Metabolite Reduces Estrogenic Activity

PubMed Central

Yin, Jie; Zhang, Jing; Feng, Yixing; Shao, Bing

2013-01-01

Bisphenol AF (BPAF), an endocrine disrupting chemical, can induce estrogenic activity through binding to estrogen receptor (ER). However, the metabolism of BPAF in vivo and the estrogenic activity of its metabolites remain unknown. In the present study, we identified four metabolites including BPAF diglucuronide, BPAF glucuronide (BPAF-G), BPAF glucuronide dehydrated and BPAF sulfate in the urine of Sprague-Dawley (SD) rats. BPAF-G was further characterized by nuclear magnetic resonance (NMR). After treatment with a single dose of BPAF, BPAF was metabolized rapidly to BPAF-G, as detected in the plasma of SD rats. Biotransformation of BPAF to BPAF-G was confirmed with human liver microsomes (HLM), and Vmax of glucuronidation for HLM was 11.6 nmol/min/mg. We also found that BPAF glucuronidation could be mediated through several human recombinant UDP-glucuronosyltransferases (UGTs) including UGT1A1, UGT1A3, UGT1A8, UGT1A9, UGT2B4, UGT2B7, UGT2B15 and UGT2B17, among which UGT2B7 showed the highest efficiency of glucuronidation. To explain the biological function of BPAF biotransformation, the estrogenic activities of BPAF and BPAF-G were evaluated in ER-positive breast cancer T47D and MCF7 cells. BPAF significantly stimulates ER-regulated gene expression and cell proliferation at the dose of 100 nM and 1 μM in breast cancer cells. However, BPAF-G did not show any induction of estrogenic activity at the same dosages, implying that formation of BPAF-G is a potential host defense mechanism against BPAF. Based on our study, biotransformation of BPAF to BPAF-G can eliminate BPAF-induced estrogenic activity, which is therefore considered as reducing the potential threat to human beings. PMID:24349450

Tissue and species differences in the glucuronidation of glabridin with UDP-glucuronosyltransferases.

PubMed

Guo, Bin; Fang, Zhongze; Yang, Lu; Xiao, Ling; Xia, Yangliu; Gonzalez, Frank J; Zhu, Liangliang; Cao, Yunfeng; Ge, Guangbo; Yang, Ling; Sun, Hongzhi

2015-04-25

Glabridin (GA) has gained wide application in the cosmetics and food industry. This study was performed to investigate its metabolic inactivation and elimination by glucuronidation by use of liver and intestine microsomes from humans (HLM and HIM) and rats (RLM and RIM), and liver microsomes from cynomolgus monkeys and beagle dogs (CyLM and DLM). Both hydroxyl groups at the C2 and C4 positions of the B ring are conjugated to generate two mono-glucuronides (M1 and M2). HIM, RIM and RLM showed the most robust activity in catalyzing M2 formation with intrinsic clearance values (Clint) above 2000 μL/min/mg, with little measurable M1 formation activity. DLM displayed considerable activity both in M1 and M2 formation, with Clint values of 71 and 214 μL/min/mg, respectively, while HLM and CyLM exhibited low activities in catalyzing M1 and M2 formation, with Clint values all below 20 μL/min/mg. It is revealed that UGT1A1, 1A3, 1A9, 2B7, 2B15 and extrahepatic UGT1A8 and 1A10 are involved in GA glucuronidation. Nearly all UGTs preferred M2 formation except for UGT1A1. Notably, UGT1A8 displayed the highest activity with a Clint value more than 5-fold higher than the other isoforms. Chemical inhibition studies, using selective inhibitors of UGT1A1, 1A9, 2B7 and 1A8, further revealed that UGT1A8 contributed significantly to intestinal GA glucuronidation in humans. In summary, this in vitro study demonstrated large species differences in GA glucuronidation by liver and intestinal microsomes, and that intestinal UGTs are important for the pathway in humans. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Soy isoflavone metabolism in cats compared with other species: Urinary metabolite concentrations and glucuronidation by liver microsomes

PubMed Central

Redmon, Joanna M.; Shrestha, Binu; Cerundolo, Rosario; Court, Michael H.

2016-01-01

Soybean is a common source of protein in many pet foods. Slow glucuronidation of soy-derived isoflavones in cats has been hypothesized to result in accumulation with adverse health consequences. Here we evaluated species’ differences in soy isoflavone glucuronidation using urine samples from cats and dogs fed a soy-based diet and liver microsomes from cats compared with microsomes from 12 other species.Significant concentrations of conjugated (but not unconjugated) genistein, daidzein, and glycitein, and the gut microbiome metabolites, dihydrogenistein and dihydrodaidzein were found in cat and dog urine samples. Substantial amounts of conjugated equol were also found in cat urine but not in dog urine.β-glucuronidase treatment showed that all these compounds were significantly glucuronidated in dog urine while only daidzein (11%) and glycitein (37%) showed any glucuronidation in cat urine suggesting that alternate metabolic pathways including sulfation predominate in cats.Glucuronidation rates of genistein, daidzein, and equol by cat livers were consistently ranked within the lowest three out of 13 species’ livers evaluated. Ferret and mongoose livers were also ranked in the lowest four species.Our results demonstrate that glucuronidation is a minor pathway for soy isoflavone metabolism in cats compared with most other species. PMID:26366946

Soy isoflavone metabolism in cats compared with other species: urinary metabolite concentrations and glucuronidation by liver microsomes.

PubMed

Redmon, Joanna M; Shrestha, Binu; Cerundolo, Rosario; Court, Michael H

2016-01-01

1. Soybean is a common source of protein in many pet foods. Slow glucuronidation of soy-derived isoflavones in cats has been hypothesized to result in accumulation with adverse health consequences. Here, we evaluated species' differences in soy isoflavone glucuronidation using urine samples from cats and dogs fed a soy-based diet and liver microsomes from cats compared with microsomes from 12 other species. 2. Significant concentrations of conjugated (but not unconjugated) genistein, daidzein and glycitein, and the gut microbiome metabolites, dihydrogenistein and dihydrodaidzein, were found in cat and dog urine samples. Substantial amounts of conjugated equol were also found in cat urine but not in dog urine. 3. β-Glucuronidase treatment showed that all these compounds were significantly glucuronidated in dog urine while only daidzein (11%) and glycitein (37%) showed any glucuronidation in cat urine suggesting that alternate metabolic pathways including sulfation predominate in cats. 4. Glucuronidation rates of genistein, daidzein and equol by cat livers were consistently ranked within the lowest 3 out of 13 species' livers evaluated. Ferret and mongoose livers were also ranked in the lowest four species. 5. Our results demonstrate that glucuronidation is a minor pathway for soy isoflavone metabolism in cats compared with most other species.

Fate of glucuronide conjugated estradiol in the environment

USDA-ARS?s Scientific Manuscript database

The fate and transport of conjugated reproductive hormones, which are polar compared to parent hormones, are little understood. Laboratory bench-scale soil (Hamar; Sandy, mixed, frigid typic Endoaquolls) sorption studies were conducted using [14C] 17ß-estradiol-3-glucuronide for a range of concentra...

Developmental changes rather than repeated administration drive paracetamol glucuronidation in neonates and infants.

PubMed

Krekels, Elke H J; van Ham, Saskia; Allegaert, Karel; de Hoon, Jan; Tibboel, Dick; Danhof, Meindert; Knibbe, Catherijne A J

2015-09-01

Based on recovered metabolite ratios in urine, it has been concluded that paracetamol glucuronidation may be up-regulated upon multiple dosing. This study investigates paracetamol clearance in neonates and infants after single and multiple dosing using a population modelling approach. A population pharmacokinetic model was developed in NONMEM VI, based on paracetamol plasma concentrations from 54 preterm and term neonates and infants, and on paracetamol, paracetamol-glucuronide and paracetamol-sulphate amounts in urine from 22 of these patients. Patients received either a single intravenous propacetamol dose or up to 12 repeated doses. Paracetamol and metabolite disposition was best described with one-compartment models. The formation clearance of paracetamol-sulphate was 1.46 mL/min/kg(1.4), which was about 5.5 times higher than the formation clearance of the glucuronide of 0.266 mL/min/kg. The renal excretion rate constants of both metabolites was estimated to be 11.4 times higher than the excretion rate constant of unchanged paracetamol, yielding values of 0.580 mL/min/kg. Developmental changes were best described by bodyweight in linear relationships on the distribution volumes, the formation of paracetamol-glucuronide and the unchanged excretion of paracetamol, and in an exponential relationship on the formation of paracetamol-sulphate. There was no evidence for up-regulation or other time-varying changes in any of the model parameters. Simulations with this model illustrate how paracetamol-glucuronide recovery in urine increases over time due to the slower formation of this metabolite and in the absence of up-regulation. Developmental changes, described by bodyweight-based functions, rather than up-regulation, explain developmental changes in paracetamol disposition in neonates and infants.

Determination of n-hexane metabolites by liquid chromatography/mass spectrometry. 2. Glucuronide-conjugated metabolites in untreated urine samples by electrospray ionization.

PubMed

Manini, P; Andreoli, R; Mutti, A; Bergamaschi, E; Niessen, W M

1998-01-01

A liquid chromatography atmospheric pressure electrospray mass spectrometry (ESI-LC/MS) system was evaluated for the identification and characterization of n-hexane conjugated metabolites (glucuronides) in untreated urine samples. Chromatography of glucuronides was obtained under ion-suppressed reversed-phase conditions, by using high-speed (3 cm, 3 microns) columns and formic acid (2 mM) as modifier in the mobile phase. The mass spectrometer was operated in negative ion (NI) mode. For the first time, four glucuronides were identified by ESI-LC/MS in untreated urine samples of rats exposed to n-hexane: 2-hexanol-glucuronide, 5-hydroxy-2-hexanone-glucuronide, 2,5-hexanediol-glucuronide and 4,5-dihydroxy-2-hexanone-glucuronide. Confirmation of the conjugated metabolites was obtained by LC/MS/MS experiments. Gas chromatography/mass spectrometry (GC/MS) and atmospheric pressure chemical ionization (APCI) LC/MS analyses were performed on the same samples. An integrated approach GC/MS-LC/MS for the semi-quantitative analysis of n-hexane glucuronides, whose standards are not commercially available, is discussed and proposed here. In order to understand the fate of the metabolites during sample pre-treatment, a study about the effects of enzymatic and acid hydrolysis on urine samples was conducted on glucuronides isolated by solid-phase extraction. Combined analyses by GC/MS and LC/MS enabled us to distinguish 'true' n-hexane metabolites from compounds resulting from sample treatment and handling (i.e. enzymatic and acid hydrolysis, extraction and GC injection).

VizieR Online Data Catalog: ETGs sample for the Coma cluster (Riguccini+, 2015)

NASA Astrophysics Data System (ADS)

Riguccini, L.; Temi, P.; Amblard, A.; Fanelli, M.; Brighenti, F.

2017-10-01

For the Coma Cluster, we utilize the work of Mahajan et al. (2010, J/MNRAS/404/1745) to build our ETG sample. Mahajan et al. (2010, J/MNRAS/404/1745) used a combination of MIPS 24 μm observations and SDSS photometry and spectra to investigate the star formation history of galaxies in the Coma supercluster. All of their galaxies from the SDSS data in the Coma supercluster region are brighter than r~17.77, the completeness limit of the SDSS spectroscopic galaxy catalog. Their 24 μm fluxes are obtained from archival data covering 2x2 deg2 for Coma Cluster. Our final sample of 124 sources is composed of 49 ellipticals and 75 lenticulars. (1 data file).

Biochemistry of metalocenes. The organ distribution of hydroxyacetyl (/sup 103/Ru)ruthenocene and its glucuronide in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taylor, A.J.; Macha, J.; Wenzel, M.

1980-01-01

Hydroxyacetyl(/sup 103/Ru)ruthenocene and its o-glucuronide were prepared in vitro by incubation of acetyl(/sup 103/Ru)ruthenocene with rat-liver homogenate, NADPH, and UDP-glucuronate. The factors affecting hydroxylation and glucuronidation in vitro were optimized for acetylruthenocene. Hydroxyacetyl(/sup 103/Ru)ruthenocene glucuronide showed no affinity for the adrenal glands, but after iv administration of hydroxyacetyl(/sup 103/Ru)ruthenocene there was a distinct accumulation of Ru-103 in adrenals, similar to that found after administration of acetyl(/sup 103/Ru)ruthenocene.

Profiling serum bile acid glucuronides in humans: gender divergences, genetic determinants and response to fenofibrate

PubMed Central

Trottier, Jocelyn; Perreault, Martin; Rudkowska, Iwona; Levy, Cynthia; Dallaire-Theroux, Amélie; Verreault, Mélanie; Caron, Patrick; Staels, Bart; Vohl, Marie-Claude; Straka, Robert J.; Barbier, Olivier

2014-01-01

Glucuronidation, catalyzed by UDP-glucuronosyltransferase (UGT) enzymes detoxifies cholestatic bile acids (BAs). We aimed at i) characterizing the circulating BA-glucuronide (-G) pool composition in humans, ii) evaluating how sex and UGT polymorphisms influence this composition, and iii) analyzing the effects of lipid-lowering drug fenofibrate on the circulating BA-G profile in 300 volunteers and 5 cholestatic patients. Eleven BA-Gs were determined in pre- and post-fenofibrate samples. Men exhibited higher BA-G concentrations, and various genotype/BA-G associations were discovered in relevant UGT genes. The chenodeoxycholic acid-3G concentration was associated with the UGT2B7 802C>T polymorphism. Glucuronidation assays confirmed the predominant role of UGT2B7 and UGT1A4 in CDCA-3G formation. Fenofibrate exposure increased the serum levels of 5 BA-G species, including CDCA-3G, and up-regulated expression of UGT1A4, but not UGT2B7, in hepatic cells. This study demonstrates that fenofibrate stimulates BA glucuronidation in humans, and thus reduces bile acid toxicity in the liver. PMID:23756370

Synthesis, physicochemical properties, and biological activity of bile acids 3-glucuronides: Novel insights into bile acid signalling and detoxification.

PubMed

Mostarda, Serena; Passeri, Daniela; Carotti, Andrea; Cerra, Bruno; Colliva, Carolina; Benicchi, Tiziana; Macchiarulo, Antonio; Pellicciari, Roberto; Gioiello, Antimo

2018-01-20

Glucuronidation is considered an important detoxification pathway of bile acids especially in cholestatic conditions. Glucuronides are less toxic than the parent free forms and are more easily excreted in urine. However, the pathophysiological significance of bile acid glucuronidation is still controversial and debated among the scientific community. Progress in this field has been strongly limited by the lack of appropriate methods for the preparation of pure glucuronides in the amount needed for biological and pharmacological studies. In this work, we have developed a new synthesis of bile acid C3-glucuronides enabling the convenient preparation of gram-scale quantities. The synthesized compounds have been characterized in terms of physicochemical properties and abilities to modulate key nuclear receptors including the farnesoid X receptor (FXR). In particular, we found that C3-glucuronides of chenodeoxycholic acid and lithocholic acid, respectively the most abundant and potentially cytotoxic species formed in patients affected by cholestasis, behave as FXR agonists and positively regulate the gene expression of transporter proteins, the function of which is critical in human conditions related to imbalances of bile acid homeostasis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Inhibition of UDP-glucuronosyltransferase (UGT)-mediated glycyrrhetinic acid 3-O-glucuronidation by polyphenols and triterpenoids.

PubMed

Koyama, Mayuko; Shirahata, Tatsuya; Hirashima, Rika; Kobayashi, Yoshinori; Itoh, Tomoo; Fujiwara, Ryoichi

2017-08-01

Glycyrrhetinic acid (GA) is an active metabolite of glycyrrhizin, which is a main constituent in licorice (Glycyrrhiza glabra). While GA exhibits a wide variety of pharmacological activities in the body, it is converted to a toxic metabolite GA 3-O-glucuronide by hepatic UDP-glucuronosyltransferases (UGTs). To avoid the development of the toxic metabolite-induced pseudohyperaldosteronism (pseudoaldosteronism), there is a limitation in maximum daily dosage of licorice and in combined usage of other glycyrrhizin-containing natural medicine. In this study, we investigated the inhibitory effects of various polyphenols and triterpenoids on the UGT-mediated GA 3-O-glucuronidation. In human liver microsomes, UGT-mediated GA glucuronidation was significantly inhibited by protopanaxadiol with an IC 50 value of 59.2 μM. Isoliquiritigenin, rosmarinic acid, alisol B, alisol acetate, and catechin moderately inhibited the GA glucuronidation with IC 50 values of 96.4 μM, 125 μM, 160 μM, 163 μM, and 164 μM. Other tested 19 polyphenols and triterpenoids, including liquiritigenin, did not inhibit UGT-mediated GA glucuronidation in human liver microsomes. Our data indicate that relatively higher dosage of licorice can be used without a risk of developing pseudohyperaldosteronism in combination of natural medicine containing protopanaxadiol such as Panax ginseng. Furthermore, supplemental protopanaxadiol and isoliquiritigenin might be useful in preventing licorice-inducing pseudoaldosteronism. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Regiospecificity of Human UDP-glucuronosyltransferase Isoforms in Chalcone and Flavanone Glucuronidation Determined by Metal Complexation and Tandem Mass Spectrometry

PubMed Central

Niemeyer, Emily D.; Brodbelt, Jennifer S.

2013-01-01

The glucuronidation of a series of chalcones (2'-hydroxychalcone, 2',4'-dihydroxychalcone, 3,2'-dihydroxychalcone, 4,2'-dihydroxychalcone, and cardamonin) and their corresponding cyclized flavanones (7-hydroxyflavanone, 3'-hydroxyflavanone, 4'-hydroxyflavanone, and alpinetin) by nine human UDP-glucuronosyltransferase (UGT) 1A enzymes was evaluated. A post-column metal complexation LC-MS/MS strategy was used successfully to produce characteristic mass spectrometric product ions that were utilized in combination with elution order trends to identify chalcone and flavanone monoglucuronides unambiguously, thus allowing determination of the regioselectivities of the UGT1A isoforms. The presence of hydroxy groups on the A or B-ring had a significant effect on the glucuronide product yield and the site where glucuronidation occurred. For example, for reaction with UGT1A9, formation of the 2'-O-glucuronide was increased for dihydroxychalcones with A-ring hydroxy substituents. In contrast, although UGT1A8 reacted with 3,2'-dihydroxychalcone and 4,2'-dihydroxychalcone to yield 2'-O-glucuronide products, the presence of a B-ring hydroxy group at the 4' position on cardamonin and 2',4'-dihydroxychalcone quenched the reaction at the OH-2' position. Moreover, the A-ring OH-4 group promoted glucuronidation at the 2' position for the reaction of 4,2'-dihydroxychalcone with UGT1A1 and 1A3. For UGT1A7, hydroxy group substituents on the chalcone A-ring also promoted cyclization and formation of the corresponding flavanone glucuronide. PMID:23713759

Regiospecificity of human UDP-glucuronosyltransferase isoforms in chalcone and flavanone glucuronidation determined by metal complexation and tandem mass spectrometry.

PubMed

Niemeyer, Emily D; Brodbelt, Jennifer S

2013-06-28

The glucuronidation of a series of chalcones (2'-hydroxychalcone, 2',4'-dihydroxychalcone, 3,2'-dihydroxychalcone, 4,2'-dihydroxychalcone, and cardamonin) and their corresponding cyclized flavanones (7-hydroxyflavanone, 3'-hydroxyflavanone, 4'-hydroxyflavanone, and alpinetin) by eight human UDP-glucuronosyltransferase (UGT) 1A enzymes was evaluated. A postcolumn metal complexation LC-MS/MS strategy was used successfully to produce characteristic mass spectrometric product ions that were utilized in combination with elution order trends to identify chalcone and flavanone monoglucuronides unambiguously, thus allowing determination of the regioselectivities of the UGT1A isoforms. The presence of hydroxy groups on the A- or B-ring had a significant effect on the glucuronide product yield and the site where glucuronidation occurred. For example, for reaction with UGT1A9, formation of the 2'-O-glucuronide was increased for dihydroxychalcones with A-ring hydroxy substituents. In contrast, although UGT1A8 reacted with 3,2'-dihydroxychalcone and 4,2'-dihydroxychalcone to yield 2'-O-glucuronide products, the presence of a B-ring hydroxy group at the 4' position on cardamonin and 2',4'-dihydroxychalcone quenched the reaction at the OH-2' position. Moreover, the A-ring OH-4 group promoted glucuronidation at the 2' position for the reaction of 4,2'-dihydroxychalcone with UGT1A1 and 1A3. For UGT1A7, hydroxy group substituents on the chalcone A-ring also promoted cyclization and formation of the corresponding flavanone glucuronide.

Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy Greyhound dogs

PubMed Central

KuKanich, Butch

2009-01-01

The purpose of this study was to determine the pharmacokinetics of codeine and the active metabolites morphine and codeine-6-glucuronide after IV codeine administration and the pharmacokinetics of acetaminophen (APAP), codeine, morphine, and codeine-6-glucuronide after oral administration of combination product containing acetaminophen and codeine to dogs. Six healthy Greyhound dogs were administered 0.734 mg/kg codeine IV and acetaminophen (10.46 mg/kg mean dose) with codeine (1.43 mg/kg mean dose) orally. Blood samples were obtained at predetermined time points for the determination of codeine, morphine, and codeine-6-glucuronide plasma concentrations by LC/MS and acetaminophen by HPLC with UV detection. Codeine was rapidly eliminated after IV administration (T½ =1.22 hr; clearance=29.94 mL/min/kg; volume of distribution=3.17 L/kg) with negligible amounts of morphine present, but large amounts of codeine-6-glucuronide (CMAX=735.75 ng/mL) were detected. The oral bioavailability of codeine was 4%, morphine concentrations were negligible, but large amounts of codeine-6-glucuronide (CMAX=1952.86 ng/mL) were detected suggesting substantial first pass metabolism. Acetaminophen was rapidly absorbed (CMAX=6.74 μg/mL; TMAX=0.85 hr) and eliminated (T½=0.96 hr). In conclusion, the pharmacokinetics of codeine were similar to other opioids in dogs with a short half-life, rapid clearance, large volume of distribution, and poor oral bioavailability. High concentrations of codeine-6-glucuronide were detected after IV and oral administration. PMID:20444020

Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy Greyhound dogs.

PubMed

KuKanich, B

2010-02-01

The purpose of this study was to determine the pharmacokinetics of codeine and the active metabolites morphine and codeine-6-glucuronide after i.v. codeine administration and the pharmacokinetics of acetaminophen (APAP), codeine, morphine, and codeine-6-glucuronide after oral administration of combination product containing acetaminophen and codeine to dogs. Six healthy Greyhound dogs were administered 0.734 mg/kg codeine i.v. and acetaminophen (10.46 mg/kg mean dose) with codeine (1.43 mg/kg mean dose) orally. Blood samples were collected at predetermined time points for the determination of codeine, morphine, and codeine-6-glucuronide plasma concentrations by LC/MS and acetaminophen by HPLC with UV detection. Codeine was rapidly eliminated after i.v. administration (T(1/2) = 1.22 h; clearance = 29.94 mL/min/kg; volume of distribution = 3.17 L/kg) with negligible amounts of morphine present, but large amounts of codeine-6-glucuronide (C(max) = 735.75 ng/mL) were detected. The oral bioavailability of codeine was 4%, morphine concentrations were negligible, but large amounts of codeine-6-glucuronide (C(max) = 1952.86 ng/mL) were detected suggesting substantial first pass metabolism. Acetaminophen was rapidly absorbed (C(max) = 6.74 microg/mL; T(max) = 0.85 h) and eliminated (T(1/2) = 0.96 h). In conclusion, the pharmacokinetics of codeine was similar to other opioids in dogs with a short half-life, rapid clearance, large volume of distribution, and poor oral bioavailability. High concentrations of codeine-6-glucuronide were detected after i.v. and oral administration.

Evidence for differences in regioselective and stereoselective glucuronidation of silybin diastereomers from milk thistle (Silybum marianum) by human UDP-glucuronosyltransferases.

PubMed

Jančová, Petra; Siller, Michal; Anzenbacherová, Eva; Křen, Vladimír; Anzenbacher, Pavel; Simánek, Vilím

2011-09-01

The flavonolignan silybin, the main component of silymarin, extract from the seeds of Silybum marianum, is used mostly as a hepatoprotectant. Silybin is almost 1:1 mixture of two diastereomers A and B. The individual UDP-glucuronosyltransferases (UGTs) contributing to the metabolism of silybin diastereomers have not been identified yet. In this study, the contribution of UGTs to silybin metabolism was examined. The potential silybin metabolites were formed in vitro by incubating silybin (i) with the human liver microsomal fraction, (ii) with human hepatocytes and finally (iii) with 12 recombinant UGTs (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15 and 2B17). High-performance liquid chromatographic (HPLC) techniques with UV detection and additionally MS detection were used for metabolite identification. Hepatocytes and microsomes formed silybin A-7-O-β-D-glucuronides, B-7-O-β-D-glucuronides, A-20-O-β-D-glucuronides and B-20-O-β-D-glucuronides. With recombinant UGTs, the major role of the UGT1A1, 1A3, 1A8 and 1A10 enzymes but also of the UGT1A6, 1A7, 1A9, 2B7 and 2B15 in the stereoselective reactions leading to the respective silybin glucuronides was confirmed. UGT1A4, UGT2B4 and UGT2B17 did not participate in silybin glucuronidation. The predominant formation of 7-O-β-D-glucuronides and the preferential glucuronidation of silybin B diastereomer in vitro by human UGTs were confirmed.

Mass spectrometric characterization of glucuronides formed by a new concept, combining Cunninghamella elegans with TEMPO.

PubMed

Rydevik, Axel; Bondesson, Ulf; Thevis, Mario; Hedeland, Mikael

2013-10-01

A new concept for the production of drug glucuronides is presented and the products formed were characterized using ultra high performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS). Glucuronic acid conjugates are important phase II metabolites of a wide range of drugs. There is a lack of commercially available glucuronides and classic synthetic methods are tedious and expensive. Thus, new methods of glucuronide synthesis are needed. Selective androgen receptor modulators (SARMs) of the aryl propionamide class were used as model compounds and were incubated with the fungus Cunninghamella elegans which was previously known to conjugate drugs with glucose. The resulting glucoside metabolites were then oxidized with tetramethylpiperidinyl-1-oxy (TEMPO). UPLC-HRMS analysis showed that the peaks corresponding to the glucosides had disappeared after the reaction and were replaced by peaks with m/z consistent with the corresponding glucuronic acid conjugates. The MS/MS spectra of the reaction products were investigated and the observed fragment ion pattern corroborated the suggested structural change. A comparison in terms of retention times and product ion spectra between the glucuronides formed by the new method and those produced by liver microsomes indicated that the conjugates from the two different sources were identical, thus demonstrating the human relevance of the presented technique. Furthermore, the glucuronides formed by the presented method were readily hydrolyzed by β-glucuronidase which further gave evidence as to the fact that they were of β configuration. The investigated method was easy to perform, required a low input of work and had a low cost. Copyright © 2013 Elsevier B.V. All rights reserved.

Effect of UDP-Glucuronosyltransferase (UGT) 1A Polymorphism (rs8330 and rs10929303) on Glucuronidation Status of Acetaminophen

PubMed Central

Tahir, Imtiaz Mahmood; Iqbal, Tahira; Saleem, Sadaf; Perveen, Sofia; Farooqi, Aboubakker

2017-01-01

Interindividual variability in polymorphic uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) ascribed to genetic diversity is associated with relative glucuronidation level among individuals. The present research was aimed to study the effect of 2 important single nucleotide polymorphisms (SNPs; rs8330 and rs10929303) of UGT1A1 gene on glucuronidation status of acetaminophen in healthy volunteers (n = 109). Among enrolled volunteers, 54.13% were male (n = 59) and 45.87% were female (n = 50). The in vivo activity of UGT1A1 was investigated by high-performance liquid chromatography-based analysis of glucuronidation status (ie, acetaminophen and acetaminophen glucuronide) in human volunteers after oral intake of a single dose (1000 mg) of acetaminophen. The TaqMan SNP genotyping assay was used for UGT1A1 genotyping. The wild-type genotype (C/C) was observed the most frequent one for both SNPs (rs8330 and rs10929303) and associated with fast glucuronidator phenotypes. The distribution of variant genotype (G/G) for SNP rs8330 was observed in 5% of male and 8% of the female population; however, for SNP rs10929303, the G/G genotype was found in 8% of both genders. A trimodal distribution (fast, intermediate, and slow) based on phenotypes was observed. Among the male participants, the glucuronidation phenotypes were observed as 7% slow, 37% intermediate, and 56% fast glucuronidators; however, these findings for the females were slightly different as 8%, 32%, and 60% respectively. The k-statistics revealed a compelling evidence for good concordance between phenotype and genotype with a k value of 1.00 for SNP rs8330 and 0.966 for SNP rs10929303 in our population. PMID:28932176

Efflux transport of estrogen glucuronides by human MRP2, MRP3, MRP4 and BCRP.

PubMed

Järvinen, Erkka; Deng, Feng; Kidron, Heidi; Finel, Moshe

2018-04-01

Estrone, estradiol and estriol are endogenous human estrogens that are rapidly conjugated with glucuronic acid in both intestinal and hepatic epithelial cells. The resulting glucuronides, estrone-3-glucuronide (E 1 -G), estradiol-3- and 17-glucuronides (E 2 -3G and E 2 -17G), as well as estriol-3- and 16-glucuronides (E 3 -3G and E 3 -16G) are found in human plasma and urine. Unlike E 2 -17G, the efflux transport of other estrogen glucuronides by human transporters has not yet been investigated comprehensively. We have studied the transport of E 1 -G, E 2 -3G, E 3 -3G, E 3 -16G and estrone-3-sulfate (E 1 -S), another important estrogen conjugate, using the vesicular transport assay with recombinant human MRP2, MRP3, MRP4, MDR1 and BCRP that were expressed in insect cells. The transport screening assays revealed that whereas E 1 -S was a good and specific substrate for BCRP, the less transporter-specific conjugates, E 1 -G and E 2 -3G, were still transported by BCRP at 10-fold higher rates than E 1 -S. BCRP also transported E 3 -16G at higher rates than the studied MRPs, while it transported E 3 -3G at lower rates than MRP3. MRP2 exhibited lower or equal transport rates of E 1 -G, E 2 -3G, E 3 -3G and E 3 -16G in comparison to MRP3 and BCRP in the screening assays, mainly due to its high K m values, between 180 and 790 μM. MRP3 transported all the tested glucuronides at rather similar rates, at K m values below 20 μM, but lower V max values than other transporters. In the case of E 3 -3G, MRP3 was the most active transporter in the screening assay. MRP4 transported only E 3 -16G at considerable rates, while none of the tested estrogen conjugates was transported by MDR1 at higher rates than control vesicles. These new results, in combination with previously reported in vivo human data, stimulate our understanding on the substrate specificity and role of efflux transporters in disposition of estrogen glucuronides in humans. Copyright © 2017 Elsevier Ltd. All

Antimicrobial and demelanizing activity of Ganoderma lucidum extract, p-hydroxybenzoic and cinnamic acids and their synthetic acetylated glucuronide methyl esters.

PubMed

Heleno, Sandrina A; Ferreira, Isabel C F R; Esteves, Ana P; Ćirić, Ana; Glamočlija, Jasmina; Martins, Anabela; Soković, Marina; Queiroz, Maria João R P

2013-08-01

Mushroom extracts or isolated compounds may be useful in the search of new potent antimicrobial agents. Herein, it is described the synthesis of protected (acetylated) glucuronide derivatives of p-hydroxybenzoic and cinnamic acids, two compounds identified in the medicinal mushroom Ganoderma lucidum. Their antimicrobial and demelanizing activities were evaluated and compared to the parent acids and G. lucidum extract. p-Hydroxybenzoic and cinnamic acids, as also their protected glucuronide derivatives revealed high antimicrobial (antibacterial and antifungal) activity, even better than the one showed by commercial standards. Despite the variation in the order of parent acids and the protected glucuronide derivatives, their antimicrobial activity was always higher than the one revealed by the extract. Nevertheless, the extract was the only one with demelanizing activity against Aspergillus niger. The acetylated glucuronide derivatives could be deprotected to obtain glucuronide metabolites, which circulate in the human organism as products of the metabolism of the parent compounds. Copyright © 2013 Elsevier Ltd. All rights reserved.

Oral coadministration of β-glucuronidase to increase exposure of extensively glucuronidated drugs that undergo enterohepatic recirculation.

PubMed

Eichenbaum, Gary; Hsu, C-P; Subrahmanyam, Vangala; Chen, Jing; Scicinski, Jan; Galemmo, Robert A; Tuman, Robert W; Johnson, Dana L

2012-07-01

Extensive first-pass metabolism can significantly limit a drug's oral exposure levels. In this work, we introduce an innovative approach for increasing the oral bioavailability of a drug that undergoes extensive reversible glucuronidation and enterohepatic recirculation through intraduodenal coadministration of the deconjugating enzyme β-glucuronidase. Intraduodenal administration of JNJ-10198409 (10 mg/kg) with β-glucuronidase (34,000-140,000 units/kg) to catheterized rats resulted in a significant increase (p < 0.005) in the mean area under the plasma concentration versus time curve (AUC; approx. threefold) and maximum plasma concentration (C(max); approx. twofold) of JNJ-10198409. The AUC and C(max) were 60 ± 18 ng h/mL and 76 ± 29 ng/mL, respectively, with no enzyme and 177 ± 55 ng h/mL and 129 ± 41 ng/mL, respectively, with β-glucuronidase coadministered. Moreover, the AUC of the primary glucuronide metabolite increased approximately sevenfold from 1173 ± 361 (ng h)/mL with no enzyme coadministered to 8723 ± 2133 ng h/mL with coadministered enzyme. These pharmacokinetic data support the hypothesis that when the primary glucuronide is secreted into the duodenum via the bile duct, the glucuronide is converted by β-glucuronidase back to the parent compound. The parent compound is then reabsorbed and reconjugated, resulting in elevated systemic exposures to both parent and glucuronide. Potential clinical and preclinical applications and considerations for this approach are discussed. Copyright © 2012 Wiley Periodicals, Inc.

S-Naproxen and desmethylnaproxen glucuronidation by human liver microsomes and recombinant human UDP-glucuronosyltransferases (UGT): role of UGT2B7 in the elimination of naproxen

PubMed Central

Bowalgaha, Kushari; Elliot, David J; Mackenzie, Peter I; Knights, Kathleen M; Swedmark, Stellan; Miners, John O

2005-01-01

Aims To characterize the kinetics of S-naproxen (‘naproxen’) acyl glucuronidation and desmethylnaproxen acyl and phenolic glucuronidation by human liver microsomes and identify the human UGT isoform(s) catalysing these reactions. Methods Naproxen and desmethylnaproxen glucuronidation were investigated using microsomes from six and five livers, respectively. Human recombinant UGTs were screened for activity towards naproxen and desmethylnaproxen. Where significant activity was observed, kinetic parameters were determined. Naproxen and desmethylnaproxen glucuronides were measured by separate high-performance liquid chromatography methods. Results Naproxen acyl glucuronidation by human liver microsomes followed biphasic kinetics. Mean apparent Km values (±SD, with 95% confidence interval in parentheses) for the high- and low-affinity components were 29 ± 13 µm (16, 43) and 473 ± 108 µm (359, 587), respectively. UGT 1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10 and 2B7 glucuronidated naproxen. UGT2B7 exhibited an apparent Km (72 µm) of the same order as the high-affinity human liver microsomal activity, which was inhibited by the UGT2B7 selective ‘probe’ fluconazole. Although data for desmethylnaproxen phenolic glucuronidation by human liver microsomes were generally adequately fitted to either the single- or two-enzyme Michaelis–Menten equation, model fitting was inconclusive for desmethylnaproxen acyl glucuronidation. UGT 1A1, 1A7, 1A9 and 1A10 catalysed both the phenolic and acyl glucuronidation of desmethylnaproxen, while UGT 1A3, 1A6 and 2B7 formed only the acyl glucuronide. Atypical glucuronidation kinetics were variably observed for naproxen and desmethylnaproxen glucuronidation by the recombinant UGTs. Conclusion UGT2B7 is responsible for human hepatic naproxen acyl glucuronidation, which is the primary elimination pathway for this drug. PMID:16187975

Oral pharmacokinetics of baicalin, wogonoside, oroxylin A 7-O-β-d-glucuronide and their aglycones from an aqueous extract of Scutellariae Radix in the rat.

PubMed

Cai, Yu; Li, Sai; Li, Ting; Zhou, Ruina; Wai, Alfred Tai-Seng; Yan, Ru

2016-07-15

Scutellariae Radix (SR) has been extensively prescribed in folk medicines due to its notable beneficial activities. The flavonoid glucuronides baicalin (BG), wogonoside (WG), oroxylin A 7-O-β-d-glucuronide (OG) and their aglycones baicalein, wogonin and oroxylin A, are the main components of the herb. So far, majority of previous studies failed to report the pharmacokinetics and none offered an explanation for the systemic exposures of these six flavonoids when the herbal extract was orally administered. In this study, when a SR extract was orally dosed to rats (800mg/kg, equivalent to BG 324.80, WG 124.00, OG 43.04, baicalein 25.36, wogonin 24.40, and oroxylin A 5.79mg/kg), all six flavonoids were detectable throughout the experimental period (48h) using an LC-MS/MS method with the Cmax and AUC0-48h of the glucuronides 10-130 times that of respective aglycones. As the lowest among the three glucuronides in the herb, OG was the most abundant in vivo, while the systemic exposure of wogonin was the highest amongst the three aglycones. The dose-normalized AUC0-48h descended in orders of OG/oroxylin A, WG/wogonin and BG/baicalein. Two di-conjugates of baicalein (BG glucuronide and BG glucoside), two BG isomers (minor BM1 and major BM2), and one WG isomer (wogonin 5-O-glucuronide) were detected in rat plasma. Semi-quantitation of the isomers with peak area data revealed that the AUPs (area under peak area ratio-time curves) of BG isomers were ∼3 times that of BG, yet the AUP of wogonin 5-O-glucuronide was only one seventh of WG. BM2, tentatively assigned as baicalein 6-O-glucuronide, was formed from both microbial isomerization of BG and hepatic glucuronidation of baicalein. Wogonin 5-O-glucuronide was only formed in hepatic glucuronidation of wogonin. Demethylated wogonin was observed in gut bacteria, offering an optional origin of BM1 apart from baicalein glucuronidation. Microbial isomerization of BG and extensive hepatic glucuronidation of baicalein to form BM2as

[Studies on ethyl acetate soluble constituents of Huanglian Jiedutang].

PubMed

Ma, Zhao-Tang; Yang, Xiu-Wei

2008-09-01

To study the ethyl acetate soluble constituents from the water extractive of Huanglian Jiedutang decoction, which are composed of Rhizoma Coptidis, Radix Scutellariae, Cortex Phellodendri and Fructus Gardeniae, and provide substances foundation for its pharmacokinetic and pharmacodynamic investigation. The chemical constituents were isolated by various column chromatographic methods and structurally elucidated by NMR and MS techniques. Thirty-five compounds were isolated, among which twenty compounds have been identified as beta-sitosterol (1), oroxylin A (2), wogonin (3), ursolic acid (4), skullcapflavone I (5), tenaxin I (6), skullcapflavone II (7), limonin (8), 5, 2'-dihydroxy-6, 7, 8, 3'-tetramethoxyflavone (9), chrysin (12), baicalein (17), tenaxin II (19), 5, 7, 2'-trihydroxy-6, 8-dimethoxyflavone (21), shihulimonin A (22), 6, 2'-dihydroxy-5, 7, 8, 6'-tetramethoxyflavone (26), viscidulin II (28), 5, 7, 4'-trihydroxy-8-methoxyflavone (29), 5, 7, 2', 6'-tetrahydroxyflavone (30), wogonin-7-O-beta-D-glucuronide methyl ester (31) and daucosterol (34). On the basis of reported results of the chemical constituents of Rhizoma Coptidis, Radix Scutellariae, Cortex Phellodendri and Fructus Gardeniae, it was estimated that all flavonoid compounds rised from the Radix Scutellariae, and compounds 8 and 22 rised from Cortex Phellodendri. Compound 22 was identified in the Cortex Phellodendri for the first time.

UGT1A and UGT2B genetic variation alters nicotine and nitrosamine glucuronidation in european and african american smokers.

PubMed

Wassenaar, Catherine A; Conti, David V; Das, Soma; Chen, Peixian; Cook, Edwin H; Ratain, Mark J; Benowitz, Neal L; Tyndale, Rachel F

2015-01-01

Identifying sources of variation in the nicotine and nitrosamine metabolic inactivation pathways is important to understanding the relationship between smoking and cancer risk. Numerous UGT1A and UGT2B enzymes are implicated in nicotine and nitrosamine metabolism in vitro; however, little is known about their roles in vivo. Within UGT1A1, UGT1A4, UGT1A9, UGT2B7, UGT2B10, and UGT2B17, 47 variants were genotyped, including UGT2B10*2 and UGT2B17*2. The association between variation in these UGTs and glucuronidation activity within European and African American current smokers (n = 128), quantified as urinary ratios of the glucuronide over unconjugated compound for nicotine, cotinine, trans-3'-hydroxycotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), was investigated in regression models assuming a dominant effect of variant alleles. Correcting for multiple testing, three UGT2B10 variants were associated with cotinine glucuronidation, rs2331559 and rs11726322 in European Americans and rs835309 in African Americans (P ≤ 0.0002). Additional variants predominantly in UGT2B10 were nominally associated with nicotine (P = 0.008-0.04) and cotinine (P = <0.001-0.02) glucuronidation in both ethnicities in addition to UGT2B10*2 in European Americans (P = 0.01, P < 0.001). UGT2B17*2 (P = 0.03) in European Americans and UGT2B7 variants (P = 0.02-0.04) in African Americans were nominally associated with 3HC glucuronidation. UGT1A (P = 0.007-0.01), UGT2B10 (P = 0.02), and UGT2B7 (P = 0.02-0.03) variants in African Americans were nominally associated with NNAL glucuronidation. Findings from this initial in vivo study support a role for multiple UGTs in the glucuronidation of tobacco-related compounds in vivo, in particular UGT2B10 and cotinine glucuronidation. Findings also provide insight into ethnic differences in glucuronidation activity, which could be contributing to ethnic disparities in the risk for smoking-related cancers. Cancer Epidemiol Biomarkers Prev

Expression of β-glucuronidase on the surface of bacteria enhances activation of glucuronide prodrugs.

PubMed

Cheng, C-M; Chen, F M; Lu, Y-L; Tzou, S-C; Wang, J-Y; Kao, C-H; Liao, K-W; Cheng, T-C; Chuang, C-H; Chen, B-M; Roffler, S; Cheng, T-L

2013-05-01

Extracellular activation of hydrophilic glucuronide prodrugs by β-glucuronidase (βG) was examined to increase the therapeutic efficacy of bacteria-directed enzyme prodrug therapy (BDEPT). βG was expressed on the surface of Escherichia coli by fusion to either the bacterial autotransporter protein Adhesin (membrane βG (mβG)/AIDA) or the lipoprotein (lpp) outermembrane protein A (mβG/lpp). Both mβG/AIDA and mβG/lpp were expressed on the bacterial surface, but only mβG/AIDA displayed enzymatic activity. The rate of substrate hydrolysis by mβG/AIDA-BL21cells was 2.6-fold greater than by pβG-BL21 cells, which express periplasmic βG. Human colon cancer HCT116 cells that were incubated with mβG/AIDA-BL21 bacteria were sensitive to a glucuronide prodrug (p-hydroxy aniline mustard β-D-glucuronide, HAMG) with an half maximal inhibitory concentration (IC50) value of 226.53±45.4 μM, similar to the IC50 value of the active drug (p-hydroxy aniline mustard, pHAM; 70.6±6.75 μM), indicating that mβG/AIDA on BL21 bacteria could rapidly and efficiently convert HAMG to an active anticancer agent. These results suggest that surface display of functional βG on bacteria can enhance the hydrolysis of glucuronide prodrugs and may increase the effectiveness of BDEPT.

The effects of alcohol-containing e-cigarettes on young adult smokers.

PubMed

Valentine, Gerald W; Jatlow, Peter I; Coffman, Marcedes; Nadim, Haleh; Gueorguieva, Ralitza; Sofuoglu, Mehmet

2016-02-01

The liquids (e-liquids) used in an electronic cigarette (e-cigarette) contain myriad chemicals without adequate human inhalation safety data. Furthermore, the absence of e-liquid labeling requirements poses a formidable challenge to understanding how e-liquid constituents may promote nicotine addiction and/or have independent or synergistic biological effects when combined with nicotine. Ethyl alcohol is such a constituent, but has received little scientific interest in this context. Using a randomized, double blind, crossover design, acute changes in subjective drug effects, motor performance and biochemical measures of alcohol and nicotine intake were evaluated after directed and ad lib puffing from two commercially available e-liquids containing nicotine (8 mg/ml), vanilla flavor and either 23.5% (high) or 0.4% (trace) alcohol. While no differences in subjective drug effects were observed between alcohol conditions, performance on the Purdue Pegboard Dexterity Test (PPDT) improved under the trace, but not under the 23.5% alcohol condition. Although plasma alcohol levels remained undetectable during testing, urine ethyl glucuronide (EtG), an alcohol metabolite, became measurable in three participants after puffing from the 23.5% alcohol e-cigarette. Brief use of a widely available type of e-cigarette containing an e-liquid purchased from an internet vendor can negatively impact psychomotor performance and in some instances, produce detectable levels of a urine alcohol metabolite. Given the widespread and unregulated use of e-cigarettes, especially by youth and other vulnerable populations, further studies are needed to evaluate both the acute safety and long-term health risks of using alcohol-containing e-cigarettes. Published by Elsevier Ireland Ltd.

Novel Strip Test for Circulating Hormones

DTIC Science & Technology

1996-10-01

estrone- 3 -glucuronide was combined with 1 equivalent of 4-amino-benzo-15-crown-5 and 1.2 equivalents of 1 -ethyl- 3 -( 3 - dimethylaminopropyl )carbodiimide...solution containing 5 mg/ml of El-g and 10 mg/ml of 1 -ethyl- 3 -( 3 -dimethylamino-propyl)carbodiimide (EDC) in water at pH 4.2. Fibers are then rinsed with... hydrochloride in water at pH 4.0. The mixture was stirred at room temperature for 48 hours and the resulting estrone- 3 -glucuronide-4-amino-benzo-15-crown

Identification of UDP-glucuronosyltransferases 1A1, 1A3 and 2B15 as the main contributors to glucuronidation of bakuchiol, a natural biologically active compound.

PubMed

Li, Feng; Wang, Shuai; Lu, Danyi; Wang, Yifei; Dong, Dong; Wu, Baojian

2017-05-01

1. Bakuchiol, one of the main active compounds of Psoralea corylifolia, possesses a variety of pharmacological activities such as anti-tumor and anti-aging effects. Here, we aimed to characterize the glucuronidation of bakuchiol using human liver microsomes (HLM) and expressed UDP-glucuronosyltransferase (UGT) enzymes. 2. The glucuronide of bakuchiol was confirmed by liquid chromatography-mass spectrometry (LC-MS) and β-glucuronidase hydrolysis assay. Glucuronidation rates and kinetic parameters were derived by enzymatic incubation and model fitting. Activity correlation analyses were performed to identify the main UGT isoforms contributing to hepatic metabolism of bakuchiol. 3. Among the three UGT enzymes (i.e., UGT1A1, UGT1A3 and UGT2B15) capable of catalyzing bakuchiol glucuronidation, UGT2B15 showed the highest activity with a CL int value of 100 μl/min/nmol. Bakuchiol glucuronidation was strongly correlated with glucuronidation of 5-hydroxyrofecoxib (r = 0.933; p < 0.001), 3-O-glucuronidation of β-estradiol (r = 0.719; p < 0.01) and significantly correlated with 24-O-glucuronidation of CDCA (r = 0.594; p < 0.05). In addition, a marked species difference existed in hepatic glucuronidation of bakuchiol. 4. In conclusion, UGT1A1, UGT1A3 and UGT2B15 were identified as the main contributors to glucuronidation of bakuchiol.

In vitro Inhibitory Effects of Andrographis paniculata, Gynura procumbens, Ficus deltoidea, and Curcuma xanthorrhiza Extracts and Constituents on Human Liver Glucuronidation Activity.

PubMed

Husni, Zulhilmi; Ismail, Sabariah; Zulkiffli, Mohd Halimhilmi; Afandi, Atiqah; Haron, Munirah

2017-07-01

Andrographis paniculata , Gynura procumbens , Ficus deltoidea and Curcuma xanthorrhiza are commonly consumed as herbal medicines. However their effects on human liver glucuronidation activity are not yet evaluated. In this study, we evaluate the inhibitory Effects of Andrographis paniculata, Gynura procumbens, Ficus deltoidea and Curcuma xanthorrhiza extracts and their constituents on human liver glucuronidation activity. Herbal extracts (aqueous, methanolic and ethanolic extracts) and their constituents were incubated with human liver microsomes with the addition of UDPGA to initiate the reaction. Working concentrations of herbal extracts and their constituents ranged from 10 μg/mL to 1000 μg/mL and 10 μM to 300 μM respectively. IC50 was determined by monitoring the decrement of glucuronidation activity with the increment of herbal extracts or phytochemical constituent's concentrations. All herbal extracts inhibited human liver glucuronidation activity in range of 34.69 μg/mL to 398.10 μg/mL whereas for the constituents, only xanthorrhizol and curcumin (constituents of Curcuma xanthorrhiza ) inhibited human liver glucuronidation activity with IC50 of 538.50 and 32.26 μM respectively. In the present study, we have proved the capabilities of Andrographis paniculata , Gynura procumbens , Ficus deltoidea and Curcuma xanthorrhiza to interfere with in vitro glucuronidation process in human liver microsomes. This study documented the capabilities of Andrographis paniculata , Gynura procumbens , Ficus deltoidea and Curcuma xanthorrhiza to inhibit human liver glucuronidation activity which may affect the metabolism of therapeutic drugs or hazardous toxicants that follow the same glucuronidation pathway. Abbreviations used: UGT: Uridine 5'-diphospho-glucuronosyltransferase; 4-MU: 4-methylumbelliferone; IC50: Half Maximal Inhibitory Concentration; Km: Michaelis constant; Vmax: Maximum velocity.

Differences in the Glucuronidation of Resveratrol and Pterostilbene: Altered Enzyme Specificity and Potential Gender Differences

PubMed Central

Dellinger, Ryan W.; Gomez Garcia, Angela M.; Meyskens, Frank L.

2015-01-01

Summary Resveratrol, a natural polyphenol found in grapes, berries and other plants, has been proposed as an ideal chemopreventative agent due to its plethora of health promoting activities. However, despite its lofty promise as a cancer prevention agent its success in human clinical trials has been limited due to its poor bioavailability. Thus, interest in other natural polyphenols is intensifying including the naturally occurring dimethylated analog of resveratrol, pterostilbene. The UDP-glucuronosyltransferase (UGT) family of enzymes plays a vital role in the metabolism of both resveratrol and pterostilbene. The current study sought to elucidate the UGT family members responsible for the metabolism of pterostilbene and to examine gender differences in the glucuronidation of resveratrol and pterostilbene. We demonstrate that UGT1A1 and UGT1A3 are mainly responsible for pterostilbene glucuronidation although UGT1A8, UGT1A9 and UGT1A10 also had detectable activity. Intriguingly, UGT1A1 exhibits the highest activity against both resveratrol and pterostilbene despite altered hydroxyl group specificity. Using pooled human liver microsomes, enzyme kinetics were determined for pterostilbene and resveratrol glucuronides. In all cases females were more efficient than males, indicating potential gender differences in stilbene metabolism. Importantly, the glucuronidation of pterostilbene is much less efficient than that of resveratrol, indicating that pterostilbene will have dramatically decreased metabolism in humans. PMID:23965644

Transport of estradiol-17β-glucuronide, estrone-3-sulfate and taurocholate across the endoplasmic reticulum membrane: evidence for different transport systems☆

PubMed Central

Wlcek, Katrin; Hofstetter, Lia; Stieger, Bruno

2014-01-01

Important reactions of drug metabolism, including UGT mediated glucuronidation and steroidsulfatase mediated hydrolysis of sulfates, take place in the endoplasmic reticulum (ER) of hepatocytes. Consequently, UGT generated glucuronides, like estradiol-17β-glucuronide, have to be translocated back into the cytoplasm to reach their site of excretion. Also steroidsulfatase substrates, including estrone-3-sulfate, have to cross the ER membrane to reach their site of hydrolysis. Based on their physicochemical properties such compounds are not favored for passive diffusion and therefore likely necessitate transport system(s) to cross the ER membrane in either direction. The current study aims to investigate the transport of taurocholate, estradiol-17β-glucuronide, and estrone-3-sulfate in smooth (SER) and rough (RER) endoplasmic reticulum membrane vesicles isolated from Wistar and TR− rat liver. Time-dependent and bidirectional transport was demonstrated for taurocholate, showing higher uptake rates in SER than RER vesicles. For estradiol-17β-glucuronide a fast time-dependent efflux with similar efficiencies from SER and RER but no clear protein-mediated uptake was shown, indicating an asymmetric transport system for this substrate. Estrone-3-sulfate uptake was time-dependent and higher in SER than in RER vesicles. Inhibition of steroidsulfatase mediated estrone-3-sulfate hydrolysis decreased estrone-3-sulfate uptake but had no effect on taurocholate or estradiol-17β-glucuronide transport. Based on inhibition studies and transport characteristics, three different transport mechanisms are suggested to be involved in the transport of taurocholate, estrone-3-sulfate and estradiol-17β-glucuronide across the ER membrane. PMID:24406246

Overestimation of Flavonoid Aglycones as a Result of the ex vivo Deconjugation of Glucuronides by the Tissue β-Glucuronidase

PubMed Central

Lu, Qing-Yi; Zhang, Lifeng; Eibl, Guido; Go, Vay-Liang W.

2013-01-01

Flavonoid glucuronides are the main circulating metabolites of flavonoids in humans and animals. There has been a growing interest in the biological function of glucuronides. In order to differentiate biological activity and to assess efficacy it is essential to accurately determine the levels of flavonoid aglycone and metabolic conjugate in vivo. Many organs and body fluids of humans and animals exhibit β-glucuronidase against flavonoid glucuronides. Studies have shown that β-glucuronidase within the tissues hydrolyzes glucuronides to their aglycones during the tissue extraction, leading to artificially higher reported tissue levels of aglycone than actual in vivo concentrations. The aims of this study were to estimate the extent by which the aglycones were overestimated and to investigate the use of saccharo-1,4-lactone, a β-glucuronidase inhibitor, to block the ex vivo hydrolysis of flavonoid glucuronides. Our data demonstrate that in mouse liver tissues and human tumor xenografts levels of quercetin and methylated quercetin aglycones could be over-estimated by 7 fold. The inhibition of deconjugation of quercetin and baicalein glucuronides by saccharo-1,4-lactone is dose-dependent. The amount of saccharo-1,4-lactone used to produce optimal inhibition of the enzyme activity is in the range of 15 – 24 μmol per gram of liver tissue. The use of β-glucuronidase inhibitor blocks the ex vivo deconjugation resulting in an accurate estimation of tissue levels of aglycone and conjugate. Our study described here can be extended to other animal models and human studies with different types of substrates of β-glucuronidase. PMID:24176739

Identification of Recent Cannabis Use: Whole-Blood and Plasma Free and Glucuronidated Cannabinoid Pharmacokinetics following Controlled Smoked Cannabis Administration

PubMed Central

Schwope, David M.; Karschner, Erin L.; Gorelick, David A.; Huestis, Marilyn A.

2013-01-01

BACKGROUND Δ9-Tetrahydrocannabinol (THC) is the most frequently observed illicit drug in investigations of accidents and driving under the influence of drugs. THC-glucuronide has been suggested as a marker of recent cannabis use, but there are no blood data following controlled THC administration to test this hypothesis. Furthermore, there are no studies directly examining whole-blood cannabinoid pharmacokinetics, although this matrix is often the only available specimen. METHODS Participants (9 men, 1 woman) resided on a closed research unit and smoked one 6.8% THC cannabis cigarette ad libitum. We quantified THC, 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol (CBD), cannabinol (CBN), THC-glucuronide and THCCOOH-glucuronide directly in whole blood and plasma by liquid chromatography/ tandem mass spectrometry within 24 h of collection to obviate stability issues. RESULTS Median whole blood (plasma) observed maximum concentrations (Cmax) were 50 (76), 6.4 (10), 41 (67), 1.3 (2.0), 2.4 (3.6), 89 (190), and 0.7 (1.4) μg/L 0.25 h after starting smoking for THC, 11-OH-THC, THCCOOH, CBD, CBN, and THCCOOH-glucuronide, respectively, and 0.5 h for THC-glucuronide. At observed Cmax, whole-blood (plasma) detection rates were 60% (80%), 80% (90%), and 50% (80%) for CBD, CBN, and THC-glucuronide, respectively. CBD and CBN were not detectable after 1 h in either matrix (LOQ 1.0 μg/L). CONCLUSIONS Human whole-blood cannabinoid data following cannabis smoking will assist whole blood and plasma cannabinoid interpretation, while furthering identification of recent cannabis intake. PMID:21836075

Transcriptome association analysis identifies miR-375 as a major determinant of variable acetaminophen glucuronidation by human liver.

PubMed

Papageorgiou, Ioannis; Freytsis, Marina; Court, Michael H

2016-10-01

Acetaminophen is the leading cause of acute liver failure (ALF) in many countries including the United States. Hepatic glucuronidation by UDP-glucuronosyltransferase (UGT) 1A subfamily enzymes is the major route of acetaminophen elimination. Reduced glucuronidation may predispose some individuals to acetaminophen-induced ALF, but mechanisms underlying reduced glucuronidation are poorly understood. We hypothesized that specific microRNAs (miRNAs) may reduce UGT1A activity by direct effects on the UGT1A 3'-UTR shared by all UGT1A enzyme transcripts, or by indirect effects on transcription factors regulating UGT1A expression. We performed an unbiased miRNA whole transcriptome association analysis using a bank of human livers with known acetaminophen glucuronidation activities. Of 754 miRNAs evaluated, 9 miRNAs were identified that were significantly overexpressed (p<0.05; >2-fold) in livers with low acetaminophen glucuronidation activities compared with those with high activities. miR-375 showed the highest difference (>10-fold), and was chosen for further mechanistic validation. We demonstrated using in silico analysis and luciferase reporter assays that miR-375 has a unique functional binding site in the 3'-UTR of the aryl hydrocarbon receptor (AhR) gene. Furthermore overexpression of miR-375 in LS180 cells demonstrated significant repression of endogenous AhR protein (by 40%) and mRNA (by 10%), as well as enzyme activity and/or mRNA of AhR regulated enzymes including UGT1A1, UGT1A6, and CYP1A2, without affecting UGT2B7, which is not regulated by AhR. Thus miR-375 is identified as a novel repressor of UGT1A-mediated hepatic acetaminophen glucuronidation through reduced AhR expression, which could predispose some individuals to increased risk for acetaminophen-induced ALF. Published by Elsevier Inc.

In vitro Inhibitory Effects of Andrographis paniculata, Gynura procumbens, Ficus deltoidea, and Curcuma xanthorrhiza Extracts and Constituents on Human Liver Glucuronidation Activity

PubMed Central

Husni, Zulhilmi; Ismail, Sabariah; Zulkiffli, Mohd Halimhilmi; Afandi, Atiqah; Haron, Munirah

2017-01-01

Background: Andrographis paniculata, Gynura procumbens, Ficus deltoidea and Curcuma xanthorrhiza are commonly consumed as herbal medicines. However their effects on human liver glucuronidation activity are not yet evaluated. Objective: In this study, we evaluate the inhibitory Effects of Andrographis paniculata, Gynura procumbens, Ficus deltoidea and Curcuma xanthorrhiza extracts and their constituents on human liver glucuronidation activity. Materials and Methods: Herbal extracts (aqueous, methanolic and ethanolic extracts) and their constituents were incubated with human liver microsomes with the addition of UDPGA to initiate the reaction. Working concentrations of herbal extracts and their constituents ranged from 10 μg/mL to 1000 μg/mL and 10 μM to 300 μM respectively. IC50 was determined by monitoring the decrement of glucuronidation activity with the increment of herbal extracts or phytochemical constituent's concentrations. Results: All herbal extracts inhibited human liver glucuronidation activity in range of 34.69 μg/mL to 398.10 μg/mL whereas for the constituents, only xanthorrhizol and curcumin (constituents of Curcuma xanthorrhiza) inhibited human liver glucuronidation activity with IC50 of 538.50 and 32.26 μM respectively. Conclusion: In the present study, we have proved the capabilities of Andrographis paniculata, Gynura procumbens, Ficus deltoidea and Curcuma xanthorrhiza to interfere with in vitro glucuronidation process in human liver microsomes. SUMMARY This study documented the capabilities of Andrographis paniculata, Gynura procumbens, Ficus deltoidea and Curcuma xanthorrhiza to inhibit human liver glucuronidation activity which may affect the metabolism of therapeutic drugs or hazardous toxicants that follow the same glucuronidation pathway. Abbreviations used: UGT: Uridine 5’-diphospho-glucuronosyltransferase; 4-MU: 4-methylumbelliferone; IC50: Half Maximal Inhibitory Concentration; Km: Michaelis constant; Vmax: Maximum velocity. PMID

Direct detection of boldenone sulfate and glucuronide conjugates in horse urine by ion trap liquid chromatography-mass spectrometry.

PubMed

Pu, Fan; McKinney, Andrew R; Stenhouse, Allen M; Suann, Craig J; McLeod, Malcolm D

2004-12-25

A study of the equine phase II metabolism of the anabolic agent boldenone is reported. Boldenone sulfate, boldenone glucuronide and their C17-epimers were synthesised as reference standards in our lab and a method was developed for their detection in a horse urine matrix. Solid phase extraction was used to purify the analytes, which were then detected by ion trap LC/MS. Negative and positive ionisation mode MS(2) were used for the detection of sulfate and glucuronide conjugates, respectively. Boldenone sulfate and 17-epiboldenone glucuronide were detected as the major and minor phase II metabolites, respectively, in horse urine samples collected following the administration of boldenone undecylenate by intramuscular injection.

Transport of estradiol-17β-glucuronide, estrone-3-sulfate and taurocholate across the endoplasmic reticulum membrane: evidence for different transport systems.

PubMed

Wlcek, Katrin; Hofstetter, Lia; Stieger, Bruno

2014-03-01

Important reactions of drug metabolism, including UGT mediated glucuronidation and steroidsulfatase mediated hydrolysis of sulfates, take place in the endoplasmic reticulum (ER) of hepatocytes. Consequently, UGT generated glucuronides, like estradiol-17β-glucuronide, have to be translocated back into the cytoplasm to reach their site of excretion. Also steroidsulfatase substrates, including estrone-3-sulfate, have to cross the ER membrane to reach their site of hydrolysis. Based on their physicochemical properties such compounds are not favored for passive diffusion and therefore likely necessitate transport system(s) to cross the ER membrane in either direction. The current study aims to investigate the transport of taurocholate, estradiol-17β-glucuronide, and estrone-3-sulfate in smooth (SER) and rough (RER) endoplasmic reticulum membrane vesicles isolated from Wistar and TR(-) rat liver. Time-dependent and bidirectional transport was demonstrated for taurocholate, showing higher uptake rates in SER than RER vesicles. For estradiol-17β-glucuronide a fast time-dependent efflux with similar efficiencies from SER and RER but no clear protein-mediated uptake was shown, indicating an asymmetric transport system for this substrate. Estrone-3-sulfate uptake was time-dependent and higher in SER than in RER vesicles. Inhibition of steroidsulfatase mediated estrone-3-sulfate hydrolysis decreased estrone-3-sulfate uptake but had no effect on taurocholate or estradiol-17β-glucuronide transport. Based on inhibition studies and transport characteristics, three different transport mechanisms are suggested to be involved in the transport of taurocholate, estrone-3-sulfate and estradiol-17β-glucuronide across the ER membrane. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Overestimation of flavonoid aglycones as a result of the ex vivo deconjugation of glucuronides by the tissue β-glucuronidase.

PubMed

Lu, Qing-Yi; Zhang, Lifeng; Eibl, Guido; Go, Vay Liang W

2014-01-01

Flavonoid glucuronides are the main circulating metabolites of flavonoids in humans and animals. There has been a growing interest in the biological function of glucuronides. In order to differentiate biological activity and to assess efficacy it is essential to accurately determine the levels of flavonoid aglycone and metabolic conjugate in vivo. Many organs and body fluids of humans and animals exhibit β-glucuronidase against flavonoid glucuronides. Studies have shown that β-glucuronidase within the tissues hydrolyzes glucuronides to their aglycones during the tissue extraction, leading to artificially higher reported tissue levels of aglycone than actual in vivo concentrations. The aims of this study were to estimate the extent by which the aglycones were overestimated and to investigate the use of saccharo-1,4-lactone, a β-glucuronidase inhibitor, to block the ex vivo hydrolysis of flavonoid glucuronides. Our data demonstrate that in mouse liver tissues and human tumor xenografts levels of quercetin and methylated quercetin aglycones could be over-estimated by 7-fold. The inhibition of deconjugation of quercetin and baicalein glucuronides by saccharo-1,4-lactone is dose-dependent. The amount of saccharo-1,4-lactone used to produce optimal inhibition of the enzyme activity is in the range of 15-24μmol per gram of liver tissue. The use of β-glucuronidase inhibitor blocks the ex vivo deconjugation resulting in an accurate estimation of tissue levels of aglycone and conjugate. Our study described here can be extended to other animal models and human studies with different types of substrates of β-glucuronidase. Copyright © 2013 Elsevier B.V. All rights reserved.

Establishment and Use of New MDCK II Cells Overexpressing Both UGT1A1 and MRP2 to Characterize Flavonoid Metabolism via the Glucuronidation Pathway

PubMed Central

Wang, Meifang; Yang, Guangyi; He, Yu; Xu, Beibei; Zeng, Min; Yin, Taijun; Gao, Song; Hu, Ming

2017-01-01

Scope The purpose of this study is to characterize how overexpression of an efflux transporter and an UDP-glucuronosyltransferase (UGT) affects the cellular kinetics of glucuronidation processes. Methods and Results A new MDCK II cell line overexpressing both MRP2 and UGT1A1 (MDCKII-UGT1A1/MRP2 cells) was developed and used to determine how overexpression of an efflux transporter affects the kinetics of cellular flavonoid glucuronide production. The results showed that most model flavonoids (from a total of 13) were mainly metabolized into glucuronides in the MDCKII-UGT1A1/MRP2 cells and the glucuronides were rapidly excreted. Flavonoids with three or fewer hydroxyl group at 7, 3′ or 6 hydroxyl group were also metabolized into sulfates. Mechanistic studies using 7-hydroxylflavone showed that its glucuronide was mainly (90%) effluxed by BCRP with a small (10%) but significant contribution from MRP2. Maximal velocity of glucuronide production MDCK-MRP2/UGT1A1 cells showed a fairly good correlation (R2 >0.8) with those derived using UGT1A1 microsomes, but other kinetic parameters (e.g., Km) did not correlate. Conclusion Overexpression of a second efficient efflux transporter did not significantly change the fact that BCRP is the dominant transporter for flavonoid glucuronide nor did it diminish the influence of the efflux transporter as the “gate keeper” of glucuronidation process. PMID:26833852

Identification of Human UDP-Glucuronosyltransferase 1A4 as the Major Isozyme Responsible for the Glucuronidation of 20(S)-Protopanaxadiol in Human Liver Microsomes

PubMed Central

Li, Jia; He, Chunyong; Fang, Lianxiang; Yang, Li; Wang, Zhengtao

2016-01-01

20(S)-protopanaxadiol (PPD), one of the representative aglycones of ginsenosides, has a broad spectrum of pharmacological activities. Although phase I metabolism has been investigated extensively, information regarding phase II metabolism of this compound remains to be elucidated. Here, a glucuronidated metabolite of PPD in human liver microsomes (HLMs) and rat liver microsomes (RLMs) was unambiguously identified as PPD-3-O-β-d-glucuronide by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry. The chemical inhibition and recombinant human UDP-Glucuronosyltransferase (UGT) isoforms assay showed that the PPD glucuronidation was mainly catalyzed by UGT1A4 in HLM, whereas UGT1A3 showed weak catalytic activity. In conclusion, PPD-3-O-β-d-glucuronide was first identified as the principal glucuronidation metabolite of PPD in HLMs, which was catalyzed by UGT1A4. PMID:27005621

Species differences in the formation of vabicaserin carbamoyl glucuronide.

PubMed

Tong, Zeen; Chandrasekaran, Appavu; DeMaio, William; Jordan, Ronald; Li, Hongshan; Moore, Robin; Poola, Nagaraju; Burghart, Peter; Hultin, Theresa; Scatina, JoAnn

2010-04-01

Vabicaserin is a potent 5-hydroxtryptamine 2C full agonist with therapeutic potential for a wide array of psychiatric disorders. Metabolite profiles indicated that vabicaserin was extensively metabolized via carbamoyl glucuronidation after oral administration in humans. In the present study, the differences in the extent of vabicaserin carbamoyl glucuronide (CG) formation in humans and in animals used for safety assessment were investigated. After oral dosing, the systemic exposure ratios of CG to vabicaserin were approximately 12 and up to 29 in monkeys and humans, respectively, and the ratios of CG to vabicaserin were approximately 1.5 and 1.7 in mice and dogs, respectively. These differences in systemic levels of CG are likely related to species differences in the rate and extent of CG formation and elimination. Whereas CG was the predominant circulating metabolite in humans and a major metabolite in mice, dogs, and monkeys, it was a relatively minor metabolite in rats, in which oxidative metabolism was the major metabolic pathway. Although the CG was not detected in plasma or urine of rats, approximately 5% of the dose was excreted in bile as CG in the 24-h collection postdose, indicating the rat had the metabolic capability of producing the CG. In vitro, in a CO(2)-enriched environment, the CG was the predominant metabolite in dog and human liver microsomes, a major metabolite in monkey and mice, and only a very minor metabolite in rats. Carbamoyl glucuronidation and hydroxylation had similar contributions to vabicaserin metabolism in mouse and monkey liver microsomes. However, only trace amounts of CG were formed in rat liver microsomes, and other metabolites were more prominent than the CG. In conclusion, significant differences in the extent of formation of the CG were observed among the various species examined. The exposure ratios of CG to vabicaserin were highest in humans, followed by monkeys, then mice and dogs, and lowest in rats, and the in vitro

40 CFR 721.10595 - Octadecen-1-aminium, N-ethyl-N,N-dimethy-, ethyl sulfate (1:1).

Code of Federal Regulations, 2013 CFR

2013-07-01

...-dimethy-, ethyl sulfate (1:1). 721.10595 Section 721.10595 Protection of Environment ENVIRONMENTAL...-, ethyl sulfate (1:1). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as octadecen-1-aminium, N-ethyl-N,N-dimethy-, ethyl sulfate (1:1) (PMN P-11...

40 CFR 721.10595 - Octadecen-1-aminium, N-ethyl-N,N-dimethy-, ethyl sulfate (1:1).

Code of Federal Regulations, 2014 CFR

2014-07-01

...-dimethy-, ethyl sulfate (1:1). 721.10595 Section 721.10595 Protection of Environment ENVIRONMENTAL...-, ethyl sulfate (1:1). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as octadecen-1-aminium, N-ethyl-N,N-dimethy-, ethyl sulfate (1:1) (PMN P-11...

5α-Androst-16-en-3α-ol β-D-glucuronide, precursor of 5α-androst-16-en-3α-ol in human sweat.

PubMed

Starkenmann, Christian; Mayenzet, Fabienne; Brauchli, Robert; Troccaz, Myriam

2013-12-01

5α-Androst-16-en-3α-ol (α-androstenol) is an important contributor to human axilla sweat odor. It is assumed that α-andostenol is excreted from the apocrine glands via a H2 O-soluble conjugate, and this precursor was formally characterized in this study for the first time in human sweat. The possible H2 O-soluble precursors, sulfate and glucuronide derivatives, were synthesized as analytical standards, i.e., α-androstenol, β-androstenol sulfates, 5α-androsta-5,16-dien-3β-ol (β-androstadienol) sulfate, α-androstenol β-glucuronide, α-androstenol α-glucuronide, β-androstadienol β-glucuronide, and α-androstenol β-glucuronide furanose. The occurrence of α-androstenol β-glucuronide was established by ultra performance liquid chromatography (UPLC)/MS (heated electrospray ionization (HESI)) in negative-ion mode in pooled human sweat, containing eccrine and apocrine secretions and collected from 25 female and 24 male underarms. Its concentration was of 79 ng/ml in female secretions and 241 ng/ml in male secretions. The release of α-androstenol was observed after incubation of the sterile human sweat or α-androstenol β-glucuronide with a commercial glucuronidase enzyme, the urine-isolated bacteria Streptococcus agalactiae, and the skin bacteria Staphylococcus warneri DSM 20316, Staphylococcus haemolyticus DSM 20263, and Propionibacterium acnes ATCC 6919, reported to have β-glucuronidase activities. We demonstrated that if α- and β-androstenols and androstadienol sulfates were present in human sweat, their concentrations would be too low to be considered as potential precursors of malodors; therefore, the H2 O-soluble precursor of α-androstenol in apocrine secretion should be a β-glucuronide. Copyright © 2013 Verlag Helvetica Chimica Acta AG, Zürich.

Bisphenol A glucuronidation in patients with Parkinson's disease.

PubMed

Landolfi, Annamaria; Troisi, Jacopo; Savanelli, Maria Cristina; Vitale, Carmine; Barone, Paolo; Amboni, Marianna

2017-12-01

Bisphenol A (BPA) is a widely distributed estrogen-mimetic molecule, with well-established effects on the dopaminergic system. It can be found in canned food, dental sealants, thermal paper, etc. BPA undergoes liver conjugation with glucuronic acid and is subsequently excreted in the urine. In the present study we quantified the concentration of free and conjugated Bisphenol A in blood of patients affected by Parkinson Disease, using their spouses as controls. An interview was performed to determine possible confounders in BPA exposure. Free and conjugated BPA were quantified by gas chromatography coupled with mass spectrometry. Parkinson's Disease patients carried a statistically significant lower amount of conjugated Bisphenol A compared to controls. The two populations were mostly homogeneous in terms of exposure to possible Bisphenol A sources. The only exceptions were exposure to canned tuna and canned tomatoes PD patients consumed significantly more of both (p<0.05). Moreover, no difference in Bisphenol A glucuronidation was found after stratification by typology of anti-Parkinson's drug taken and after conversion to the Levodopa Equivalent Daily Dose. BPA glucuronidation was decreased in patients with Parkinson disease. The possible unique mechanisms underlying Bisphenol A metabolism in PD patients deserve further elucidation. Moreover, further study is needed to assess a possible BPA role in Parkinson's Disease pathogenesis, due to its documented dopaminergic toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Analysis of intact glucuronides and sulfates of serotonin, dopamine, and their phase I metabolites in rat brain microdialysates by liquid chromatography-tandem mass spectrometry.

PubMed

Uutela, Päivi; Reinilä, Ruut; Harju, Kirsi; Piepponen, Petteri; Ketola, Raimo A; Kostiainen, Risto

2009-10-15

A method for the analysis of intact glucuronides and sulfates of common neurotransmitters serotonin (5-HT) and dopamine (DA) as well as of 5-hydroxy-3-indoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in rat brain microdialysates by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. Enzyme-assisted synthesis using rat liver microsomes as a biocatalyst was employed for the production of 5-HT-, 5-HIAA-, DOPAC-, and HVA-glucuronides for reference compounds. The sulfate conjugates were synthesized either chemically or enzymatically using a rat liver S9 fraction. The LC-MS/MS method was validated by determining the limits of detection and quantitation, linearity, and repeatability for the quantitative analysis of 5-HT and DA and their glucuronides, as well as of 5-HIAA, DOPAC, and HVA and their sulfate-conjugates. In this study, 5-HT-glucuronide was for the first time detected in rat brain. The concentration of 5-HT-glucuronide (1.0-1.7 nM) was up to 2.5 times higher than that of free 5-HT (0.4-2.1 nM) in rat brain microdialysates, whereas the concentration of DA-glucuronide (1.0-1.4 nM) was at the same level or lower than the free DA (1.2-2.4 nM). The acidic metabolites of neurotransmitters, 5-HIAA, HVA, and DOPAC, were found in free and sulfated form, whereas their glucuronidation was not observed.

Confirmation of diosmetin 3-O-glucuronide as major metabolite of diosmin in humans, using micro-liquid-chromatography-mass spectrometry and ion mobility mass spectrometry.

PubMed

Silvestro, Luigi; Tarcomnicu, Isabela; Dulea, Constanta; Attili, Nageswara Rao B N; Ciuca, Valentin; Peru, Dan; Rizea Savu, Simona

2013-10-01

Diosmin is a flavonoid often administered in the treatment of chronic venous insufficiency, hemorrhoids, and related affections. Diosmin is rapidly hydrolized in the intestine to its aglicone, diosmetin, which is further metabolized to conjugates. In this study, the development and validations of three new methods for the determination of diosmetin, free and after enzymatic deconjugation, and of its potential glucuronide metabolites, diosmetin-3-O-glucuronide, diosmetin-7-O-glucuronide, and diosmetin-3,7-O-glucuronide from human plasma and urine are presented. First, the quantification of diosmetin, free and after deconjugation, was carried out by high-performance liquid chromatography coupled with tandem mass spectrometry, on an Ascentis RP-Amide column (150 × 2.1 mm, 5 μm), in reversed-phase conditions, after enzymatic digestion. Then glucuronide metabolites from plasma were separated by micro-liquid chromatography coupled with tandem mass spectrometry on a HALO C18 (50 × 0.3 mm, 2.7 μm, 90 Å) column, after solid-phase extraction. Finally, glucuronides from urine were measured using a Discovery HSF5 (100 × 2.1 mm, 5 μm) column, after simple dilution with mobile phase. The methods were validated by assessing linearity, accuracy, precision, low limit of quantification, selectivity, extraction recovery, stability, and matrix effects; results in agreement with regulatory (Food and Drug Administration and European Medicines Agency) guidelines acceptance criteria were obtained in all cases. The methods were applied to a pharmacokinetic study with diosmin (450 mg orally administered tablets). The mean C max of diosmetin in plasma was 6,049.3 ± 5,548.6 pg/mL. A very good correlation between measured diosmetin and glucuronide metabolites concentrations was obtained. Diosmetin-3-O-glucuronide was identified as a major circulating metabolite of diosmetin in plasma and in urine, and this finding was confirmed by supplementary experiments with differential ion

Glucuronidated Quercetin Lowers Blood Pressure in Spontaneously Hypertensive Rats via Deconjugation

PubMed Central

Galindo, Pilar; Rodriguez-Gómez, Isabel; González-Manzano, Susana; Dueñas, Montserrat; Jiménez, Rosario; Menéndez, Carmen; Vargas, Félix; Tamargo, Juan; Santos-Buelga, Celestino; Pérez-Vizcaíno, Francisco; Duarte, Juan

2012-01-01

Background Chronic oral quercetin reduces blood pressure and restores endothelial dysfunction in hypertensive animals. However, quercetin (aglycone) is usually not present in plasma, because it is rapidly metabolized into conjugated, mostly inactive, metabolites. The aim of the study is to analyze whether deconjugation of these metabolites is involved in the blood pressure lowering effect of quercetin. Methodology/Principal Findings We have analyzed the effects on blood pressure and vascular function in vitro of the conjugated metabolites of quercetin (quercetin-3-glucuronide, Q3GA; isorhamnetin-3-glucuronide, I3GA; and quercetin-3′-sulfate, Q3'S) in spontaneously hypertensive rats (SHR). Q3GA and I3GA (1 mg/kg i.v.), but not Q3'S, progressively reduced mean blood pressure (MBP), measured in conscious SHR. The hypotensive effect of Q3GA was abolished in SHR treated with the specific inhibitor of β-glucuronidase, saccharic acid 1,4-lactone (SAL, 10 mg/ml). In mesenteric arteries, unlike quercetin, Q3GA had no inhibitory effect in the contractile response to phenylephrine after 30 min of incubation. However, after 1 hour of incubation Q3GA strongly reduced this contractile response and this effect was prevented by SAL. Oral administration of quercetin (10 mg/Kg) induced a progressive decrease in MBP, which was also suppressed by SAL. Conclusions Conjugated metabolites are involved in the in vivo antihypertensive effect of quercetin, acting as molecules for the plasmatic transport of quercetin to the target tissues. Quercetin released from its glucuronidated metabolites could be responsible for its vasorelaxant and hypotensive effect. PMID:22427863

Age-related increases in F344 rat intestine microsomal quercetin glucuronidation

USDA-ARS?s Scientific Manuscript database

The objective of this study was to establish the extent age modifies intestinal quercetin glucuronidation capacity. Pooled microsomal fractions of three equidistant small intestine (SI) segments from 4, 12, 18, and 28 mo male F344 rats (n=8/group) were employed to model the enzyme kinetics of UDP-gl...

Methylation, Glucuronidation, and Sulfonation of Daphnetin in Human Hepatic Preparations In Vitro: Metabolic Profiling, Pathway Comparison, and Bioactivity Analysis.

PubMed

Liang, Si-Cheng; Xia, Yang-Liu; Hou, Jie; Ge, Guang-Bo; Zhang, Jiang-Wei; He, Yu-Qi; Wang, Jia-Yue; Qi, Xiao-Yi; Yang, Ling

2016-02-01

Our previous study demonstrated that daphnetin is subject to glucuronidation in vitro. However, daphnetin metabolism is still poorly documented. This study aimed to investigate daphnetin metabolism and its consequent effect on the bioactivity. Metabolic profiles obtained by human liver S9 fractions and human hepatocytes showed that daphnetin was metabolized by glucuronidation, sulfonation, and methylation to form 6 conjugates which were synthesized and identified as 7-O-glucuronide, 8-O-glucuronide, 7-O-sulfate and 8-O-sulfate, 8-O-methylate, and 7-O-suflo-8-O-methylate. Regioselective 8-O-methylation of daphnetin was investigated using in silico docking calculations, and the results suggested that a close proximity (2.03 Å) of 8-OH to the critical residue Lysine 144 might be the responsible mechanism. Compared with glucuronidation and sulfonation pathways, the methylation of daphnetin had a high clearance rate (470 μL/min/mg) in human liver S9 fractions and contributed to a large amount (37.3%) of the methyl-derived metabolites in human hepatocyte. Reaction phenotyping studies showed the major role of SULT1A1, -1A2, and -1A3 in daphnetin sulfonation, and soluble COMT in daphnetin 8-O-methylation. Of the metabolites, only 8-O-methyldaphnetin exhibited an inhibitory activity on lymphocyte proliferation comparable to that of daphnetin. In conclusion, methylation is a crucial pathway for daphnetin clearance and might be involved in pharmacologic actions of daphnetin in humans. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Influence of substrates on the in vitro kinetics of steviol glucuronidation and interaction between steviol glycosides metabolites and UGT2B7.

PubMed

Chen, Jun-Ming; Xia, Yong-Mei; Zhang, Yan-Dong; Zhang, Tong-Tong; Peng, Qing-Rui; Fang, Yun

2018-06-01

Steviol glycosides, a natural sweetener, may perform bioactivities via steviol, their main metabolite in human digestion. The metabolising kinetics, i.e. glucuronidation kinetics and interaction between steviol glycosides or their metabolites and metabolising enzyme, are important for understanding the bioactivity and cytotoxicity. The present study investigated kinetics of steviol glucuronidation in human liver microsome and a recombinant human UDP-glucuronosyltransferases isomer, UGT2B7, along with molecular docking to analyse interaction between UGT2B7 and steviol or glucose. The active pocket of UGT2B7 is consisted of Arg352, Leu347, Lys343, Phe339, Tyr354, Lys355 and Leu353. The influence of stevioside, rebaudioside A, glucose and some chemotherapy reagents on the glucuronidation was also studied. The predicted hepatic clearence suggested that steviol could be classified as high-clearence drug. The steviol glycosides did not affect the glucuronidation of steviol notably.

Antioxidant activity of phenolic acids and their metabolites: synthesis and antioxidant properties of the sulfate derivatives of ferulic and caffeic acids and of the acyl glucuronide of ferulic acid.

PubMed

Piazzon, A; Vrhovsek, U; Masuero, D; Mattivi, F; Mandoj, F; Nardini, M

2012-12-19

The main metabolites of caffeic and ferulic acids (ferulic acid-4'-O-sulfate, caffeic acid-4'-O-sulfate, and caffeic acid-3'-O-sulfate), the most representative phenolic acids in fruits and vegetables, and the acyl glucuronide of ferulic acid were synthesized, purified, and tested for their antioxidant activity in comparison with those of their parent compounds and other related phenolics. Both the ferric reducing antioxidant power (FRAP) assay and the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging method were used. Ferulic acid-4'-O-sulfate and ferulic acid-4'-O-glucuronide exhibited very low antioxidant activity, while the monosulfate derivatives of caffeic acid were 4-fold less efficient as the antioxidant than caffeic acid. The acyl glucuronide of ferulic acid showed strong antioxidant action. The antioxidant activity of caffeic acid-3'-O-glucuronide and caffeic acid-4'-O-glucuronide was also studied. Our results demonstrate that some of the products of phenolic acid metabolism still retain strong antioxidant properties. Moreover, we first demonstrate the ex vivo synthesis of the acyl glucuronide of ferulic acid by mouse liver microsomes, in addition to the phenyl glucuronide.

Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer's disease

PubMed Central

Ho, Lap; Ferruzzi, Mario G.; Janle, Elsa M.; Wang, Jun; Gong, Bing; Chen, Tzu-Ying; Lobo, Jessica; Cooper, Bruce; Wu, Qing Li; Talcott, Stephen T.; Percival, Susan S.; Simon, James E.; Pasinetti, Giulio Maria

2013-01-01

Epidemiological and preclinical studies indicate that polyphenol intake from moderate consumption of red wines may lower the relative risk for developing Alzheimer's disease (AD) dementia. There is limited information regarding the specific biological activities and cellular and molecular mechanisms by which wine polyphenolic components might modulate AD. We assessed accumulations of polyphenols in the rat brain following oral dosage with a Cabernet Sauvignon red wine and tested brain-targeted polyphenols for potential beneficial AD disease-modifying activities. We identified accumulations of select polyphenolic metabolites in the brain. We demonstrated that, in comparison to vehicle-control treatment, one of the brain-targeted polyphenol metabolites, quercetin-3-O-glucuronide, significantly reduced the generation of β-amyloid (Aβ) peptides by primary neuron cultures generated from the Tg2576 AD mouse model. Another brain-targeted metabolite, malvidin-3-O-glucoside, had no detectable effect on Aβ generation. Moreover, in an in vitro analysis using the photo-induced cross-linking of unmodified proteins (PICUP) technique, we found that quercetin-3-O-glucuronide is also capable of interfering with the initial protein-protein interaction of Aβ1–40 and Aβ1–42 that is necessary for the formation of neurotoxic oligomeric Aβ species. Lastly, we found that quercetin-3-O-glucuronide treatment, compared to vehicle-control treatment, significantly improved AD-type deficits in hippocampal formation basal synaptic transmission and long-term potentiation, possibly through mechanisms involving the activation of the c-Jun N-terminal kinases and the mitogen-activated protein kinase signaling pathways. Brain-targeted quercetin-3-O-glucuronide may simultaneously modulate multiple independent AD disease-modifying mechanisms and, as such, may contribute to the benefits of dietary supplementation with red wines as an effective intervention for AD.—Ho, L., Ferruzzi, M. G

Effects of model traumatic injury on hepatic drug metabolism in the rat. IV. Glucuronidation.

PubMed

Griffeth, L K; Rosen, G M; Rauckman, E J

1985-01-01

A previously validated small mammal trauma model, hind-limb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to investigate the effects of traumatic injury on hepatic glucuronidation activity. As was previously observed with hepatic oxidative drug metabolism, model trauma resulted in a significant decrease in the in vivo glucuronidation of chloramphenicol, with a 23% drop in clearance of this drug. The effect on in vivo pharmacokinetics appeared to result from a complex interaction between trauma's differential influences on conjugating enzyme(s), deconjugating enzyme(s), and hepatic UDP-glucuronic acid levels, as well as the relative physiological importance of these variables. Hepatic UDP-glucuronyltransferase activities towards both p-nitrophenol and chloramphenicol were elevated (44-54%) after model injury when measured in native hepatic microsomes. However, microsomes which had been "activated" by treatment with Triton X-100 showed no significant difference between control and traumatized animals. Serum beta-glucuronidase activities were elevated by 58%, while hepatic beta-glucuronidase rose by about 16%. Nevertheless, in vivo deconjugation showed no significant change. Model trauma also resulted in a 46% decrease in hepatic UDP-glucuronic acid content. Thus, the observed post-traumatic depression of in vivo chloramphenicol glucuronidation could be due either to a diminished availability of a necessary cofactor (UDP-glucuronic acid) or to an alteration in enzyme kinetics or function in vivo.

Gender and oral contraceptive steroids as determinants of drug glucuronidation: effects on clofibric acid elimination.

PubMed Central

Miners, J O; Robson, R A; Birkett, D J

1984-01-01

The disposition of clofibric acid, a drug metabolised largely by glucuronidation, was studied in eight males, eight females and eight females receiving oral contraceptive steroids (OCS). Clofibric acid plasma clearance was not significantly different in males compared to the control female group but was 48% greater (P less than 0.01) in women receiving OCS compared to non-pill using females. This difference was due to an alteration in clofibric acid metabolic clearance as there were no differences between the groups in clofibric acid free fraction. Along with previous data the results suggest that induction of drug glucuronidation by OCS may be of clinical importance, although any sex-related differences are unlikely to be of clinical significance. PMID:6487463

DEVELOPMENT OF A CLASS-SELECTIVE ENZYME IMMUNOASSAY FOR URINARY PHENOLIC GLUCURONIDES. (R825433)

EPA Science Inventory

Class-selective immunoassays for the measurement of glucuronides in human urine can aid evaluation of human exposure to complex mixtures of xenobiotics. Therefore, an enzyme immunoassay (EIA) for the group-selective detection of phenolic The Inhibition of Hepatic and Renal Glucuronidation of p-Nitrophenol and 4-Methylumbelliferone by Oil Palm Empty Fruit Bunch Lignin and Its Main Oxidation Compounds

PubMed Central

Salleh, Norliyana Mohamad; Ismail, Sabariah; Ibrahim, Mohamad Nasir Mohamad

2017-01-01

Background: In order to develop oil palm empty fruit bunch (EFB) lignin as a nutraceutical and health supplement, the investigation of its potential in interacting with other drugs via inhibition of drug-metabolizing enzymes (DMEs) would ensure product safety. Objective: The study was aimed to investigate the in vitro effect of oil palm EFB lignin and its main oxidation compounds on phase II DME UDP-glucuronosyltransferases (UGTs) in rat liver and kidney microsomes. Materials and Methods: The p-nitrophenol (p-NP) and 4-methylumbelliferone (4-MU) were employed as probe substrates in glucuronidation assays. The effect of soda oil palm EFB lignin on Vmax, Km, CLint, Ki, and mode of inhibition of 4-MU glucuronidation in RLM was also determined. Results: The inhibitory potency of oil palm EFB lignin for both p-NP and 4-MU glucuronidation in rat liver microsome (RLM) and rat kidneys microsomes (RKM) was found to be in the rank order of soda > kraft > organosolv. However, the inhibitory potency of its main oxidation compounds were in the rank order of vanillin > syringaldehyde > p-hydroxybenzaldehyde. Soda oil palm EFB lignin exhibited mixed-type inhibition against 4-MU glucuronidation in RLM, showing the change in apparent Vmax and with only a minor effect on Km compared with control. Conclusions: The findings showed that effect of oil palm EFB lignin on both p-NP and 4-MU glucuronidation in RLM and RKM was enhanced by the presence of vanillin as well as flavonoids. Kinetic study showed that soda oil palm EFB lignin exhibited strong inhibition on UGT activity in RLM with mixed-type inhibition mode. SUMMARY The inhibitory potential of oil palm EFB lignin extracts for p-NP and 4-MU glucuronidation in RLM and RKM can be listed in the following rank order: soda > kraft > organosolvThe inhibitory potential of oil palm EFB lignin main oxidation compounds for p-NP and 4-MU glucuronidation in RLM and RKM can be listed in the following rank order: vanillin > syringaldehyde > p

The Inhibition of Hepatic and Renal Glucuronidation of p-Nitrophenol and 4-Methylumbelliferone by Oil Palm Empty Fruit Bunch Lignin and Its Main Oxidation Compounds.

PubMed

Salleh, Norliyana Mohamad; Ismail, Sabariah; Ibrahim, Mohamad Nasir Mohamad

2017-01-01

In order to develop oil palm empty fruit bunch (EFB) lignin as a nutraceutical and health supplement, the investigation of its potential in interacting with other drugs via inhibition of drug-metabolizing enzymes (DMEs) would ensure product safety. The study was aimed to investigate the in vitro effect of oil palm EFB lignin and its main oxidation compounds on phase II DME UDP-glucuronosyltransferases (UGTs) in rat liver and kidney microsomes. The p -nitrophenol ( p -NP) and 4-methylumbelliferone (4-MU) were employed as probe substrates in glucuronidation assays. The effect of soda oil palm EFB lignin on V max , K m , CL int , K i , and mode of inhibition of 4-MU glucuronidation in RLM was also determined. The inhibitory potency of oil palm EFB lignin for both p -NP and 4-MU glucuronidation in rat liver microsome (RLM) and rat kidneys microsomes (RKM) was found to be in the rank order of soda > kraft > organosolv. However, the inhibitory potency of its main oxidation compounds were in the rank order of vanillin > syringaldehyde > p -hydroxybenzaldehyde. Soda oil palm EFB lignin exhibited mixed-type inhibition against 4-MU glucuronidation in RLM, showing the change in apparent V max and with only a minor effect on K m compared with control. The findings showed that effect of oil palm EFB lignin on both p -NP and 4-MU glucuronidation in RLM and RKM was enhanced by the presence of vanillin as well as flavonoids. Kinetic study showed that soda oil palm EFB lignin exhibited strong inhibition on UGT activity in RLM with mixed-type inhibition mode. The inhibitory potential of oil palm EFB lignin extracts for p -NP and 4-MU glucuronidation in RLM and RKM can be listed in the following rank order: soda > kraft > organosolvThe inhibitory potential of oil palm EFB lignin main oxidation compounds for p -NP and 4-MU glucuronidation in RLM and RKM can be listed in the following rank order: vanillin > syringaldehyde > p-hydroxybenzaldehydeResults suggested that the effect of oil

49 CFR 173.322 - Ethyl chloride.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 2 2010-10-01 2010-10-01 false Ethyl chloride. 173.322 Section 173.322 Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS SAFETY... SHIPMENTS AND PACKAGINGS Gases; Preparation and Packaging § 173.322 Ethyl chloride. Ethyl chloride must be...

Application of phosphatidylethanol (PEth) in whole blood in comparison to ethyl glucuronide in hair (hEtG) in driving aptitude assessment (DAA).

PubMed

Schröck, Alexandra; Pfäffli, Matthias; König, Stefan; Weinmann, Wolfgang

2016-11-01

For driving aptitude assessment (DAA), the analysis of several alcohol biomarkers is essential for the detection of alcohol intake besides psycho-medical exploration. In Switzerland, EtG in hair (hEtG) is often the only direct marker for abstinence monitoring in DAA. Therefore, the suitability of phosphatidylethanol (PEth) was investigated as additional biomarker. PEth 16:0/18:1 and 16:0/18:2 were determined by online-SPE-LC-MS/MS in 136 blood samples of persons undergoing DAA and compared to hEtG, determined in hair segments taken at the same time. With a PEth 16:0/18:1 threshold of 210 ng/mL for excessive alcohol consumption, all (n = 30) but one tested person also had hEtG values ≥30 pg/mg. In 54 cases, results are not in contradiction to an abstinence as neither PEth (<20 ng/mL) nor hEtG (<7 pg/mg) was detected. In eight cases, both markers showed moderate consumption. Altogether, PEth and hEtG were in accordance in 68 % of the samples, although covering different time periods of alcohol consumption. With receiver operating characteristic analysis, PEth was evaluated to differentiate abstinence, moderate, and excessive alcohol consumption in accordance with hEtG limits. A PEth 16:0/18:1 threshold of 150 ng/mL resulted in the best sensitivity (70.6 %) and specificity (98.8 %) for excessive consumption. Values between 20 and 150 ng/mL passed for moderate consumption, values <20 ng/mL passed for abstinence. As PEth mostly has a shorter detection window (2-4 weeks) than hEtG (up to 6 months depending on hair length), changes in drinking behavior can be detected earlier by PEth than by hEtG analysis alone. Therefore, PEth helps to improve the diagnostic information and is a valuable additional alcohol marker for DAA.

21 CFR 184.1293 - Ethyl alcohol.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Ethyl alcohol. 184.1293 Section 184.1293 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN... Substances Affirmed as GRAS § 184.1293 Ethyl alcohol. (a) Ethyl alcohol (ethanol) is the chemical C2H5OH. (b...

21 CFR 184.1293 - Ethyl alcohol.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Ethyl alcohol. 184.1293 Section 184.1293 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN... Substances Affirmed as GRAS § 184.1293 Ethyl alcohol. (a) Ethyl alcohol (ethanol) is the chemical C2H5OH. (b...

Cremophor EL-based nanoemulsion enhances transcellular permeation of emodin through glucuronidation reduction in UGT1A1-overexpressing MDCKII cells.

PubMed

Zhang, Tianpeng; Dong, Dong; Lu, Danyi; Wang, Shuai; Wu, Baojian

2016-03-30

Oral emodin, a natural anthraquinone and active component of many herbal medicines, is poorly bioavailable because of extensive first-pass glucuronidation. Here we aimed to prepare emodin nanoemulsion (EMO-NE) containing cremophor EL, and to assess its potential for enhancing transcellular absorption of emodin using UGT1A1-overexpressing MDCKII cells (or MDCK1A1 cells). EMO-NE was prepared using a modified emulsification technique and subsequently characterized by particle size, morphology, stability, and drug release. MDCKII cells were stably transfected with UGT1A1 using the lentiviral transfection approach. Emodin transport and metabolism were evaluated in Transwell-cultured MDCK1A1 cells after apical dosing of EMO-NE or control solution. The obtained EMO-NE (116 ± 6.5 nm) was spherical and stable for at least 2 months. Emodin release in vitro was a passive diffusion-driven process. EMO-NE administration increased the apparent permeability of emodin by a 2.3-fold (p<0.001) compared to the pure emodin solution (1.2 × 10(-5) cm/s vs 5.3 × 10(-6) cm/s). Further, both apical and basolateral excretion of emodin glucuronide (EMO-G) were significantly decreased (≥56.5%, p<0.001) in EMO-NE group. This was accompanied by a marked reduction (57.4%, p<0.001) in total emodin glucuronidation. It was found that the reduced glucuronidation was due to inhibition of cellular metabolism by cremophor EL. Cremophor EL inhibited UGT1A1-mediated glucuronidation of emodin using the mixed-type inhibition mechanism. In conclusion, cremophor EL-based nanoemulsion greatly enhanced transcellular permeation of emodin through inhibition of UGT metabolism. This cremophor EL-based nanoformulation may be a promising strategy to improve the oral bioavailability of emodin. Copyright © 2016 Elsevier B.V. All rights reserved.

A novel method for the quantitation of gingerol glucuronides in human plasma or urine based on stable isotope dilution assays.

PubMed

Schoenknecht, Carola; Andersen, Gaby; Schieberle, Peter

2016-11-15

The bio-active compounds of ginger (Zingiber officinale Roscoe), the gingerols, are gaining considerable attention due to their numerous beneficial health effects. In order to elucidate the physiological relevance of the ascribed effects their bioavailability has to be determined taking their metabolization into account. To quantitate in vivo generated [6]-, [8]- and [10]-gingerol glucuronides in human plasma and urine after ginger tea consumption, a simultaneous and direct liquid chromatography-tandem mass spectrometry method based on stable isotope dilution assays was established and validated. The respective references as well as the isotopically labeled substances were synthesized and characterized by mass spectrometry and NMR. Selective isolation of gingerol glucuronides from human plasma and urine by a mixed-phase anion-exchange SPE method led to recovery rates between 80.8 and 98.2%. LC-MS/MS analyses in selected reaction monitoring modus enabled a highly sensitive quantitation of gingerol glucuronides with LoQs between 3.9-9.8nmol/L in plasma and 39.3-161.1nmol/L in urine. The method precision in plasma and urine varied in the range±15%, whereas the intra-day accuracy in plasma and urine showed values between 78 and 122%. The developed method was then applied to a pilot study in which two volunteers consumed one liter ginger tea. Pharmacokinetic parameters like the maximum concentration (c max ), the time to reach c max (t max ), area under the curve (AUC), elimination rate constant (k el ) and elimination half-life (t 1/2 ) were calculated from the concentration-time curve of each gingerol glucuronide. The obtained results will enable more detailed investigation of gingerol glucuronides as bioactives in their physiologically relevant concentrations. Copyright © 2016 Elsevier B.V. All rights reserved.

40 CFR 721.3152 - Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl...

Code of Federal Regulations, 2013 CFR

2013-07-01

...-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates (salts). 721.3152 Section 721... Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates... ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates...

40 CFR 721.3152 - Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl...

Code of Federal Regulations, 2014 CFR

2014-07-01

...-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates (salts). 721.3152 Section 721... Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates... ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates...

40 CFR 721.3152 - Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl...

Code of Federal Regulations, 2012 CFR

2012-07-01

...-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates (salts). 721.3152 Section 721... Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates... ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates...

40 CFR 721.3152 - Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl...

Code of Federal Regulations, 2011 CFR

2011-07-01

...-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates (salts). 721.3152 Section 721... Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates... ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates...

Effects of quercetin and quercetin 3-glucuronide on the expression of bone sialoprotein gene.

PubMed

Kim, Dong-Soon; Takai, Hideki; Arai, Masato; Araki, Shouta; Mezawa, Masaru; Kawai, Yoshichika; Murota, Kaeko; Terao, Junji; Ogata, Yorimasa

2007-06-01

Quercetin is a typical flavonol-type flavonoid and is present in a variety of vegetables, and their antioxidant effect implies their possible role in the prevention of oxidative stress related chronic diseases. Bone sialoprotein (BSP) is a noncollagenous protein of the extracellular matrix in the mineralized connective tissues that has been implicated in the nucleation of hydroxyapatite crystals. Previously, we reported that isoflavone (genistein) activated BSP gene transcription is mediated through an inverted CCAAT box in the proximal BSP gene promoter. The present study investigates the regulation of BSP transcription in a rat osteoblast-like cell line, ROS 17/2.8 cells, by quercetin and its conjugated metabolite quercetin 3-glucuronide. Quercetin and quercetin 3-glucuronide (5 microM) increased the BSP mRNA levels at 12 h and quercetin upregulated the Cbfa1/Runx2 mRNA expression at 12 h. From transient transfection assays using various sized BSP promoter-luciferase constructs, quercetin increased the luciferase activity of the construct (pLUC3), including the promoter sequence nucleotides -116 to -43. Transcriptional stimulations by quercetin were almost completely abrogated in the constructs that included 2 bp mutations in the inverted CCAAT and FRE elements whereas the CCAAT-protein complex did not change after stimulation by quercetin according to gel shift assays. Quercetin increased the nuclear protein binding to the FRE and 3'-FRE. These data suggest that quercetin and quercetin 3-glucuronide increased the BSP mRNA expression, and that the inverted CCAAT and FRE elements in the promoter of the BSP gene are required for quercetin induced BSP transcription.

Screening for Hazardous Drinking in Nursing Home Residents: Evaluating the Validity of the Current Cutoffs of the Alcohol Use Disorder Identification Test-Consumption Questions by Using Ethyl Glucuronide in Hair.

PubMed

Dreher-Weber, Monika; Laireiter, Anton-Rupert; Kühberger, Anton; Kunz, Isabella; Yegles, Michel; Binz, Tina; Rumpf, Hans-Jürgen; Hoffmann, Rainer; Praxenthaler, Verena; Lang, Siegfried; Wurst, Friedrich M

2017-09-01

Because of physiological changes, elderly people are much more exposed to the adverse effects of alcohol. Therefore, hazardous drinking is defined at lower levels as compared to younger adults. This work aimed to evaluate the validity of the current cutoff levels of the Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) questions to detect hazardous drinking in the elderly by using ethyl glucuronide in hair (HEtG). In a border region between Austria and Germany, 344 nursing home residents were included from 33 of the 107 nursing homes. Residents were asked to answer the AUDIT-C questions, hair samples were obtained, and nursing staff members were asked for their assessments of the residents' alcohol consumption. Hair samples were analyzed for HEtG using gas chromatography-mass spectrometry. Receiver-operating characteristic (ROC) curve analysis was performed to determine the validity of cutoff values for the AUDIT-C to detect an alcohol consumption of ≥10 g of alcohol/d. A total of 11.3% of the nursing home residents (n = 344) drank ≥10 g of alcohol/d (4.9% >60 g of alcohol/d, 6.4% 10 to 60 g of alcohol/d, 88.7% <10 g of alcohol/d)). For the drinking limit of ≥10 g of alcohol/d, ROC curve analysis showed a balanced sensitivity and specificity, with an AUDIT-C cutoff of ≥4 for men (sensitivity: 70%, specificity: 83.6%; AUC = 0.823, CI = 0.718 to 0.928, p < 0.001) and ≥2 for women (sensitivity: 73.7%, specificity: 81.9%; AUC = 0.783, CI = 0.653 to 0.914, p < 0.001). Nursing staff (n = 274) underestimated alcohol consumption and evaluated 40% of the chronic-excessive alcohol consumers (>60 g of alcohol/d) as being abstinent. Our data suggest that an AUDIT-C cutoff of ≥4 for men and ≥2 for women can be recommended to detect the consumption of ≥10 g of alcohol/d in the elderly. Because the nursing staff to a large extent underestimates the alcohol consumption among nursing home residents, further teaching of the staff

Glucuronidation and Sulfation Kinetics of Diflunisal in Man.

NASA Astrophysics Data System (ADS)

Loewen, Gordon Rapheal

Diflunisal is a nonsteroidal anti-inflammatory drug used in the treatment of arthritis and musculoskeletal pain. Diflunisal exhibits concentration- and dose-dependent kinetics, the mechanism of which has not been determined. The purpose of this study was to determine the mechanism(s) responsible for non-linear disposition of diflunisal and to examine environmental factors which may affect the elimination of diflunisal. The metabolites of diflunisal, including a new metabolite, the sulphate conjugate, were purified by column and semi-preparative high pressure liquid chromatography. Assays for the quantitation of diflunisal and conjugates in urine and diflunisal in plasma were developed. Plasma protein binding of diflunisal in blank plasma and in plasma obtained following multiple doses of diflunisal was determined by equilibrium dialysis. Total body clearance of diflunisal decreased when dose increased from 100 to 750 mg. Total clearance increased when dose increased from 750 to 1000 mg. The percent of recovered dose eliminated as the acyl glucuronide decreased and the percent eliminated as the sulphate increased with increasing dose of diflunisal. Plasma protein binding of diflunisal was concentration dependent over a range of diflunisal plasma concentrations of 3 to 257 mug/ml. Total clearance, and to a lesser degree, unbound clearance of diflunisal were decreased following multiple dose administration of 250 and 500 mg diflunisal. Percent of recovered dose eliminated as the acyl glucuronide decreased and percent eliminated as the sulphate conjugate increased following multiple dosing. Plasma protein binding of diflunisal was similar in blank plasma and plasma obtained at steady state. Unbound clearance of diflunisal exceeded liver plasma flow. Frequency distributions of the elimination of the conjugates of diflunisal were normally distributed. Sex, smoking, and use of vitamins or oral contraceptives were identified as factors which may affect the elimination of

Detection of interstellar ethyl cyanide

NASA Technical Reports Server (NTRS)

Johnson, D. R.; Lovas, F. J.; Gottlieb, C. A.; Gottlieb, E. W.; Litvak, M. M.; Thaddeus, P.; Guelin, M.

1977-01-01

Twenty-four millimeter-wave emission lines of ethyl cyanide (CH3CH2CN) have been detected in the Orion Nebula (OMC-1) and seven in Sgr B2. To derive precise radial velocities from the astronomical data, a laboratory measurement of the rotational spectrum of ethyl cyanide has been made at frequencies above 41 GHz. In OMC-1, the rotational temperature of ethyl cyanide is 90 K (in good agreement with other molecules), the local-standard-of-rest radial velocity is 4.5 + or - 1.0 km/s (versus 8.5 km/s for most molecules), and the column density is 1.8 by 10 to the 14th power per sq cm (a surprisingly high figure for a complicated molecule). The high abundance of ethyl cyanide in the Orion Nebula suggests that ethane and perhaps larger saturated hydrocarbons may be common constituents of molecular clouds and have escaped detection only because they are nonpolar or only weakly polar.

Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups

PubMed Central

Murphy, Sharon E.; Park, Sung-Shim L.; Thompson, Elizabeth F.; Wilkens, Lynne R.; Patel, Yesha; Stram, Daniel O.; Le Marchand, Loic

2014-01-01

Nicotine metabolism influences smoking behavior and differences in metabolism probably contribute to ethnic variability in lung cancer risk. We report here on the proportion of nicotine metabolism by cytochrome P450 2A6-catalyzed C-oxidation, UDP-glucuronosyl transferase 2B10 (UGT2B10)-catalyzed N-glucuronidation and flavin monooxygenase 3-catalyzed N-oxidation in five ethnic/racial groups and the role of UGT2B10 genotype on the metabolic patterns observed. Nicotine and its metabolites were quantified in urine from African American (AA, n = 364), Native Hawaiian (NH, n = 311), White (n = 437), Latino (LA, n = 453) and Japanese American (JA, n = 674) smokers. Total nicotine equivalents, the sum of nicotine and six metabolites, and nicotine metabolism phenotypes were calculated. The relationship of UGT2B10 genotype to nicotine metabolic pathways was determined for each group; geometric means were computed and adjusted for age, sex, creatinine, and body mass index. Nicotine metabolism patterns were unique across the groups, C-oxidation was lowest in JA and NH (P < 0.0001), and N-glucuronidation lowest in AA (P < 0.0001). There was no difference in C-oxidation among Whites and AA and LA. Nicotine and cotinine glucuronide ratios were 2- and 3-fold lower in AA compared with Whites. Two UGT variants, a missense mutation (Asp67Tyr, rs61750900) and a splice variant (rs116294140) accounted for 33% of the variation in glucuronidation. In AA, the splice variant accounted for the majority of the reduced nicotine glucuronidation. UGT2B10 variant allele carriers had increased levels of C-oxidation (P = 0.0099). Our data indicate that the relative importance of nicotine metabolic pathways varies by ethnicity, and all pathways should be considered when characterizing the role of nicotine metabolism on smoking behavior and cancer risk. PMID:25233931

Three-dimensional quantitative structure-activity relationship studies on UGT1A9-mediated 3-O-glucuronidation of natural flavonols using a pharmacophore-based comparative molecular field analysis model.

PubMed

Wu, Baojian; Morrow, John Kenneth; Singh, Rashim; Zhang, Shuxing; Hu, Ming

2011-02-01

Glucuronidation is often recognized as one of the rate-determining factors that limit the bioavailability of flavonols. Hence, design and synthesis of more bioavailable flavonols would benefit from the establishment of predictive models of glucuronidation using kinetic parameters [e.g., K(m), V(max), intrinsic clearance (CL(int)) = V(max)/K(m)] derived for flavonols. This article aims to construct position (3-OH)-specific comparative molecular field analysis (CoMFA) models to describe UDP-glucuronosyltransferase (UGT) 1A9-mediated glucuronidation of flavonols, which can be used to design poor UGT1A9 substrates. The kinetics of recombinant UGT1A9-mediated 3-O-glucuronidation of 30 flavonols was characterized, and kinetic parameters (K(m), V(max), CL(int)) were obtained. The observed K(m), V(max), and CL(int) values of 3-O-glucuronidation ranged from 0.04 to 0.68 μM, 0.04 to 12.95 nmol/mg/min, and 0.06 to 109.60 ml/mg/min, respectively. To model UGT1A9-mediated glucuronidation, 30 flavonols were split into the training (23 compounds) and test (7 compounds) sets. These flavonols were then aligned by mapping the flavonols to specific common feature pharmacophores, which were used to construct CoMFA models of V(max) and CL(int), respectively. The derived CoMFA models possessed good internal and external consistency and showed statistical significance and substantive predictive abilities (V(max) model: q(2) = 0.738, r(2) = 0.976, r(pred)(2) = 0.735; CL(int) model: q(2) = 0.561, r(2) = 0.938, r(pred)(2) = 0.630). The contour maps derived from CoMFA modeling clearly indicate structural characteristics associated with rapid or slow 3-O-glucuronidation. In conclusion, the approach of coupling CoMFA analysis with a pharmacophore-based structural alignment is viable for constructing a predictive model for regiospecific glucuronidation rates of flavonols by UGT1A9.

40 CFR 180.430 - Fenoxaprop-ethyl; tolerances for residues.

Code of Federal Regulations, 2010 CFR

2010-07-01

... combined residues of the herbicide fenoxaprop-ethyl [(±)-ethyl 2-[4-[(6-chloro-2-benzoxazolyl)oxy]phenoxy... herbicide fenoxaprop-ethyl, [(±)-ethyl 2-[4-[(6-chloro-2-benzoxazolyl)oxy]phenoxy]propanoic acid], and its...

Skin sterility after application of ethyl chloride spray.

PubMed

Polishchuk, Daniil; Gehrmann, Robin; Tan, Virak

2012-01-18

Ethyl chloride topical anesthetic spray is labeled as nonsterile, yet it is widely used during injection procedures performed in an outpatient setting. The purpose of this study was to investigate the sterility of ethyl chloride topical anesthetic spray applied before an injection. Our a priori hypothesis was that application of the spray after the skin has been prepared would not alter the sterility of the injection site. We conducted a prospective, blinded, controlled study to assess the effect of ethyl chloride spray on skin sterility. Fifteen healthy adult subjects (age, twenty-three to sixty-one years) were prepared for mock injections into both shoulders and both knees, although no injection was actually performed. Three culture samples were obtained from each site on the skin: one before skin preparation with isopropyl alcohol, one after skin preparation and before application of ethyl chloride, and one after ethyl chloride had been sprayed on the site. In addition, the sterility of the ethyl chloride was tested directly by inoculating cultures with spray from the bottles. Growth occurred in 70% of the samples obtained before skin preparation, 3% of the samples obtained after skin preparation but before application of ethyl chloride, and 5% of the samples obtained after the injection site had been sprayed with ethyl chloride. The percentage of positive cultures did not increase significantly after application of ethyl chloride (p = 0.65). Spraying of ethyl chloride directly on agar plates resulted in growth on 13% of these plates compared with 11% of the control plates; this difference was also not significant (p = 0.80). Although ethyl chloride spray is not sterile, its application did not alter the sterility of the injection sites in the shoulder and knee.

Icosapent Ethyl

MedlinePlus

... doctor if you have or have ever had diabetes or liver, thyroid, or pancreatic disease.tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking icosapent ethyl, ...

Fabrication of polymerized crystalline colloidal array thin film modified β-cyclodextrin polymer for paraoxon-ethyl and parathion-ethyl detection.

PubMed

Bui, Minh-Phuong N; Seo, Seong S

2014-01-01

We have developed an optical chemical sensor for the detection of organophosphate (OP) compounds using a polymerized crystalline colloidal array (PCCA) thin film composed of a close-packed colloidal array of polystyrene particles. The PCCA thin film was modified with β-cyclodextrin (β-CD) polymer as a capping cavity for the selective detection of paraoxon-ethyl and parathion-ethyl chemical agents. The fabrication of the modified PCCA thin film was optimized and the structure was characterized using scanning electron microscopy (SEM). The arrangement of polystyrene particles in the PCCA follows a pattern of the fcc (111) planes with strong diffraction peak in the visible spectral region and pH dependence. The diffraction peak of the β-CD modified PCCA thin film showed a red shift according to the change of paraoxon-ethyl and parathion-ethyl concentrations at a fast response time (10 s) and high sensitivity with detection limits of 2.0 and 3.4 ppb, respectively. Furthermore, the proposed interaction mechanism of β-CD with paraoxon-ethyl and parathion-ethyl in the β-CD modified PCCA thin film were discussed.

Assessing cannabis consumption frequency: Is the combined use of free and glucuronidated THCCOOH blood levels of diagnostic utility?

PubMed

Hädener, Marianne; Martin Fabritius, Marie; König, Stefan; Giroud, Christian; Weinmann, Wolfgang

2017-07-01

Heavy cannabis consumption is considered incompatible with safe driving. In Swiss traffic policy, drivers suspected of regular cannabis use are therefore required to undergo medical assessment of their long-term fitness to drive. A whole blood concentration of the cannabis metabolite 11-nor-9-carboxy-Δ 9 -tetrahydrocannabinol (THCCOOH) of 40 µg/L is currently used by Swiss forensic experts as the decision limit for regular cannabis consumption. The present study aimed to investigate the suitability of THCCOOH-glucuronide blood levels as an additional and/or better marker for the frequency of cannabis use. Whole blood samples collected from 23 heavy (≥10 joints/month) and 25 occasional smokers (≥1 joint/month, but ≤ 1 joint/week) enrolled in a placebo-controlled cannabis smoking study were analyzed for THCCOOH and THCCOOH-glucuronide. Based on receiver operating characteristic (ROC) curve analysis, concentration thresholds could be established for distinguishing between these two groups. Proposed thresholds for heavy use were THCCOOH-glucuronide > 52 µg/L (100% specificity; 41% sensitivity) and/or total THCCOOH > 58 µg/L (100% specificity; 43% sensitivity). Optimum thresholds for occasional use were THCCOOH-glucuronide < 5 µg/L (73% specificity; 97% sensitivity) and/or total THCCOOH < 5 µg/L (62% specificity; 98% sensitivity). Our results indicate that the THCCOOH-glucuronide whole blood concentration is a useful parameter that complements the free THCCOOH level to assess the frequency of cannabis consumption. The consideration of the blood concentrations of both free and glucuronidated THCCOOH improves the identification of heavy users whose fitness to drive has to be carefully assessed. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Chlorimuron-ethyl

Integrated Risk Information System (IRIS)

Integrated Risk Information System ( IRIS ) Chemical Assessment Summary U.S . Environmental Protection Agency National Center for Environmental Assessment This IRIS Summary has been removed from the IRIS database and is available for historical reference purposes . ( July 2016 ) Chlorimuron - ethyl

Use of Isoform-Specific UGT Metabolism to Determine and Describe Rates and Profiles of Glucuronidation of Wogonin and Oroxylin A by Human Liver and Intestinal Microsomes

PubMed Central

Zhou, Qiong; Zheng, Zhijie; Xia, Bijun; Tang, Lan; Lv, Chang; Liu, Wei; Liu, Zhongqiu; Hu, Ming

2010-01-01

Purposes Glucuronidation via UDP-glucuronosyltransferases (or UGTs) is a major metabolic pathway. The purposes of this study are to determine the UGT-isoform specific metabolic fingerprint (or GSMF) of wogonin and oroxylin A, and to use isoform-specific metabolism rates and kinetics to determine and describe their glucuronidation behaviors in tissue microsomes. Methods In vitro glucuronidation rates and profiles were measured using expressed UGTs and human intestinal and liver microsomes. Results GSMF experiments indicated that both flavonoids were metabolized mainly by UGT1As, with major contributions from UGT1A3 and UGT1A7-1A10. Isoform-specific metabolism showed that kinetic profiles obtained using expressed UGT1A3 and UGT1A7-1A10 could fit to known kinetic models. Glucuronidation of both flavonoids in human intestinal and liver microsomes followed simple Michaelis-Menten kinetics. A comparison of the kinetic parameters and profiles suggests that UGT1A9 is likely the main isoform responsible for liver metabolism. In contrast, a combination of UGT1As with a major contribution from UGT1A10 contributed to their intestinal metabolism. Correlation studies clearly showed that UGT isoform-specific metabolism could describe their metabolism rates and profiles in human liver and intestinal microsomes. Conclusion GSMF and isoform-specific metabolism profiles can determine and describe glucuronidation rates and profiles in human tissue microsomes. PMID:20411407

An activity-based near-infrared glucuronide trapping probe for imaging β-glucuronidase expression in deep tissues.

PubMed

Cheng, Ta-Chun; Roffler, Steve R; Tzou, Shey-Cherng; Chuang, Kuo-Hsiang; Su, Yu-Cheng; Chuang, Chih-Hung; Kao, Chien-Han; Chen, Chien-Shu; Harn, I-Hong; Liu, Kuan-Yi; Cheng, Tian-Lu; Leu, Yu-Ling

2012-02-15

β-glucuronidase is an attractive reporter and prodrug-converting enzyme. The development of near-IR (NIR) probes for imaging of β-glucuronidase activity would be ideal to allow estimation of reporter expression and for personalized glucuronide prodrug cancer therapy in preclinical studies. However, NIR glucuronide probes are not yet available. In this work, we developed two fluorescent probes for detection of β-glucuronidase activity, one for the NIR range (containing IR-820 dye) and the other for the visible range [containing fluorescein isothiocyanate (FITC)], by utilizing a difluoromethylphenol-glucuronide moiety (TrapG) to trap the fluorochromes in the vicinity of the active enzyme. β-glucuronidase-mediated hydrolysis of the glucuronyl bond of TrapG generates a highly reactive alkylating group that facilitates the attachment of the fluorochrome to nucleophilic moieties located near β-glucuronidase-expressing sites. FITC-TrapG was selectively trapped on purified β-glucuronidase or β-glucuronidase-expressing CT26 cells (CT26/mβG) but not on bovine serum albumin or non-β-glucuronidase-expressing CT26 cells used as controls. β-glucuronidase-activated FITC-TrapG did not interfere with β-glucuronidase activity and could label bystander proteins near β-glucuronidase. Both FITC-TrapG and NIR-TrapG specifically imaged subcutaneous CT26/mβG tumors, but only NIR-TrapG could image CT26/mβG tumors transplanted deep in the liver. Thus NIR-TrapG may provide a valuable tool for visualizing β-glucuronidase activity in vivo.

Nitrosamine-induced carcinogenesis. The alkylation of N-7 of guanine of nucleic acids of the rat by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonate

PubMed Central

Swann, P. F.; Magee, P. N.

1971-01-01

1. The extent of ethylation of N-7 of guanine in the nucleic acids of rat tissue in vivo by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonate was measured. 2. All compounds produced measurable amounts of 7-ethyl-guanine. 3. A single dose of diethylnitrosamine or N-ethyl-N-nitrosourea produced tumours of the kidney in the rat. Three doses of ethyl methanesulphonate produced kidney tumours, but a single dose did not. 4. A single dose of diethylnitrosamine produced twice as much ethylation of N-7 of guanine in DNA of kidney as did N-ethyl-N-nitrosourea. A single dose of both compounds induced kidney tumours, although of a different histological type. 5. A single dose of ethyl methanesulphonate produced ten times as much ethylation of N-7 of guanine in kidney DNA as did N-ethyl-N-nitrosourea without producing tumours. 6. The relevance of these findings to the hypothesis that alkylation of a cellular component is the mechanism of induction of tumours by nitroso compounds is discussed. PMID:5145908

Tentative Structural Assignment of a Glucuronide Metabolite of Methyltestosterone in Tilapia Bile by Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry.

PubMed

Nishshanka, Upul; Chu, Pak-Sin; Evans, Eric; Reimschuessel, Renate; Hasbrouck, Nicholas; Amarasinghe, Kande; Jayasuriya, Hiranthi

2015-06-24

Methyltestosterone (MT), a strong androgenic steroid, is not approved for use in fish aquaculture in the United States. It is used in the U.S. under an investigational new animal drug exemption (INAD) only during the early life stages of fish. There is a possibility that farmers feed fish with MT to enhance production for economic gains. Therefore, there is a need to develop methods for the detection of MT and its metabolite residues in fish tissue for monitoring purposes. Previously, our laboratory developed a liquid chromatography-quadrupole time-of-flight (LC-QTOF) method for characterization of 17-O-glucuronide metabolite (MT-glu) in bile of tilapia dosed with MT. The system used was an Agilent 6530 Q-TOF equipped with electrospray jet stream technology, operating in positive ion mode. Retrospective analysis of the data generated in that experiment by a feature-finding algorithm, combined with a search against an in-house library of possible MT-metabolites, resulted in the discovery of a major glucuronide metabolite of MT in the bile extracts. Preliminary data indicate it to be a glucuronide of a hydroxylated MT (OHMT-glu) which persists in tilapia bile for at least 2 weeks after dosing. We present the tentative structural assignment of the OHMT-glu in tilapia bile and time course of development. This glucuronide can serve as a marker to monitor illegal use of MT in tilapia culture.

Differential correlations between maternal hair levels of tobacco and alcohol with fetal growth restriction clinical subtypes.

PubMed

Sabra, Sally; Malmqvist, Ebba; Almeida, Laura; Gratacos, Eduard; Gomez Roig, Maria Dolores

2018-08-01

Maternal exposure to tobacco and alcohol is a known cause, among others, for fetal growth restriction (FGR). Clinically, FGR can be subclassified into two forms: intrauterine growth restriction (IUGR) and small for gestational age (SGA), based on the severity of the growth retardation, and abnormal uterine artery Doppler or cerebro-placental ratio. This study aimed at investigating any differential correlation between maternal exposures to these toxins with the two clinical forms of FGR. Therefore, a case-control study was conducted in Barcelona, Spain. Sixty-four FGR subjects, who were further subclassified into IUGR (n = 36) and SGA (n = 28), and 89 subjects matched appropriate-for-gestational age (AGA), were included. The levels of nicotine (NIC) and ethyl glucuronide (EtG), biomarkers of tobacco and alcohol exposure, respectively, were assessed in the maternal hair in the third trimester. Our analysis showed 65% of the pregnant women consumed alcohol, 25% smoked, and 19% did both. The odds ratios (ORs) of IUGR were 21 times versus 14 times for being SGA with maternal heavy smoking, while with alcohol consumption the ORs for IUGR were 22 times versus 37 times for the SGA group. The differential correlations between these toxins with the two subtypes of FGR suggest different mechanisms influencing fetal weight. Our alarming data of alcohol consumption during pregnancy should be considered for further confirmation among Spanish women. Copyright © 2018 Elsevier Inc. All rights reserved.

Ethyl ether

Integrated Risk Information System (IRIS)

Ethyl ether ; CASRN 60 - 29 - 7 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 Noncarcinogenic Effect

Ethyl acetate

Integrated Risk Information System (IRIS)

Ethyl acetate ; CASRN 141 - 78 - 6 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 Noncarcinogenic Eff

Ethyl chloride

Integrated Risk Information System (IRIS)

Ethyl chloride ; CASRN 75 - 00 - 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 Noncarcinogenic Eff

Ethyl carbamate

Integrated Risk Information System (IRIS)

Ethyl carbamate ; CASRN 51 - 79 - 6 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 Noncarcinogenic Ef

21 CFR 177.1320 - Ethylene-ethyl acrylate copolymers.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Ethylene-ethyl acrylate copolymers. 177.1320... Basic Components of Single and Repeated Use Food Contact Surfaces § 177.1320 Ethylene-ethyl acrylate copolymers. Ethylene-ethyl acrylate copolymers may be safely used to produce packaging materials, containers...

21 CFR 573.420 - Ethyl cellulose.

Code of Federal Regulations, 2013 CFR

2013-04-01

..., FEEDS, AND RELATED PRODUCTS FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF ANIMALS Food Additive Listing § 573.420 Ethyl cellulose. The food additive ethyl cellulose may be safely used in animal feed in accordance with the following prescribed conditions: (a) The food additive is a cellulose ether containing...

21 CFR 573.420 - Ethyl cellulose.

Code of Federal Regulations, 2011 CFR

2011-04-01

..., FEEDS, AND RELATED PRODUCTS FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF ANIMALS Food Additive Listing § 573.420 Ethyl cellulose. The food additive ethyl cellulose may be safely used in animal feed in accordance with the following prescribed conditions: (a) The food additive is a cellulose ether containing...

21 CFR 573.420 - Ethyl cellulose.

Code of Federal Regulations, 2014 CFR

2014-04-01

..., FEEDS, AND RELATED PRODUCTS FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF ANIMALS Food Additive Listing § 573.420 Ethyl cellulose. The food additive ethyl cellulose may be safely used in animal feed in accordance with the following prescribed conditions: (a) The food additive is a cellulose ether containing...

21 CFR 573.420 - Ethyl cellulose.

Code of Federal Regulations, 2010 CFR

2010-04-01

..., FEEDS, AND RELATED PRODUCTS FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF ANIMALS Food Additive Listing § 573.420 Ethyl cellulose. The food additive ethyl cellulose may be safely used in animal feed in accordance with the following prescribed conditions: (a) The food additive is a cellulose ether containing...

21 CFR 573.420 - Ethyl cellulose.

Code of Federal Regulations, 2012 CFR

2012-04-01

..., FEEDS, AND RELATED PRODUCTS FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF ANIMALS Food Additive Listing § 573.420 Ethyl cellulose. The food additive ethyl cellulose may be safely used in animal feed in accordance with the following prescribed conditions: (a) The food additive is a cellulose ether containing...

Poly (N-ethyl aniline)/Ag Nanocomposite as Humidity Sensor

NASA Astrophysics Data System (ADS)

Pande, Nishigandh S.; Jaspal, Dipika; Ambekar, Jalindar

Poly (N-ethyl aniline)/Ag organic-inorganic composite has been synthesized by a single step in situ chemical oxidative polymerization method. The synthesis of Poly (N-ethyl aniline)/Ag nanocomposite has been confirmed by X-ray diffraction (XRD), Ultraviolet-Vis Spectroscopy (UV-visible), Fourier transform infrared analysis (FTIR) and FE-SEM investigations. XRD spectral study exhibited major diffraction in the range 20-80∘ (2θ) and indicated the semicrystalline nature of poly (N-ethyl aniline)/Ag nanocomposite. Characteristic peaks in UV-visible and FTIR spectra of poly (N-ethyl aniline) switched to higher wave numbers in poly (N-ethyl aniline)/Ag nanocomposite. Peaks at 1789cm-1, 1595cm-1, 667cm-1 and 501cm-1 in FTIR spectrum confirmed the formation of poly (N-ethyl aniline)/Ag nanocomposite. FE-SEM photographs reported agglomerated granular particulate nature of poly (N-ethyl aniline)/Ag nanocomposite. Synthesized poly (N-ethyl aniline)/Ag nanocomposite exhibited a high response to humidity, good reproducibility and stability at room temperature. An appreciable response was shown in the presence of 40% humid atmosphere for up to successive four cycles. Composite sensitivity has been found to increase with the increasing concentration of humidity, at room temperature.

21 CFR 184.1295 - Ethyl formate.

Code of Federal Regulations, 2010 CFR

2010-04-01

...)(22) of this chapter; and 0.01 percent in all other food categories. (e) Prior sanctions for ethyl... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Ethyl formate. 184.1295 Section 184.1295 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN...

Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product–Drug Interaction

PubMed Central

Gufford, Brandon T.; Chen, Gang; Vergara, Ana G.; Lazarus, Philip; Oberlies, Nicholas H.

2015-01-01

Women at high risk of developing breast cancer are prescribed selective estrogen response modulators, including raloxifene, as chemoprevention. Patients often seek complementary and alternative treatment modalities, including herbal products, to supplement prescribed medications. Milk thistle preparations, including silibinin and silymarin, are top-selling herbal products that may be consumed by women taking raloxifene, which undergoes extensive first-pass glucuronidation in the intestine. Key constituents in milk thistle, flavonolignans, were previously shown to be potent inhibitors of intestinal UDP-glucuronosyl transferases (UGTs), with IC50s ≤ 10 μM. Taken together, milk thistle preparations may perpetrate unwanted interactions with raloxifene. The objective of this work was to evaluate the inhibitory effects of individual milk thistle constituents on the intestinal glucuronidation of raloxifene using human intestinal microsomes and human embryonic kidney cell lysates overexpressing UGT1A1, UGT1A8, and UGT1A10, isoforms highly expressed in the intestine that are critical to raloxifene clearance. The flavonolignans silybin A and silybin B were potent inhibitors of both raloxifene 4′- and 6-glucuronidation in all enzyme systems. The Kis (human intestinal microsomes, 27–66 µM; UGT1A1, 3.2–8.3 µM; UGT1A8, 19–73 µM; and UGT1A10, 65–120 µM) encompassed reported intestinal tissue concentrations (20–310 µM), prompting prediction of clinical interaction risk using a mechanistic static model. Silibinin and silymarin were predicted to increase raloxifene systemic exposure by 4- to 5-fold, indicating high interaction risk that merits further evaluation. This systematic investigation of the potential interaction between a widely used herbal product and chemopreventive agent underscores the importance of understanding natural product–drug interactions in the context of cancer prevention. PMID:26070840

Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product-Drug Interaction.

PubMed

Gufford, Brandon T; Chen, Gang; Vergara, Ana G; Lazarus, Philip; Oberlies, Nicholas H; Paine, Mary F

2015-09-01

Women at high risk of developing breast cancer are prescribed selective estrogen response modulators, including raloxifene, as chemoprevention. Patients often seek complementary and alternative treatment modalities, including herbal products, to supplement prescribed medications. Milk thistle preparations, including silibinin and silymarin, are top-selling herbal products that may be consumed by women taking raloxifene, which undergoes extensive first-pass glucuronidation in the intestine. Key constituents in milk thistle, flavonolignans, were previously shown to be potent inhibitors of intestinal UDP-glucuronosyl transferases (UGTs), with IC50s ≤ 10 μM. Taken together, milk thistle preparations may perpetrate unwanted interactions with raloxifene. The objective of this work was to evaluate the inhibitory effects of individual milk thistle constituents on the intestinal glucuronidation of raloxifene using human intestinal microsomes and human embryonic kidney cell lysates overexpressing UGT1A1, UGT1A8, and UGT1A10, isoforms highly expressed in the intestine that are critical to raloxifene clearance. The flavonolignans silybin A and silybin B were potent inhibitors of both raloxifene 4'- and 6-glucuronidation in all enzyme systems. The Kis (human intestinal microsomes, 27-66 µM; UGT1A1, 3.2-8.3 µM; UGT1A8, 19-73 µM; and UGT1A10, 65-120 µM) encompassed reported intestinal tissue concentrations (20-310 µM), prompting prediction of clinical interaction risk using a mechanistic static model. Silibinin and silymarin were predicted to increase raloxifene systemic exposure by 4- to 5-fold, indicating high interaction risk that merits further evaluation. This systematic investigation of the potential interaction between a widely used herbal product and chemopreventive agent underscores the importance of understanding natural product-drug interactions in the context of cancer prevention. Copyright © 2015 by The American Society for Pharmacology and Experimental

Process for the preparation of ethyl benzene

DOEpatents

Smith, L.A. Jr.; Arganbright, R.P.; Hearn, D.

1995-12-19

Ethyl benzene is produced in a catalyst bed under 0.25 to 50 atmospheres of pressure and at temperatures in the range of 50 C to 300 C, using as the catalyst a mole sieve characterized as acidic by feeding ethylene to the catalyst bed while benzene is conveniently added through the reflux to result in a molar excess present in the reactor to that required to react with ethylene, thereby reacting substantially all of the ethylene and recovering benzene as the principal overhead and ethyl benzene and diethyl benzene in the bottoms. The bottoms are fractionated, the ethyl benzene recovered and the bottoms are contacted with benzene in the liquid phase in a fixed bed straight pass reactor under conditions to transalkylate the benzene thereby converting most of the diethyl benzene to ethyl benzene which is again separated and recovered. 2 figs.

Process for the preparation of ethyl benzene

DOEpatents

Smith, Jr., Lawrence A.; Arganbright, Robert P.; Hearn, Dennis

1995-01-01

Ethyl benzene is produced in a catalyst bed under 0.25 to 50 atmospheres of pressure and at temperatures in the range of 50.degree. C. to 300.degree. C., using as the catalyst a mole sieve characterized as acidic by feeding ethylene to the catalyst bed while benzene is conveniently added through the reflux to result in a molar excess present in the reactor to that required to react with ethylene, thereby reacting substantially all of the ethylene and recovering benzene as the principal overhead and ethyl benzene and diethyl benzene in the bottoms. The bottoms are fractionated, the ethyl benzene recovered and the bottoms are contacted with benzene in the liquid phase in a fixed bed straight pass reactor under conditions to transalkylate the benzene thereby converting most of the diethyl benzene to ethyl benzene which is again separated and recovered.

40 CFR 180.441 - Quizalofop ethyl; tolerances for residues.

Code of Federal Regulations, 2013 CFR

2013-07-01

... residues of the herbicide quizalofop ethyl, including its metabolites and degradates, in or on the....05 (2) Tolerances are established for residues of the herbicide quizalofop ethyl, including its... the herbicide quizalofop ethyl, including its metabolites and degradates, in or on the commodities in...

40 CFR 180.441 - Quizalofop ethyl; tolerances for residues.

Code of Federal Regulations, 2012 CFR

2012-07-01

... residues of the herbicide quizalofop ethyl, including its metabolites and degradates, in or on the....05 (2) Tolerances are established for residues of the herbicide quizalofop ethyl, including its... the herbicide quizalofop ethyl, including its metabolites and degradates, in or on the commodities in...

40 CFR 180.441 - Quizalofop ethyl; tolerances for residues.

Code of Federal Regulations, 2014 CFR

2014-07-01

... residues of the herbicide quizalofop ethyl, including its metabolites and degradates, in or on the....05 (2) Tolerances are established for residues of the herbicide quizalofop ethyl, including its... the herbicide quizalofop ethyl, including its metabolites and degradates, in or on the commodities in...

Challenges in the indirect quantitation of acyl-glucuronide metabolites of a cardiovascular drug from complex biological mixtures in the absence of reference standards.

PubMed

Srinivasan, Karthik; Nouri, Parya; Kavetskaia, Olga

2010-07-01

This paper describes the quantitation of acyl-glucuronide metabolites (M26 and M5) of a cardiovascular-drug (torcetrapib) from monkey urine, in the absence of their reference standards. LC/MS/MS assays for M1 and M4 (aglycones of M26 and M5, respectively) were characterized from normal and base-treated urine, as their respective reference standards were available. The in vivo study samples containing M26 and M5 were treated with 1 n sodium hydroxide to hydrolyze them to their respective aglycones. The study samples were assayed for M1 and M4 before and after alkaline hydrolysis and the difference in the concentrations provided an estimate of the urinary levels of M26 and M5. Prior to the main sample analysis, conditions for alkaline hydrolysis of the glucuronides were optimized by incubating pooled study samples. During incubations, a prolonged increase in M4 levels over time was observed, which is inconsistent with the base-hydrolysis of an acyl-glucuronide (expected to hydrolyze rapidly). Possible interference of the metabolite M9 (an ether-glucuronide metabolite isobaric to M4) was investigated to explain this observation using chromatographic and wet-chemistry approaches. The strategies adopted herein established that the LC/MS/MS assay and our approach were reliable. The metabolite exposure was then correlated to toxicological observations to gain initial insights into the physiological role of these metabolites. Copyright (c) 2009 John Wiley & Sons, Ltd.

Microwave spectroscopy and curious molecular dynamics of ethyl trifluoroacetate

NASA Astrophysics Data System (ADS)

Bohn, Robert K.; Montgomery, John A.; Harvey Michels, H.; Acharte, Christian

2017-05-01

The first ethyl ester whose structure was determined by microwave spectroscopy is ethyl formate. It exists in two conformations. In the 1970s, that study was used as a model to determine the structures of other ethyl esters, ethyl cyanoformate, chloroformate, and trifluoroacetate. They display the same conformations as ethyl formate. But under the experimental conditions used, Stark modulation with a maximum electric field, static low pressure gas, rapid sweeping, and long detector time constants, each of those esters displays bands of an additional third species. A careful, high resolution study of ethyl cyanoformate only observed two conformers. A model has been proposed that the third species derives from a dense array of torsionally excited states with broadened transitions due to short lifetimes. The present study of ethyl trifluoroacetate in a pulsed jet Fourier Transform spectrometer is intended to clarify the earlier results. Two conformers are observed including all their monosubstituted 13C and 18O isotopologs. In a pulsed jet Fourier Transform spectrometer using argon as the carrier gas, only one conformer is observed. Switching to helium as the carrier gas, another, higher energy conformer is also observed.

40 CFR 180.430 - Fenoxaprop-ethyl; tolerances for residues.

Code of Federal Regulations, 2014 CFR

2014-07-01

... residues of the herbicide fenoxaprop-ethyl, including its metabolites and degradates, in or on the... for residues of the herbicide fenoxaprop-ethyl, including its metabolites and degradates, in or on the... registration, as defined in § 180.1(l), are established for residues of the herbicide fenoxaprop-ethyl...

Gas chromatography-mass spectrometry of ethyl palmitate calibration and resolution with ethyl oleate as biomarker ethanol sub acute in urine application study

NASA Astrophysics Data System (ADS)

Suaniti, Ni Made; Manurung, Manuntun

2016-03-01

Gas Chromatography-Mass Spectrometry is used to separate two and more compounds and identify fragment ion specific of biomarker ethanol such as palmitic acid ethyl ester (PAEE), as one of the fatty acid ethyl esters as early detection through conyugated reaction. This study aims to calibrate ethyl palmitate and develop analysis with oleate acid. This methode can be used analysis ethanol and its chemistry biomarker in ethanol sub-acute consumption as analytical forensic toxicology. The result show that ethanol level in urine rats Wistar were 9.21 and decreased 6.59 ppm after 48 hours consumption. Calibration curve of ethyl palmitate was y = 0.2035 x + 1.0465 and R2 = 0.9886. Resolution between ethyl palmitate and oleate were >1.5 as good separation with fragment ion specific was 88 and the retention time was 18 minutes.

Is enzymatic hydrolysis a reliable analytical strategy to quantify glucuronidated and sulfated polyphenol metabolites in human fluids?

PubMed

Quifer-Rada, Paola; Martínez-Huélamo, Miriam; Lamuela-Raventos, Rosa M

2017-07-19

Phenolic compounds are present in human fluids (plasma and urine) mainly as glucuronidated and sulfated metabolites. Up to now, due to the unavailability of standards, enzymatic hydrolysis has been the method of choice in analytical chemistry to quantify these phase II phenolic metabolites. Enzymatic hydrolysis procedures vary in enzyme concentration, pH and temperature; however, there is a lack of knowledge about the stability of polyphenols in their free form during the process. In this study, we evaluated the stability of 7 phenolic acids, 2 flavonoids and 3 prenylflavanoids in urine during enzymatic hydrolysis to assess the suitability of this analytical procedure, using three different concentrations of β-glucuronidase/sulfatase enzymes from Helix pomatia. The results indicate that enzymatic hydrolysis negatively affected the recovery of the precursor and free-form polyphenols present in the sample. Thus, enzymatic hydrolysis does not seem an ideal analytical strategy to quantify glucuronidated and sulfated polyphenol metabolites.

Hepatic Disposition of Gemfibrozil and Its Major Metabolite Gemfibrozil 1-O-β-Glucuronide.

PubMed

Kimoto, Emi; Li, Rui; Scialis, Renato J; Lai, Yurong; Varma, Manthena V S

2015-11-02

Gemfibrozil (GEM), which decreases serum triglycerides and low density lipoprotein, perpetrates drug-drug interactions (DDIs) with several drugs. These DDIs are primarily attributed to the inhibition of drug transporters and metabolic enzymes, particularly cytochrome P450 (CYP) 2C8 by the major circulating metabolite gemfibrozil 1-O-β-glucuronide (GG). Here, we characterized the transporter-mediated hepatic disposition of GEM and GG using sandwich-cultured human hepatocytes (SCHH) and transporter-transfect systems. Significant active uptake was noted in SCHH for the metabolite. GG, but not GEM, showed substrate affinity to organic anion transporting polypeptide (OATP) 1B1, 1B3, and 2B1. In SCHH, glucuronidation was characterized affinity constants (Km) of 7.9 and 61.4 μM, and biliary excretion of GG was observed. Furthermore, GG showed active basolateral efflux from preloaded SCHH and ATP-dependent uptake into membrane vesicles overexpressing multidrug resistance-associated protein (MRP) 2, MRP3, and MRP4. A mathematical model was developed to estimate hepatic uptake and efflux kinetics of GEM and GG based on SCHH studies. Collectively, the hepatic transporters play a key role in the disposition and thus determine the local concentrations of GEM and more so for GG, which is the predominant inhibitory species against CYP2C8 and OATP1B1.

Icosapent ethyl (eicosapentaenoic acid ethyl ester): Effects on remnant-like particle cholesterol from the MARINE and ANCHOR studies.

PubMed

Ballantyne, Christie M; Bays, Harold E; Philip, Sephy; Doyle, Ralph T; Braeckman, Rene A; Stirtan, William G; Soni, Paresh N; Juliano, Rebecca A

2016-10-01

Remnant-like particle cholesterol (RLP-C) is atherogenic and may increase atherosclerotic cardiovascular disease risk. Icosapent ethyl is a high-purity prescription eicosapentaenoic acid ethyl ester (approved as an adjunct to diet to reduce triglyceride [TG] levels in adult patients with TGs ≥500 mg/dL [≥5.65 mmol/L] at 4 g/day). In the MARINE and ANCHOR studies, icosapent ethyl reduced TG and other atherogenic lipid parameter levels without increasing low-density lipoprotein cholesterol (LDL-C) levels. This exploratory analysis evaluated the effects of icosapent ethyl on calculated and directly measured RLP-C. MARINE (TGs ≥500 and ≤2000 mg/dL [≥5.65 mmol/L and ≤22.6 mmol/L]) and ANCHOR (TGs ≥200 and <500 mg/dL [≥2.26 and <5.65 mmol/L] despite statin-controlled LDL-C) were phase 3, 12-week, double-blind studies that randomized adult patients to icosapent ethyl 4 g/day, 2 g/day, or placebo. This analysis assessed median percent change from baseline to study end in directly measured (immunoseparation assay) RLP-C levels (MARINE, n = 218; ANCHOR, n = 252) and calculated RLP-C levels in the full populations. Icosapent ethyl 4 g/day significantly reduced directly measured RLP-C levels -29.8% (p = 0.004) in MARINE and -25.8% (p = 0.0001) in ANCHOR versus placebo, and also reduced directly measured RLP-C levels to a greater extent in subgroups with higher versus lower baseline TG levels, in patients receiving statins versus no statins (MARINE), and in patients receiving medium/higher-intensity versus lower-intensity statins (ANCHOR). Strong correlations were found between calculated and directly measured RLP-C for baseline, end-of-treatment, and percent change values in ANCHOR and MARINE (0.73-0.92; p < 0.0001 for all). Icosapent ethyl 4 g/day significantly reduced calculated and directly measured RLP-C levels versus placebo in patients with elevated TG levels from the MARINE and ANCHOR studies. Copyright © 2016 The Authors

Targeted delivery of vitamin D to the colon using β-glucuronides of vitamin D: therapeutic effects in a murine model of inflammatory bowel disease

PubMed Central

Koszewski, Nicholas J.; Haynes, Joseph S.; Horst, Ronald L.

2012-01-01

1,25-Dihydroxyvitamin D3 [1,25(OH)2D] has been shown to inhibit development of dextran sodium sulfate (DSS)-induced colitis in mice but can also cause hypercalcemia. The aim of this study was to evaluate whether β-glucuronides of vitamin D could deliver 1,25(OH)2D to the colon to ameliorate colitis while reducing the risk of hypercalcemia. Initial studies demonstrated that bacteria residing in the lower intestinal tract were capable of liberating 1,25(OH)2D from 1,25-dihydroxyvitamin D3-25-β-glucuronide [β-gluc-1,25(OH)2D]. We also determined that a much greater upregulation of the vitamin D-dependent 24-hydroxylase gene (Cyp24) was induced in the colon by treatment of mice with an oral dose of β-gluc-1,25(OH)2D than 1,25(OH)2D, demonstrating targeted delivery of 1,25(OH)2D to the colon. We then tested β-glucuronides of vitamin D in the mouse DSS colitis model in two studies. In mice receiving DSS dissolved in distilled water and treated with 1,25(OH)2D or β-gluc-1,25(OH)2D, severity of colitis was reduced. Combination of β-gluc-1,25(OH)2D with 25-hydroxyvitamin D3-25-β-glucuronide [β-gluc-25(OH)D] resulted in the greatest reduction of colitis lesions and symptoms in DSS-treated mice. Plasma calcium concentrations were lower in mice treated with β-gluc-1,25(OH)2D alone or in combination with β-gluc-25(OH)D than in mice treated with 1,25(OH)2D, which were hypercalcemic at the time of death. β-Glucuronides of vitamin D compounds can deliver 1,25(OH)2D to the lower intestine and can reduce symptoms and lesions of acute colitis in this model. PMID:22114117

19 CFR 10.99 - Importation of ethyl alcohol for nonbeverage purposes.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 1 2011-04-01 2011-04-01 false Importation of ethyl alcohol for nonbeverage... Provisions Ethyl Alcohol § 10.99 Importation of ethyl alcohol for nonbeverage purposes. (a) If claim is made... of ethyl alcohol of an alcoholic strength by volume of 80 percent volume or higher under subheading...

Glucuronidation of OTS167 in Humans Is Catalyzed by UDP-Glucuronosyltransferases UGT1A1, UGT1A3, UGT1A8, and UGT1A10

PubMed Central

Ramírez, Jacqueline; Mirkov, Snezana; House, Larry K.

2015-01-01

OTS167 is a potent maternal embryonic leucine zipper kinase inhibitor undergoing clinical testing as antineoplastic agent. We aimed to identify the UDP-glucuronosyltransferases (UGTs) involved in OTS167 metabolism, study the relationship between UGT genetic polymorphisms and hepatic OTS167 glucuronidation, and investigate the inhibitory potential of OTS167 on UGTs. Formation of a single OTS167-glucuronide (OTS167-G) was observed in pooled human liver (HLM) (Km = 3.4 ± 0.2 µM), intestinal microsomes (HIM) (Km = 1.7 ± 0.1 µM), and UGTs. UGT1A1 (64 µl/min/mg) and UGT1A8 (72 µl/min/mg) exhibited the highest intrinsic clearances (CLint) for OTS167, followed by UGT1A3 (51 µl/min/mg) and UGT1A10 (47 µl/min/mg); UGT1A9 was a minor contributor. OTS167 glucuronidation in HLM was highly correlated with thyroxine glucuronidation (r = 0.91, P < 0.0001), SN-38 glucuronidation (r = 0.79, P < 0.0001), and UGT1A1 mRNA (r = 0.72, P < 0.0001). Nilotinib (UGT1A1 inhibitor) and emodin (UGT1A8 and UGT1A10 inhibitor) exhibited the highest inhibitory effects on OTS167-G formation in HLM (68%) and HIM (47%). We hypothesize that OTS167-G is an N-glucuronide according to mass spectrometry. A significant association was found between rs6706232 and reduced OTS167-G formation (P = 0.03). No or weak UGT inhibition (range: 0–21%) was observed using clinically relevant OTS167 concentrations (0.4–2 µM). We conclude that UGT1A1 and UGT1A3 are the main UGTs responsible for hepatic formation of OTS167-G. Intestinal UGT1A1, UGT1A8, and UGT1A10 may contribute to first-pass OTS167 metabolism after oral administration. PMID:25870101

Glucuronidation of OTS167 in Humans Is Catalyzed by UDP-Glucuronosyltransferases UGT1A1, UGT1A3, UGT1A8, and UGT1A10.

PubMed

Ramírez, Jacqueline; Mirkov, Snezana; House, Larry K; Ratain, Mark J

2015-07-01

OTS167 is a potent maternal embryonic leucine zipper kinase inhibitor undergoing clinical testing as antineoplastic agent. We aimed to identify the UDP-glucuronosyltransferases (UGTs) involved in OTS167 metabolism, study the relationship between UGT genetic polymorphisms and hepatic OTS167 glucuronidation, and investigate the inhibitory potential of OTS167 on UGTs. Formation of a single OTS167-glucuronide (OTS167-G) was observed in pooled human liver (HLM) (Km = 3.4 ± 0.2 µM), intestinal microsomes (HIM) (Km = 1.7 ± 0.1 µM), and UGTs. UGT1A1 (64 µl/min/mg) and UGT1A8 (72 µl/min/mg) exhibited the highest intrinsic clearances (CLint) for OTS167, followed by UGT1A3 (51 µl/min/mg) and UGT1A10 (47 µl/min/mg); UGT1A9 was a minor contributor. OTS167 glucuronidation in HLM was highly correlated with thyroxine glucuronidation (r = 0.91, P < 0.0001), SN-38 glucuronidation (r = 0.79, P < 0.0001), and UGT1A1 mRNA (r = 0.72, P < 0.0001). Nilotinib (UGT1A1 inhibitor) and emodin (UGT1A8 and UGT1A10 inhibitor) exhibited the highest inhibitory effects on OTS167-G formation in HLM (68%) and HIM (47%). We hypothesize that OTS167-G is an N-glucuronide according to mass spectrometry. A significant association was found between rs6706232 and reduced OTS167-G formation (P = 0.03). No or weak UGT inhibition (range: 0-21%) was observed using clinically relevant OTS167 concentrations (0.4-2 µM). We conclude that UGT1A1 and UGT1A3 are the main UGTs responsible for hepatic formation of OTS167-G. Intestinal UGT1A1, UGT1A8, and UGT1A10 may contribute to first-pass OTS167 metabolism after oral administration. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent-Metabolite Population Pharmacokinetic Model

PubMed Central

Cook, Sarah F.; Stockmann, Chris; Samiee-Zafarghandy, Samira; King, Amber D.; Deutsch, Nina; Williams, Elaine F.; Wilkins, Diana G.; van den Anker, John N.

2017-01-01

Objectives This study aimed to model the population pharmacokinetics of intravenous paracetamol and its major metabolites in neonates and to identify influential patient characteristics, especially those affecting the formation clearance (CLformation) of oxidative pathway metabolites. Methods Neonates with a clinical indication for intravenous analgesia received five 15-mg/kg doses of paracetamol at 12-h intervals (<28 weeks’ gestation) or seven 15-mg/kg doses at 8-h intervals (≥28 weeks’ gestation). Plasma and urine were sampled throughout the 72-h study period. Concentration-time data for paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine) were simultaneously modeled in NONMEM 7.2. Results The model incorporated 259 plasma and 350 urine samples from 35 neonates with a mean gestational age of 33.6 weeks (standard deviation 6.6). CLformation for all metabolites increased with weight; CLformation for glucuronidation and oxidation also increased with postnatal age. At the mean weight (2.3 kg) and postnatal age (7.5 days), CLformation estimates (bootstrap 95% confidence interval; between-subject variability) were 0.049 L/h (0.038–0.062; 62 %) for glucuronidation, 0.21 L/h (0.17–0.24; 33 %) for sulfation, and 0.058 L/h (0.044–0.078; 72 %) for oxidation. Expression of individual oxidation CLformation as a fraction of total individual paracetamol clearance showed that, on average, fractional oxidation CLformation increased <15 % when plotted against weight or postnatal age. Conclusions The parent-metabolite model successfully characterized the pharmacokinetics of intravenous paracetamol and its metabolites in neonates. Maturational changes in the fraction of paracetamol undergoing oxidation were small relative to between-subject variability. PMID:27209292

40 CFR 180.483 - O-[2-(1,1-Dimethylethyl)-5-pyrimidinyl] O-ethyl-O-(1-methyl-ethyl) phosphorothioate; tolerances...

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 23 2010-07-01 2010-07-01 false O-[2-(1,1-Dimethylethyl)-5-pyrimidinyl] O-ethyl-O-(1-methyl-ethyl) phosphorothioate; tolerances for residues. 180.483 Section 180.483... EXEMPTIONS FOR PESTICIDE CHEMICAL RESIDUES IN FOOD Specific Tolerances § 180.483 O-[2-(1,1-Dimethylethyl)-5...

Determining the partial photoionization cross-sections of ethyl radicals.

PubMed

FitzPatrick, B L; Maienschein-Cline, M; Butler, L J; Lee, S-H; Lin, J J

2007-12-13

Using a crossed laser-molecular beam scattering apparatus, these experiments photodissociate ethyl chloride at 193 nm and detect the Cl and ethyl products, resolved by their center-of-mass recoil velocities, with vacuum ultraviolet photoionization. The data determine the relative partial cross-sections for the photoionization of ethyl radicals to form C2H5+, C2H4+, and C2H3+ at 12.1 and 13.8 eV. The data also determine the internal energy distribution of the ethyl radical prior to photoionization, so we can assess the internal energy dependence of the photoionization cross-sections. The results show that the C2H4++H and C2H3++H2 dissociative photoionization cross-sections strongly depend on the photoionization energy. Calibrating the ethyl radical partial photoionization cross-sections relative to the bandwidth-averaged photoionization cross-section of Cl atoms near 13.8 eV allows us to use these data in conjunction with literature estimates of the Cl atom photoionization cross-sections to put the present bandwidth-averaged cross-sections on an absolute scale. The resulting bandwidth-averaged cross-section for the photoionization of ethyl radicals to C2H5+ near 13.8 eV is 8+/-2 Mb. Comparison of our 12.1 eV data with high-resolution ethyl radical photoionization spectra allows us to roughly put the high-resolution spectrum on the same absolute scale. Thus, one obtains the photoionization cross-section of ethyl radicals to C2H5+ from threshold to 12.1 eV. The data show that the onset of the C2H4++H dissociative photoionization channel is above 12.1 eV; this result offers a simple way to determine whether the signal observed in photoionization experiments on complex mixtures is due to ethyl radicals. We discuss an application of the results for resolving the product branching in the O+allyl bimolecular reaction.

Supercritical antisolvent co-precipitation of rifampicin and ethyl cellulose.

PubMed

Djerafi, Rania; Swanepoel, Andri; Crampon, Christelle; Kalombo, Lonji; Labuschagne, Philip; Badens, Elisabeth; Masmoudi, Yasmine

2017-05-01

Rifampicin-loaded submicron-sized particles were prepared through supercritical anti-solvent process using ethyl cellulose as polymeric encapsulating excipient. Ethyl acetate and a mixture of ethyl acetate/dimethyl sulfoxide (70/30 and 85/15) were used as solvents for both drug and polymeric excipient. When ethyl acetate was used, rifampicin was crystallized separately without being embedded within the ethyl cellulose matrix while by using the ethyl acetate/dimethyl sulfoxide mixture, reduced crystallinity of the active ingredient was observed and a simultaneous precipitation of ethyl cellulose and drug was achieved. The effect of solvent/CO 2 molar ratio and polymer/drug mass ratio on the co-precipitates morphology and drug loading was investigated. Using the solvent mixture, co-precipitates with particle sizes ranging between 190 and 230nm were obtained with drug loading and drug precipitation yield from respectively 8.5 to 38.5 and 42.4 to 77.2% when decreasing the ethyl cellulose/rifampicin ratio. Results show that the solvent nature and the initial drug concentrations affect morphology and drug precipitation yield of the formulations. In vitro dissolution studies revealed that the release profile of rifampicin was sustained when co-precipitation was carried out with the solvent mixture. It was demonstrated that the drug to polymer ratio influenced amorphous content of the SAS co-precipitates. Differential scanning calorimetry thermograms and infrared spectra revealed that there is neither interaction between rifampicin and the polymer nor degradation of rifampicin during co-precipitation. In addition, stability stress tests on SAS co-precipitates were carried out at 75% relative humidity and room temperature in order to evaluate their physical stability. SAS co-precipitates were X-ray amorphous and remained stable after 6months of storage. The SAS co-precipitation process using a mixture of ethyl acetate/dimethyl sulfoxide demonstrates that this strategy can

Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome.

PubMed

Kulke, Matthew H; Hörsch, Dieter; Caplin, Martyn E; Anthony, Lowell B; Bergsland, Emily; Öberg, Kjell; Welin, Staffan; Warner, Richard R P; Lombard-Bohas, Catherine; Kunz, Pamela L; Grande, Enrique; Valle, Juan W; Fleming, Douglas; Lapuerta, Pablo; Banks, Phillip; Jackson, Shanna; Zambrowicz, Brian; Sands, Arthur T; Pavel, Marianne

2017-01-01

Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.

Quantification of Cannabinoids and their Free and Glucuronide Metabolites in Whole Blood by Disposable Pipette Extraction and Liquid Chromatography Tandem Mass Spectrometry

PubMed Central

Scheidweiler, Karl B.; Newmeyer, Matthew N.; Barnes, Allan J.; Huestis, Marilyn A.

2016-01-01

Identifying recent cannabis intake is confounded by prolonged cannabinoid excretion in chronic frequent cannabis users. We previously observed detection times ≤2.1 h for cannabidiol (CBD) and cannabinol (CBN) and THC-glucuronide in whole blood after smoking, suggesting their applicability for identifying recent intake. However, whole blood collection may not occur for up to 4 h during driving under the influence of drugs investigations, making a recent-use marker with a 6-8 h detection window helpful for improving whole blood cannabinoid interpretation. Other minor cannabinoids cannabigerol (CBG), Δ9-tetrahydrocannabivarin (THCV), and its metabolite 11-nor-9-carboxy-THCV (THCVCOOH) might also be useful. We developed and validated a sensitive and specific liquid chromatography-tandem mass spectrometry method for quantification of THC, its phase I and glucuronide phase II metabolites, and 5 five minor cannabinoids. Cannabinoids were extracted from 200 μL whole blood via disposable pipette extraction, separated on a C18 column, and detected via electrospray ionization in negative mode with scheduled multiple reaction mass spectrometric monitoring. Linear ranges were 0.5-100 μg/L for THC and THCCOOH; 0.5-50 μg/L for 11-OH-THC, CBD, CBN, and THC-glucuronide; 1-50 μg/L for CBG, THCV, and THCVCOOH; and 5-500 μg/L for THCCOOH-glucuronide. Inter-day accuracy and precision at low, mid and high quality control (QC) concentrations were 95.1-113% and 2.4-8.5%, respectively (n=25). Extraction recoveries and matrix effects at low and high QC concentrations were 54.0-84.4% and −25.8-30.6%, respectively. By simultaneously monitoring multiple cannabinoids and metabolites, identification of recent cannabis administration or discrimination between licit medicinal and illicit recreational cannabis use can be improved. PMID:27236483

Quantification of cannabinoids and their free and glucuronide metabolites in whole blood by disposable pipette extraction and liquid chromatography-tandem mass spectrometry.

PubMed

Scheidweiler, Karl B; Newmeyer, Matthew N; Barnes, Allan J; Huestis, Marilyn A

2016-07-01

Identifying recent cannabis intake is confounded by prolonged cannabinoid excretion in chronic frequent cannabis users. We previously observed detection times ≤2.1h for cannabidiol (CBD) and cannabinol (CBN) and Δ(9)-tetrahydrocannabinol (THC)-glucuronide in whole blood after smoking, suggesting their applicability for identifying recent intake. However, whole blood collection may not occur for up to 4h during driving under the influence of drugs investigations, making a recent-use marker with a 6-8h detection window helpful for improving whole blood cannabinoid interpretation. Other minor cannabinoids cannabigerol (CBG), Δ9-tetrahydrocannabivarin (THCV), and its metabolite 11-nor-9-carboxy-THCV (THCVCOOH) might also be useful. We developed and validated a sensitive and specific liquid chromatography-tandem mass spectrometry method for quantification of THC, its phase I and glucuronide phase II metabolites, and 5 five minor cannabinoids. Cannabinoids were extracted from 200μL whole blood via disposable pipette extraction, separated on a C18 column, and detected via electrospray ionization in negative mode with scheduled multiple reaction mass spectrometric monitoring. Linear ranges were 0.5-100μg/L for THC and 11-nor-9-carboxy-THC (THCCOOH); 0.5-50μg/L for 11-hydroxy-THC (11-OH-THC), CBD, CBN, and THC-glucuronide; 1-50μg/L for CBG, THCV, and THCVCOOH; and 5-500μg/L for THCCOOH-glucuronide. Inter-day accuracy and precision at low, mid and high quality control (QC) concentrations were 95.1-113% and 2.4-8.5%, respectively (n=25). Extraction recoveries and matrix effects at low and high QC concentrations were 54.0-84.4% and -25.8-30.6%, respectively. By simultaneously monitoring multiple cannabinoids and metabolites, identification of recent cannabis administration or discrimination between licit medicinal and illicit recreational cannabis use can be improved. Published by Elsevier B.V.

Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent-Metabolite Population Pharmacokinetic Model.

PubMed

Cook, Sarah F; Stockmann, Chris; Samiee-Zafarghandy, Samira; King, Amber D; Deutsch, Nina; Williams, Elaine F; Wilkins, Diana G; Sherwin, Catherine M T; van den Anker, John N

2016-11-01

This study aimed to model the population pharmacokinetics of intravenous paracetamol and its major metabolites in neonates and to identify influential patient characteristics, especially those affecting the formation clearance (CL formation ) of oxidative pathway metabolites. Neonates with a clinical indication for intravenous analgesia received five 15-mg/kg doses of paracetamol at 12-h intervals (<28 weeks' gestation) or seven 15-mg/kg doses at 8-h intervals (≥28 weeks' gestation). Plasma and urine were sampled throughout the 72-h study period. Concentration-time data for paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine) were simultaneously modeled in NONMEM 7.2. The model incorporated 259 plasma and 350 urine samples from 35 neonates with a mean gestational age of 33.6 weeks (standard deviation 6.6). CL formation for all metabolites increased with weight; CL formation for glucuronidation and oxidation also increased with postnatal age. At the mean weight (2.3 kg) and postnatal age (7.5 days), CL formation estimates (bootstrap 95% confidence interval; between-subject variability) were 0.049 L/h (0.038-0.062; 62 %) for glucuronidation, 0.21 L/h (0.17-0.24; 33 %) for sulfation, and 0.058 L/h (0.044-0.078; 72 %) for oxidation. Expression of individual oxidation CL formation as a fraction of total individual paracetamol clearance showed that, on average, fractional oxidation CL formation increased <15 % when plotted against weight or postnatal age. The parent-metabolite model successfully characterized the pharmacokinetics of intravenous paracetamol and its metabolites in neonates. Maturational changes in the fraction of paracetamol undergoing oxidation were small relative to between-subject variability.

Icosapent ethyl: a review of its use in severe hypertriglyceridemia.

PubMed

Kim, Esther S; McCormack, Paul L

2014-12-01

Icosapent ethyl (Vascepa®) is a high-purity ethyl ester of eicosapentaenoic acid (EPA) that is de-esterified to EPA following oral administration. Both EPA and docosahexaenoic acid (DHA) are long-chain omega-3 fatty acids that have been associated with triglyceride (TG)-lowering. However, DHA has been associated with increased low-density lipoprotein cholesterol (LDL-C) levels. Icosapent ethyl contains ≥96 % of the EPA ethyl ester, does not contain DHA, and is approved in the USA for use as an adjunct to diet to lower TG levels in adult patients with severe (≥500 mg/dL [≥5.65 mmol/L]) hypertriglyceridemia. In a pivotal phase III trial, oral icosapent ethyl 4 g/day significantly decreased the placebo-corrected median TG levels by 33.1 %. It did not increase LDL-C, had favorable effects on other lipid parameters, and had a tolerability profile similar to that of placebo. Therefore, icosapent ethyl is an effective and well-tolerated agent for the treatment of severe hypertriglyceridemia in adults.

Dielectric Relaxation of the Ionic Liquid 1-Ethyl-3-methylimidazolium Ethyl Sulfate: Microwave and Far-IR Properties.

PubMed

Dhumal, Nilesh R; Kiefer, Johannes; Turton, David; Wynne, Klaas; Kim, Hyung J

2017-05-11

Dielectric relaxation of the ionic liquid, 1-ethyl-3-methylimidazolium ethyl sulfate (EMI + ETS - ), is studied using molecular dynamics (MD) simulations. The collective dynamics of polarization arising from cations and anions are examined. Characteristics of the rovibrational and translational components of polarization dynamics are analyzed to understand their respective roles in the microwave and terahertz regions of dielectric relaxation. The MD results are compared with the experimental low-frequency spectrum of EMI + ETS - , obtained via ultrafast optical Kerr effect (OKE) measurements.

40 CFR 180.430 - Fenoxaprop-ethyl; tolerances for residues.

Code of Federal Regulations, 2013 CFR

2013-07-01

... residues of the herbicide fenoxaprop-ethyl, including its metabolites and degradates, in or on the... for residues of the herbicide fenoxaprop-ethyl, including its metabolites and degradates, in or on the...

40 CFR 180.430 - Fenoxaprop-ethyl; tolerances for residues.

Code of Federal Regulations, 2012 CFR

2012-07-01

... residues of the herbicide fenoxaprop-ethyl, including its metabolites and degradates, in or on the... for residues of the herbicide fenoxaprop-ethyl, including its metabolites and degradates, in or on the...

Morphine 6 glucuronide stimulates nitric oxide release in mussel neural tissues: evidence for a morphine 6 glucuronide opiate receptor subtype.

PubMed

Mantione, K; Zhu, W; Rialas, C; Casares, F; Cadet, P; Franklin, A L; Tonnesen, J; Stefano, G B

2002-03-01

We have previously demonstrated that Mytilus edulis pedal ganglia contain opiate alkaloids, i.e., morphine and morphine 6 glucuronide (M6G), as well as mu opiate receptor subtype fragments exhibiting high sequence similarity to those found in mammals. Now we demonstrate that M6G stimulates pedal ganglia constitutive nitric oxide (NO) synthase (cNOS)-derived NO release at identical concentrations and to similar peak levels as morphine. However, the classic opiate antagonist, naloxone, only blocked the ability of morphine to stimulate cNOS-derived NO release and not that of M6G. CTOP, a mu-specific antagonist, blocked the ability of M6G to induce cNOS-derived NO release as well as that of morphine, suggesting that a novel mu opiate receptor was present and selective toward M6G. In examining a receptor displacement analysis, both opiate alkaloids displaced [3H]-dihydromorphine binding to the mu opiate receptor subtype. However, morphine exhibited a twofold higher affinity, again suggesting that a novel mu opiate receptor may be present.

PET imaging of β-glucuronidase activity by an activity-based 124I-trapping probe for the personalized glucuronide prodrug targeted therapy.

PubMed

Su, Yu-Cheng; Cheng, Ta-Chun; Leu, Yu-Ling; Roffler, Steve R; Wang, Jaw-Yuan; Chuang, Chih-Hung; Kao, Chien-Han; Chen, Kai-Chuan; Wang, Hsin-Ell; Cheng, Tian-Lu

2014-12-01

Beta-glucuronidase (βG) is a potential biomarker for cancer diagnosis and prodrug therapy. The ability to image βG activity in patients would assist in personalized glucuronide prodrug cancer therapy. However, whole-body imaging of βG activity for medical usage is not yet available. Here, we developed a radioactive βG activity-based trapping probe for positron emission tomography (PET). We generated a (124)I-tyramine-conjugated difluoromethylphenol beta-glucuronide probe (TrapG) to form (124)I-TrapG that could be selectively activated by βG for subsequent attachment of (124)I-tyramine to nucleophilic moieties near βG-expressing sites. We estimated the specificity of a fluorescent FITC-TrapG, the cytotoxicity of tyramine-TrapG, and the serum half-life of (124)I-TrapG. βG targeting of (124)I-TrapG in vivo was examined by micro-PET. The biodistribution of (131)I-TrapG was investigated in different organs. Finally, we imaged the endogenous βG activity and assessed its correlation with therapeutic efficacy of 9-aminocamptothecin glucuronide (9ACG) prodrug in native tumors. FITC-TrapG showed specific trapping at βG-expressing CT26 (CT26/mβG) cells but not in CT26 cells. The native TrapG probe possessed low cytotoxicity. (124)I-TrapG preferentially accumulated in CT26/mβG but not CT26 cells. Meanwhile, micro-PET and whole-body autoradiography results demonstrated that (124)I-TrapG signals in CT26/mβG tumors were 141.4-fold greater than in CT26 tumors. Importantly, Colo205 xenografts in nude mice that express elevated endogenous βG can be monitored by using infrared glucuronide trapping probes (NIR-TrapG) and suppressed by 9ACG prodrug treatment. (124)I-TrapG exhibited low cytotoxicity allowing long-term monitoring of βG activity in vivo to aid in the optimization of prodrug targeted therapy. ©2014 American Association for Cancer Research.

RELATIONSHIP BETWEEN HEPATIC MICROSOMAL THYROXINE GLUCURONIDATION AND TOTAL SERUM THYROXINE CONCENTRATIONS IN RATS TREATED WITH PCDDS, PCDFS AND PCBS

EPA Science Inventory

RELATIONSHIP BETWEEN HEPATIC MICROSOMAL THYROXINE GLUCURONIDATION AND TOTAL SERUM THYROXINE CONCENTRATIONS IN RATS TREATED WITH PCDDs, PCDFs AND PCBs. D G Ross, K M Crofton, M J DeVito, NHEERL, ORD, USEPA, RTP, NC.
Many PHAHs decrease thyroxine (T4), possibly due to inducti...

Human and Rat ABC Transporter Efflux of Bisphenol A and Bisphenol A Glucuronide: Interspecies Comparison and Implications for Pharmacokinetic Assessment

EPA Science Inventory

Significant interspecies differences exist between human and rodent with respect to absorption, distribution, and excretion of bisphenol A (BPA) and its primary metabolite, BPA-glucuronide (BPA-G). ATP-Binding Cassette (ABC) transporter enzymes play important roles in these physi...

S-Ethyl dipropylthiocarbamate (EPTC)

Integrated Risk Information System (IRIS)

Integrated Risk Information System ( IRIS ) Chemical Assessment Summary U.S . Environmental Protection Agency National Center for Environmental Assessment This IRIS Summary has been removed from the IRIS database and is available for historical reference purposes . ( July 2016 ) S - Ethyl dipropylth

Fragmentation dynamics of the ethyl bromide and ethyl iodide cations: a velocity-map imaging study.

PubMed

Gardiner, Sara H; Karsili, Tolga N V; Lipciuc, M Laura; Wilman, Edward; Ashfold, Michael N R; Vallance, Claire

2014-02-07

The photodissociation dynamics of ethyl bromide and ethyl iodide cations (C2H5Br(+) and C2H5I(+)) have been studied. Ethyl halide cations were formed through vacuum ultraviolet (VUV) photoionization of the respective neutral parent molecules at 118.2 nm, and were photolysed at a number of ultraviolet (UV) photolysis wavelengths, including 355 nm and wavelengths in the range from 236 to 266 nm. Time-of-flight mass spectra and velocity-map images have been acquired for all fragment ions and for ground (Br) and spin-orbit excited (Br*) bromine atom products, allowing multiple fragmentation pathways to be investigated. The experimental studies are complemented by spin-orbit resolved ab initio calculations of cuts through the potential energy surfaces (along the RC-Br/I stretch coordinate) for the ground and first few excited states of the respective cations. Analysis of the velocity-map images indicates that photoexcited C2H5Br(+) cations undergo prompt C-Br bond fission to form predominantly C2H5(+) + Br* products with a near-limiting 'parallel' recoil velocity distribution. The observed C2H3(+) + H2 + Br product channel is thought to arise via unimolecular decay of highly internally excited C2H5(+) products formed following radiationless transfer from the initial excited state populated by photon absorption. Broadly similar behaviour is observed in the case of C2H5I(+), along with an additional energetically accessible C-I bond fission channel to form C2H5 + I(+) products. HX (X = Br, I) elimination from the highly internally excited C2H5X(+) cation is deemed the most probable route to forming the C2H4(+) fragment ions observed from both cations. Finally, both ethyl halide cations also show evidence of a minor C-C bond fission process to form CH2X(+) + CH3 products.

40 CFR 180.595 - Flufenpyr-ethyl; tolerances for residues.

Code of Federal Regulations, 2013 CFR

2013-07-01

... residues of the herbicide, flufenpyr-ethyl; acetic acid, [2-chloro-4-fluoro-5-[5-methyl-6-oxo-4... established for residues of the herbicide flufenpyr-ethyl; acetic acid, [2-chloro-4-fluoro-5-[5-methyl-6-oxo-4...

40 CFR 180.595 - Flufenpyr-ethyl; tolerances for residues.

Code of Federal Regulations, 2012 CFR

2012-07-01

... residues of the herbicide, flufenpyr-ethyl; acetic acid, [2-chloro-4-fluoro-5-[5-methyl-6-oxo-4... established for residues of the herbicide flufenpyr-ethyl; acetic acid, [2-chloro-4-fluoro-5-[5-methyl-6-oxo-4...

40 CFR 180.595 - Flufenpyr-ethyl; tolerances for residues.

Code of Federal Regulations, 2014 CFR

2014-07-01

... residues of the herbicide, flufenpyr-ethyl; acetic acid, [2-chloro-4-fluoro-5-[5-methyl-6-oxo-4... established for residues of the herbicide flufenpyr-ethyl; acetic acid, [2-chloro-4-fluoro-5-[5-methyl-6-oxo-4...

40 CFR 180.595 - Flufenpyr-ethyl; tolerances for residues.

Code of Federal Regulations, 2011 CFR

2011-07-01

... residues of the herbicide, flufenpyr-ethyl; acetic acid, [2-chloro-4-fluoro-5-[5-methyl-6-oxo-4... established for residues of the herbicide flufenpyr-ethyl; acetic acid, [2-chloro-4-fluoro-5-[5-methyl-6-oxo-4...

40 CFR 180.595 - Flufenpyr-ethyl; tolerances for residues.

Code of Federal Regulations, 2010 CFR

2010-07-01

... residues of the herbicide, flufenpyr-ethyl; acetic acid, [2-chloro-4-fluoro-5-[5-methyl-6-oxo-4... established for residues of the herbicide flufenpyr-ethyl; acetic acid, [2-chloro-4-fluoro-5-[5-methyl-6-oxo-4...

Spectroscopy reveals that ethyl esters interact with proteins in wine.

PubMed

Di Gaspero, Mattia; Ruzza, Paolo; Hussain, Rohanah; Vincenzi, Simone; Biondi, Barbara; Gazzola, Diana; Siligardi, Giuliano; Curioni, Andrea

2017-02-15

Impairment of wine aroma after vinification is frequently associated to bentonite treatments and this can be the result of protein removal, as recently demonstrated for ethyl esters. To evaluate the existence of an interaction between wine proteins and ethyl esters, the effects induced by these fermentative aroma compounds on the secondary structure and stability of VVTL1, a Thaumatin-like protein purified from wine, was analyzed by Synchrotron Radiation Circular Dichroism (SRCD) spectroscopy. The secondary structure of wine VVTL1 was not strongly affected by the presence of selected ethyl esters. In contrast, VVTL1 stability was slightly increased by the addition of ethyl-octanoate, -decanoate and -dodecanoate, but decreased by ethyl-hexanoate. This indicates the existence of an interaction between VVTL1 and at least some aroma compounds produced during fermentation. The data suggest that proteins removal from wine by bentonite can result in indirect removal of at least some aroma compounds associated with them. Copyright © 2016 Elsevier Ltd. All rights reserved.

Direct measurement of the glucuronide conjugate of 1-hydroxypyrene in human urine by using liquid chromatography with tandem mass spectrometry.

PubMed

Kakimoto, Kensaku; Toriba, Akira; Ohno, Takanori; Ueno, Mariko; Kameda, Takayuki; Tang, Ning; Hayakawa, Kazuichi

2008-05-15

To evaluate human exposure to polycyclic aromatic hydrocarbons (PAHs), we developed a rapid, simple and sensitive method for determining 1-hydroxypyrene-glucuronide (1-OHP-G) in human urine. To improve precision, a deuterated glucuronide was used as an internal standard. The method requires only 1 mL of urine. The urine was treated with a mixed-mode anion-exchange and reversed-phase solid-phase extraction cartridge (Oasis MAX). The analytes were analyzed with a C(18) reversed-phase column with a gradient elution, followed by tandem mass spectrometry with electrospray ionization in negative ion mode. The detection limit of 1-OHP-G (corresponding to a signal-to-noise ratio of 3) was 0.13 fmol/injection. Urinary concentrations of 1-OHP-G determined by this method were strongly correlated (r(2)=0.961) with concentrations of 1-hydroxypyrene by conventional HPLC with fluorescence detection.

Inhibitory effect of ciprofloxacin on β-glucuronidase-mediated deconjugation of mycophenolic acid glucuronide.

PubMed

Kodawara, Takaaki; Masuda, Satohiro; Yano, Yoshitaka; Matsubara, Kazuo; Nakamura, Toshiaki; Masada, Mikio

2014-07-01

The interaction between mycophenolate (MPA) and quinolone antibiotics such as ciprofloxacin is considered to reduce the enterohepatic recycling of MPA, which is biotransformed in the intestine from MPA glucuronide (MPAG) conjugate excreted via the biliary system; however, the molecular mechanism underlying this biotransformation of MPA is still unclear. In this study, an in vitro system was established to evaluate β-glucuronidase-mediated deconjugation and to examine the influence of ciprofloxacin on the enzymatic deconjugation of MPAG and MPA resynthesis. Resynthesis of MPA via deconjugation of MPAG increased in a time-dependent manner from 5 to 60 min in the presence of β-glucuronidase. Ciprofloxacin and phenolphthalein-β-d-glucuronide (PhePG), a typical β-glucuronidase substrate, significantly decreased the production of MPA from MPAG in the β-glucuronidase-mediated deconjugation system. In addition, enoxacin significantly inhibited the production of MPA from MPAG, while levofloxacin and ofloxacin had no inhibitory effect on MPA synthesis. Pharmacokinetic analysis revealed that ciprofloxacin showed a dose-dependent inhibitory effect on MPA production from MPAG via β-glucuronidase with a half-maximal inhibitory concentration (IC50 ) value of 30.4 µm. While PhePG inhibited the β-glucuronidase-mediated production of MPA from MPAG in a competitive manner, ciprofloxacin inhibited MPA synthesis via noncompetitive inhibition. These findings suggest that the reduction in the serum MPA concentration during the co-administration of ciprofloxacin is at least in part due to the decreased enterohepatic circulation of MPA because of noncompetitive inhibition of deconjugation of MPAG by intestinal β-glucuronidase. Copyright © 2014 John Wiley & Sons, Ltd.

Methyl ethyl ketone (MEK)

Integrated Risk Information System (IRIS)

Methyl ethyl ketone ( MEK ) ( CASRN 78 - 93 - 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 Nonc

19 CFR 10.99 - Importation of ethyl alcohol for nonbeverage purposes.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 1 2010-04-01 2010-04-01 false Importation of ethyl alcohol for nonbeverage purposes. 10.99 Section 10.99 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND... Provisions Ethyl Alcohol § 10.99 Importation of ethyl alcohol for nonbeverage purposes. (a) If claim is made...

D2 dopaminergic and 5-HT1A serotonergic activity of 2-(1-naphthyl)ethyl- and 2-(2-naphthyl)ethyl amines.

PubMed

Šukalović, V; Roglić, G; Husinec, S; Kostić-Rajaćić, S; Andrić, D; Šoškić, Vukić

2003-11-01

Several tertiary 2-phenylethyl, 2-(1-naphthyl)ethyl and 2-(2-naphthyl)ethyl amines were synthesized and their binding affinities for dopamine D(1), D(2) and serotonin 5-HT(1A) receptors evaluated in radioligand binding assays. All compounds were inactive in D(1) dopamine radioligand binding assay. The 2-(1-naphthyl)ethyl analogues expressed a low but significant binding affinity for the D(2) and moderate one for the 5-HT(1A) receptor subtypes. Most of the remaining compounds expressed binding affinity at the 5-HT(1A) receptor subtype but were inactive in D(2) receptor binding assay. Based on these results and considering the chemical characteristics of the compounds synthesized and evaluated for dopaminergic and serotonergic activity throughout the present study it can be concluded that hydrophobic type of interaction (stacking or edge-to-face) plays a significant role in the formation of receptor-ligand complexes of 2-(1-naphthyl)ethyl amines. This structural motive can be applied to design and synthesize new, more potent dopaminergic/serotonergic ligands by slight chemical modifications.

Uptake of acetaldehyde-modified (ethylated) low-density lipoproteins by mouse peritoneal macrophages.

PubMed

Wehr, Hanna; Mirkiewicz, Ewa; Rodo, Maria; Bednarska-Makaruk, Malgorzata

2002-04-01

The uptake of acetaldehyde-modified (ethylated) low-density lipoproteins (LDLs) by murine peritoneal macrophages is described and compared with the uptake of acetylated LDLs. The fluorescent marker DiI was used. No competition between ethylated and acetylated LDLs was observed. Ethylated LDL uptake was not inhibited by polyinosinic acid or fucoidin. Our conclusion is that uptake of ethylated and acetylated LDLs can be done by two different receptors.

Determination of Serotonin and Dopamine Metabolites in Human Brain Microdialysis and Cerebrospinal Fluid Samples by UPLC-MS/MS: Discovery of Intact Glucuronide and Sulfate Conjugates

PubMed Central

Suominen, Tina; Uutela, Päivi; Ketola, Raimo A.; Bergquist, Jonas; Hillered, Lars; Finel, Moshe; Zhang, Hongbo; Laakso, Aki; Kostiainen, Risto

2013-01-01

An UPLC-MS/MS method was developed for the determination of serotonin (5-HT), dopamine (DA), their phase I metabolites 5-HIAA, DOPAC and HVA, and their sulfate and glucuronide conjugates in human brain microdialysis samples obtained from two patients with acute brain injuries, ventricular cerebrospinal fluid (CSF) samples obtained from four patients with obstructive hydrocephalus, and a lumbar CSF sample pooled mainly from patients undergoing spinal anesthesia in preparation for orthopedic surgery. The method was validated by determining the limits of detection and quantification, linearity, repeatability and specificity. The direct method enabled the analysis of the intact phase II metabolites of 5-HT and DA, without hydrolysis of the conjugates. The method also enabled the analysis of the regioisomers of the conjugates, and several intact glucuronide and sulfate conjugates were identified and quantified for the first time in the human brain microdialysis and CSF samples. We were able to show the presence of 5-HIAA sulfate, and that dopamine-3-O-sulfate predominates over dopamine-4-O-sulfate in the human brain. The quantitative results suggest that sulfonation is a more important phase II metabolism pathway than glucuronidation in the human brain. PMID:23826355

IRIS Toxicological Review of Methyl Ethyl Ketone (2003 Final)

EPA Science Inventory

EPA announced the release of the final report, Toxicological Review of Methyl Ethyl Ketone: in support of the Integrated Risk Information System (IRIS). The updated Summary for Methyl Ethyl Ketone and accompanying toxicological review have been added to the IRIS Database....

Non-enzymatic cyclization of creatine ethyl ester to creatinine.

PubMed

Giese, Matthew W; Lecher, Carl S

2009-10-16

Creatine ethyl ester was incubated at 37 degrees C in both water and phosphate-buffered saline and the diagnostic methylene resonances in the (1)H NMR spectrum were used to identify the resultant products. It was found that mild aqueous conditions result in the cyclization of creatine ethyl ester to provide inactive creatinine as the exclusive product, and this transformation becomes nearly instantaneous as the pH approaches 7.4. This study demonstrates that mild non-enzymatic conditions are sufficient for the cyclization of creatine ethyl ester into creatinine, and together with previous results obtained under enzymatic conditions suggests that there are no physiological conditions that would result in the production of creatine. It is concluded that creatine ethyl ester is a pronutrient for creatinine rather than creatine under all physiological conditions encountered during transit through the various tissues, thus no ergogenic effect is to be expected from supplementation.

Monitoring of ovarian activity by measurement of urinary excretion rates of estrone glucuronide and pregnanediol glucuronide using the Ovarian Monitor, Part II: reliability of home testing.

PubMed

Blackwell, Leonard F; Vigil, Pilar; Gross, Barbara; d'Arcangues, Catherine; Cooke, Delwyn G; Brown, James B

2012-02-01

The UNDP/WHO/World Bank/Special Programme of Research, Development and Research Training in Human Reproduction (Geneva) set up a study to determine whether it is feasible for women to monitor their ovarian activity reliably by home testing. Daily self-monitoring of urinary hormone metabolites for menstrual cycle assessment was evaluated by comparison of results obtained with the Home Ovarian Monitor by untrained users both at home and in study centres. Women collected daily data for urinary estrone glucuronide (E1G) and pregnanediol glucuronide (PdG) for two cycles, then the procedure was repeated in the women's local centre (in Chile, Australia or New Zealand) giving a total of 113 duplicate cycles. The tests were performed without the benefit of replicates or quality controls. The home and centre cycles were normalized and compared to identify assay errors, and the resulting home and centre menstrual cycle profiles were averaged. Reliable mean cycle profiles were obtained with the home and centre excretion rates agreeing to within 36 ± 21 nmol/24 h for E1G and 0.77 ± 0.28 µmol/24 h for baseline PdG values (1-5 µmol/24 h). The cycles had a mean length of 28.1 ± 3.1 days (n = 112; 5th and 95th percentiles: 24 and 35 days, respectively), a mean follicular phase of 14.8 ± 3.1 days (n = 107; 5th and 95th percentiles: 11 and 21 days) and a mean luteal phase length of 13.3 ± 1.5 days (n = 106; 5th and 95th percentiles: 11 and 17 days), calculated from the day of the LH peak. The study confirmed that the Ovarian Monitor pre-coated assay tubes worked well even in the hands of lay users, without standard curves, quality controls or replicates. Point-of-care monitoring to give reliable fertility data is feasible.

Electronic structure and normal vibrations of the 1-ethyl-3-methylimidazolium ethyl sulfate ion pair.

PubMed

Dhumal, Nilesh R; Kim, Hyung J; Kiefer, Johannes

2011-04-21

Electronic and structural properties of the ion pair 1-ethyl-3-methylimidazolium ethyl sulfate are studied using density functional methods. Three locally stable conformers of the ion pair complex are considered to analyze molecular interactions between its cation and anion. Manifestations of these interactions in the vibrational spectra are discussed and compared with experimental IR and Raman spectroscopy data. NBO analysis and difference electron density coupled with molecular electron density topography are used to interpret the frequency shifts of the normal vibrations of the ion pair, compared to the free anion and cation. Excitation energies of low-lying singlet excited states of the conformers are also studied. The density functional theory results are found to be in a reasonable agreement with experimental UV/vis absorption spectra.

Validation of a rapid and sensitive LC-MS/MS method for determination of exemestane and its metabolites, 17β-hydroxyexemestane and 17β-hydroxyexemestane-17-O-β-D-glucuronide: application to human pharmacokinetics study.

PubMed

Wang, Ling-Zhi; Goh, Sok-Hwei; Wong, Andrea Li-Ann; Thuya, Win-Lwin; Lau, Jie-Ying Amelia; Wan, Seow-Ching; Lee, Soo-Chin; Ho, Paul C; Goh, Boon-Cher

2015-01-01

A novel, rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the evaluation of exemestane pharmacokinetics and its metabolites, 17β-dihydroexemestane (active metabolite) and 17β-dihydroexemestane-17-O-β-D-glucuronide (inactive metabolite) in human plasma. Their respective D3 isotopes were used as internal standards. Chromatographic separation of analytes was achieved using Thermo Fisher BDS Hypersil C18 analytic HPLC column (100 × 2.1 mm, 5 μm). The mobile phase was delivered at a rate of 0.5 mL/min by gradient elution with 0.1% aqueous formic acid and acetonitrile. The column effluents were detected by API 4000 triple quadrupole mass spectrometer using electrospray ionisation (ESI) and monitored by multiple reaction monitoring (MRM) in positive mode. Mass transitions 297 > 121 m/z, 300 > 121 m/z, 299 > 135 m/z, 302 > 135 m/z, 475 > 281 m/z, and 478 > 284 m/z were monitored for exemestane, exemestane-d3, 17β-dihydroexemestane, 17β-dihydroexemestane-d3, 17β-dihydroexemestane-17-O-β-D-glucuronide, and 17β-dihydroexemestane-17-O-β-D-glucuronide-d3 respectively. The assay demonstrated linear ranges of 0.4-40.0 ng/mL, for exemestane; and 0.2-15.0 ng/mL, for 17β-dihydroexemestane and 17β-dihydroexemestane-17-O-β-D-glucuronide, with coefficient of determination (r2) of > 0.998. The precision (coefficient of variation) were ≤10.7%, 7.7% and 9.5% and the accuracies ranged from 88.8 to 103.1% for exemestane, 98.5 to 106.1% for 17β-dihydroexemestane and 92.0 to 103.2% for 17β-dihydroexemestane-17-O-β-D-glucuronide. The method was successfully applied to a pharmacokinetics/dynamics study in breast cancer patients receiving exemestane 25 mg daily orally. For a representative patient, 20.7% of exemestane in plasma was converted into 17β-dihydroexemestane and 29.0% of 17β-dihydroexemestane was inactivated as 17β-dihydroexemestane-17-O-β-D-glucuronide 24 hours after ingestion of exemestane

Reactivity of 2-ethyl-1-hexanol in the atmosphere.

PubMed

Gallego-Iniesta García, María Paz; Moreno Sanroma, Alberto; Martín Porrero, María Pilar; Tapia Valle, Araceli; Cabañas Galán, Beatriz; Salgado Muñoz, María Sagrario

2010-04-07

Rate coefficients at room temperature for the reaction of 2-ethyl-1-hexanol with OH and NO(3) radicals and with Cl atoms have been determined in a 150 L PTFE chamber using GC-FID/SPME and FTIR as detection systems. The rate coefficients k (in units of cm(3) molecule(-1) s(-1)) obtained were: (1.13 +/- 0.31) 10(-11) for the OH reaction, (2.93 +/- 0.92) 10(-15) for the NO(3) reaction and (1.88 +/- 0.25) 10(-10) for the Cl reaction. Despite the high concentrations of 2-ethyl-1-hexanol, especially in indoor air, this is the first kinetic study carried out to date for these reactions. The results are consistent with the expected reactivity given the chemical structure of 2-ethyl-1-hexanol. Calculated atmospheric lifetimes reveal that the dominant loss process for 2-ethyl-1-hexanol is clearly the daytime reaction with the hydroxyl radical.

Contribution of citrulline to the formation of ethyl carbamate during Chinese rice wine production.

PubMed

Wang, Peihong; Sun, Junyong; Li, Xiaomin; Wu, Dianhui; Li, Tong; Lu, Jian; Chen, Jian; Xie, Guangfa

2014-04-01

Ethyl carbamate is a well-known carcinogen and widely occurs in Chinese rice wine. To provide more clues to minimise ethyl carbamate accumulation, the levels of possible precursors of ethyl carbamate in Chinese rice wine were investigated by HPLC. Studies of the possible precursors of ethyl carbamate in Chinese raw rice wine with various additives and treatments indicated that significant amounts of urea can account for ethyl carbamate formation. It was also recognised that citrulline is another important precursor that significantly affects ethyl carbamate production during the boiling procedure used in the Chinese rice wine manufacturing process. Besides urea and citrulline, arginine was also found to be an indirect ethyl carbamate precursor due to its ability to form urea and citrulline by microorganism metabolism.

Diabetes mellitus reduces activity of human UDP-glucuronosyltransferase 2B7 in liver and kidney leading to decreased formation of mycophenolic acid acyl-glucuronide metabolite.

PubMed

Dostalek, Miroslav; Court, Michael H; Hazarika, Suwagmani; Akhlaghi, Fatemeh

2011-03-01

Mycophenolic acid (MPA) is an immunosuppressive agent commonly used after organ transplantation. Altered concentrations of MPA metabolites have been reported in diabetic kidney transplant recipients, although the reason for this difference is unknown. We aimed to compare MPA biotransformation and UDP-glucuronosyltransferase (UGT) expression and activity between liver (n = 16) and kidney (n = 8) from diabetic and nondiabetic donors. Glucuronidation of MPA, as well as the expression and probe substrate activity of UGTs primarily responsible for MPA phenol glucuronide (MPAG) formation (UGT1A1 and UGT1A9), and MPA acyl glucuronide (AcMPAG) formation (UGT2B7), was characterized. We have found that both diabetic and nondiabetic human liver microsomes and kidney microsomes formed MPAG with similar efficiency; however, AcMPAG formation was significantly lower in diabetic samples. This finding is supported by markedly lower glucuronidation of the UGT2B7 probe zidovudine, UGT2B7 protein, and UGT2B7 mRNA in diabetic tissues. UGT genetic polymorphism did not explain this difference because UGT2B7*2 or *1c genotype were not associated with altered microsomal UGT2B7 protein levels or AcMPAG formation. Furthermore, mRNA expression and probe activities for UGT1A1 or UGT1A9, both forming MPAG but not AcMPAG, were comparable between diabetic and nondiabetic tissues, suggesting the effect may be specific to UGT2B7-mediated AcMPAG formation. These findings suggest that diabetes mellitus is associated with significantly reduced UGT2B7 mRNA expression, protein level, and enzymatic activity of human liver and kidney, explaining in part the relatively low circulating concentrations of AcMPAG in diabetic patients.

Bioactive Androgens and Glucuronidated Androgen Metabolites are Associated with Subcutaneous and Ectopic Skeletal Muscle Adiposity among Older Black Men

PubMed Central

Miljkovic, Iva; Cauley, Jane A; Dressen, Amy S; Gordon, Christopher L; Goodpaster, Bret H; Kuller, Lewis H; Bunker, Clareann H; Patrick, Alan L; Wheeler, Victor W; Orwoll, Eric S; Zmuda, Joseph M

2011-01-01

Aging is associated with declining serum levels of androgenic hormones and with increased skeletal muscle fat infiltration, an emerging risk factor for type 2 diabetes mellitus (T2DM). Androgens regulate fat mass and glucose homeostasis, but the effect of androgenic hormones on skeletal muscle fat infiltration is largely unknown. Thus, the aim of the current study was to examine the association of serum androgens and their precursors and metabolites with skeletal muscle fat infiltration and T2DM in a black male population group at high risk of T2DM. Serum androgens, estrogens, and androgen precursors and metabolites were measured using mass spectrometry, and calf skeletal muscle fat distribution [subcutaneous and intermuscular fat; skeletal muscle density] were measured using quantitative computed tomography in 472 Afro-Caribbean men aged 65 and older. Bioactive androgens, testosterone, free testosterone and dihydrotestosterone, were associated with less skeletal muscle fat infiltration (r=−0.14 to −0.18, P<0.05) and increased skeletal muscle density (r=0.10 to 0.14, P<0.05), independent of total adiposity. Additionally, glucuronidated androgen metabolites were associated with less subcutaneous fat (r=−0.11 to −0.15, P<0.05). Multivariate logistic regression analysis identified an increased level of 3α-diol-3 glucuronide (OR=1.38, P<0.01) and a decreased level of dihydrotestosterone (OR=0.66, P<0.01) to be significantly associated with T2DM. Our findings suggest that in elderly black men, independent of total adiposity, bioactive androgens and glucuronidated androgen metabolites may play previously unrecognized role in skeletal muscle fat distribution. Longitudinal studies are needed to further evaluate the relationship between androgens and androgen metabolites with changes in skeletal muscle fat distribution with aging and the incidence of T2DM. PMID:21353258

Interaction between rhein acyl glucuronide and methotrexate based on human organic anion transporters.

PubMed

Yuan, Yuan; Yang, Hua; Kong, Linghua; Li, Yuan; Li, Ping; Zhang, Hongjian; Ruan, Jianqing

2017-11-01

Rhein, a major bioactive compound of many medicinal herbs and the prodrug of diacerein, is often used with low dose of methotrexate as drug combination to treat rheumatoid arthritis. In this study, potential drug-drug interaction between methotrexate and rhein was investigated based on organic anion transporters (OAT). Our study demonstrated that rhein acyl glucuronide (RAG), the major metabolite of rhein in the human blood circulation, significantly inhibited the uptake of p-aminohippurate in hOAT1 transfected cells with IC 50 value of 691 nM and estrone sulfate uptake in hOAT3 transfected cells with IC 50 value of 78.5 nM. As the substrate of both hOAT1 and hOAT3, the methotrexate transport was significantly inhibited by RAG in hOAT1 transfected cells at 50 μM and hOAT3 transfected cells at 1 μM by 69% and 87%, respectively. Further in vivo study showed that after co-administrated with RAG in rats the AUC 0-24 values of methotrexate increased from 3109 to 5370 ng/mL*hr and the t 1/2 was prolonged by 40.5% (from 7.4 to 10.4 h), demonstrating the inhibitory effect of RAG on methotrexate excretion. In conclusion, rhein acyl glucuronide could significantly decrease the transport of methotrexate by both hOAT1 and hOAT3. The combination use of rhein, diacerein or other rhein-containing herbs with methotrexate may cause obvious drug-drug interaction and require close monitoring for potential drug interaction in clinical practice. Copyright © 2017 Elsevier B.V. All rights reserved.

Fungal degradation of an acetolactate synthase (ALS) inhibitor pyrazosulfuron-ethyl in soil.

PubMed

Sondhia, Shobha; Waseem, Uzma; Varma, R K

2013-11-01

Owing to reported phytotoxicity of some sulfonylurea class of herbicides in number of sensitive crops and higher persistence in soil, present study was conducted to isolate and identify pyrazosulfuron-ethyl degrading fungi from soil of rice field. Penicillium chrysogenum and Aspergillus niger, were isolated and identified from rhizospere soil of rice field, as potent pyrazosulfuron-ethyl degrading fungi. Degradation of pyrazosulfuron-ethyl by P. chrysogenum and A. niger, yielded transformation products/metabolites which were identified and characterized by LC/MS/MS. The rate of dissipation of pyrazosulfuron-ethyl was found higher in soil of rice field and soil inoculated with P. chrysogenum. This showed important route of degradation of pyrazosulfuron-ethyl by microbes apart from chemical degradation. Copyright © 2013 Elsevier Ltd. All rights reserved.

Development of a fast screening and confirmatory method by liquid chromatography-quadrupole-time-of-flight mass spectrometry for glucuronide-conjugated methyltestosterone metabolite in tilapia.

PubMed

Amarasinghe, Kande; Chu, Pak-Sin; Evans, Eric; Reimschuessel, Renate; Hasbrouck, Nicholas; Jayasuriya, Hiranthi

2012-05-23

This paper describes the development of a fast method to screen and confirm methyltestosterone 17-O-glucuronide (MT-glu) in tilapia bile. The method consists of solid-phase extraction (SPE) followed by high-performance liquid chromatography-mass spectrometry. The system used was an Agilent 6530 Q-TOF with an Agilent Jet stream electrospray ionization interface. The glucuronide detected in the bile was characterized as MT-glu by comparison with a chemically synthesized standard. MT-glu was detected in bile for up to 7 days after dosing. Semiquantification was done with matrix-matched calibration curves, because MT-glu showed signal suppression due to matrix effects. This method provides a suitable tool to monitor the illegal use of methyltestosterone in tilapia culture.

Biodegradation and detoxification of chlorimuron-ethyl by Enterobacter ludwigii sp. CE-1.

PubMed

Pan, Xiong; Wang, Saige; Shi, Nan; Fang, Hua; Yu, Yunlong

2018-04-15

The application of the herbicide chlorimuron-ethyl has a lasting toxic effect on some succession crops. Here, a bacterium capable of utilizing chlorimuron-ethyl as the sole source of nitrogen was isolated from the contaminated soil and was identified as Enterobacter ludwigii sp. CE-1, and its detoxification and degradation of the herbicide were then examined. The biodegradation of chlorimuron-ethyl by the isolate CE-1 was significantly accelerated with increasing concentration (1-10mg/l) and temperature (20-40°C). The optimal pH for the degradation of chlorimuron-ethyl by the isolate CE-1 was pH 7.0. A pathway for the biodegradation of chlorimuron-ethyl by the isolate CE-1 was proposed, in which it could be first converted into 2-amino-4-chloro-6-methoxypyrimidine and an intermediate product by the cleavage of the sulfonylurea bridge and then transformed into saccharin via hydrolysis and amidation. The plant height and fresh weight of corn that had been incubated in nutrient solution containing 0.2mg/l of chlorimuron-ethyl significantly recovered to 83.9% and 83.1% compared with those in the uninoculated control, although the root growth inhibition of chlorimuron-ethyl could not be alleviated after inoculation for 14 d. The results indicate that the isolate CE-1 is a promising bacterial resource for the biodegradation and detoxification of chlorimuron-ethyl. Copyright © 2017 Elsevier Inc. All rights reserved.

Catalyst-free ethyl biodiesel production from rice bran under subcritical condition

NASA Astrophysics Data System (ADS)

Zullaikah, Siti; Afifudin, Riza; Amalia, Rizky

2015-12-01

In-situ ethyl biodiesel production from rice bran under subcritical water and ethanol with no catalyst was employed. This process is environmentally friendly and is very flexible in term of feedstock utilization since it can handle relatively high moisture and free fatty acids (FFAs) contents. In addition, the alcohol, i.e. bioethanol, is a non-toxic, biodegradable, and green raw material when produced from non-edible biomass residues, leading to a 100% renewable biodiesel. The fatty acid ethyl esters (FAEEs, ethyl biodiesel) are better than fatty acid methyl esters (FAMEs, methyl biodiesel) in terms of fuel properties, including cetane number, oxidation stability and cold flow properties. The influences of the operating variables such as reaction time (1 - 10 h), ethanol concentration (12.5 - 87.5%), and pressurizing gas (N2 and CO2) on the ethyl biodiesel yield and purity have been investigated systematically while the temperature and pressure were kept constant at 200 °C and 40 bar. The optimum results were obtained at 5 h reaction time and 75% ethanol concentration using CO2 as compressing gas. Ethyl biodiesel yield and purity of 58.78% and 61.35%, respectively, were obtained using rice bran with initial FFAs content of 37.64%. FFAs level was reduced to 14.22% with crude ethyl biodiesel recovery of 95.98%. Increasing the reaction time up to 10 h only increased the yield and purity by only about 3%. Under N2 atmosphere and at the same operating conditions (5h and 75% ethanol), ethyl biodiesel yield and purity decreased to 54.63% and 58.07%, respectively, while FFAs level was increased to 17.93% and crude ethyl biodiesel recovery decreased to 87.32%.

Impact of glucuronide interferences on therapeutic drug monitoring of posaconazole by tandem mass spectrometry.

PubMed

Krüger, Ralf; Vogeser, Michael; Burghardt, Stephan; Vogelsberger, Rita; Lackner, Karl J

2010-12-01

Posaconazole is a novel antifungal drug for oral application intended especially for therapy of invasive mycoses. Due to variable gastrointestinal absorption, adverse side effects, and suspected drug-drug interactions, therapeutic drug monitoring (TDM) of posaconazole is recommended. A fast ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification of posaconazole with a run-time <3 min was developed and compared to a LC-MS/MS method and HPLC method with fluorescence detection. During evaluation of UPLC-MS/MS, two earlier eluting peaks were observed in the MRM trace of posaconazole. This was only seen in patient samples, but not in spiked calibrator samples. Comparison with LC-MS/MS disclosed a significant bias with higher concentrations measured by LC-MS/MS, while UPLC-MS/MS showed excellent agreement with the commercially available HPLC method. In the LC-MS/MS procedure, comparably wide and left side shifted peaks were noticed. This could be ascribed to in-source fragmentation of conjugate metabolites during electrospray ionisation. Precursor and product ion scans confirmed the assumption that the additional compounds are posaconazole glucuronides. Reducing the cone voltage led to disappearance of the glucuronide peaks. Slight modification of the LC-MS/MS method enabled separation of the main interference, leading to significantly reduced deviation. These results highlight the necessity to reliably eliminate interference from labile drug metabolites for correct TDM results, either by sufficient separation or selective MS conditions. The presented UPLC-MS/MS method provides a reliable and fast assay for TDM of posaconazole.

2,2′-Bi(9,9-di­ethyl­fluorene)

PubMed Central

Park, Ki-Min; Oh, Hankook; Kang, Youngjin

2014-01-01

The title compound, C34H34, systematic name 9,9,9′,9′-tetra­ethyl-2,2′-bi(9H-fluorene), crystallized with two crystallographically independent mol­ecules (A and B) in the asymmetric unit. These differ mainly in the orientation of the lateral ethyl chains: in mol­ecule A, they are both on the same side of the mol­ecule whereas in mol­ecule B, one di­ethyl­fluorene moiety has undergone a 180° rotation such that the two pairs of ethyl residues appear on opposite sides of the mol­ecule. The fluorene ring systems subtend dihedral angles of 31.37 (4) and 43.18 (3)° in mol­ecules A and B, respectively. Hence the two fluorene moieties are tilted slightly toward one another. This may be due to the presence of inter­molecular C—H⋯π inter­actions between neighboring mol­ecules. The lateral ethyl chains (excluding H atoms) are also almost planar, with each pair almost perpendicular to the plane of the fluorene system to which they are attached with dihedral angles between the ethyl and fluorene planes in the range 86.04 (8)–89.5 (1)°. PMID:24764898

40 CFR 180.585 - Pyraflufen-ethyl; tolerances for residues.

Code of Federal Regulations, 2010 CFR

2010-07-01

... residues of the herbicide, pyraflufen-ethyl, ethyl 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenoxyacetate, and its acid metabolite, E-1, 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenoxyacetic acid, expressed in terms of the parent in or on the...

The UDP-Glucuronosyltransferase (UGT) 1A Polymorphism c.2042C>G (rs8330) Is Associated with Increased Human Liver Acetaminophen Glucuronidation, Increased UGT1A Exon 5a/5b Splice Variant mRNA Ratio, and Decreased Risk of Unintentional Acetaminophen-Induced Acute Liver FailureS⃞

PubMed Central

Freytsis, Marina; Wang, Xueding; Peter, Inga; Guillemette, Chantal; Hazarika, Suwagmani; Duan, Su X.; Greenblatt, David J.; Lee, William M.

2013-01-01

Acetaminophen is cleared primarily by hepatic glucuronidation. Polymorphisms in genes encoding the acetaminophen UDP-glucuronosyltransferase (UGT) enzymes could explain interindividual variability in acetaminophen glucuronidation and variable risk for liver injury after acetaminophen overdose. In this study, human liver bank samples were phenotyped for acetaminophen glucuronidation activity and genotyped for the major acetaminophen-glucuronidating enzymes (UGTs 1A1, 1A6, 1A9, and 2B15). Of these, only three linked single nucleotide polymorphisms (SNPs) located in the shared UGT1A-3′UTR region (rs10929303, rs1042640, rs8330) were associated with acetaminophen glucuronidation activity, with rs8330 consistently showing higher acetaminophen glucuronidation at all the tested concentrations of acetaminophen. Mechanistic studies using luciferase-UGT1A-3′UTR reporters indicated that these SNPs do not alter mRNA stability or translation efficiency. However, there was evidence for allelic imbalance and a gene-dose proportional increase in the amount of exon 5a versus exon 5b containing UGT1A mRNA spliced transcripts in livers with the rs8330 variant allele. Cotransfection studies demonstrated an inhibitory effect of exon 5b containing cDNAs on acetaminophen glucuronidation by UGT1A1 and UGT1A6 cDNAs containing exon 5a. In silico analysis predicted that rs8330 creates an exon splice enhancer site that could favor exon 5a (over exon 5b) utilization during splicing. Finally, the prevalence of rs8330 was significantly lower (P = 0.027, χ2 test) in patients who had acute liver failure from unintentional acetaminophen overdose compared with patients with acute liver failure from other causes or a race- or ethnicity-matched population. Together, these findings suggest that rs8330 is an important determinant of acetaminophen glucuronidation and could affect an individual’s risk for acetaminophen-induced liver injury. PMID:23408116

Impact of trans-resveratrol-sulfates and -glucuronides on endothelial nitric oxide synthase activity, nitric oxide release and intracellular reactive oxygen species.

PubMed

Ladurner, Angela; Schachner, Daniel; Schueller, Katharina; Pignitter, Marc; Heiss, Elke H; Somoza, Veronika; Dirsch, Verena M

2014-10-17

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenolic natural product mainly present in grape skin, berries and peanuts. In the vasculature resveratrol is thought to boost endothelial function by increasing endothelial nitric oxide synthase (eNOS) expression, by enhancing eNOS activity, and by reduction of reactive oxygen species (ROS) levels. Recent studies show that dietary resveratrol is metabolized in the liver and intestine into resveratrol-sulfate and -glucuronide derivatives questioning the relevance of multiple reported mechanistic in vitro data on resveratrol. In this study, we compare side by side different physiologically relevant resveratrol metabolites (resveratrol sulfates- and -glucuronides) and their parent compound in their influence on eNOS enzyme activity, endothelial NO release, and intracellular ROS levels. In contrast to resveratrol, none of the tested resveratrol metabolites elevated eNOS enzyme activity and endothelial NO release or affected intracellular ROS levels, leaving the possibility that not tested metabolites are active and able to explain in vivo findings.

Impact of Trans-Resveratrol-Sulfates and -Glucuronides on Endothelial Nitric Oxide Synthase Activity, Nitric Oxide Release and Intracellular Reactive Oxygen Species

PubMed Central

Ladurner, Angela; Schachner, Daniel; Schueller, Katharina; Pignitter, Marc; Heiss, Elke H.; Somoza, Veronika; Dirsch, Verena M.

2015-01-01

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a polyphenolic natural product mainly present in grape skin, berries and peanuts. In the vasculature resveratrol is thought to boost endothelial function by increasing endothelial nitric oxide synthase (eNOS) expression, by enhancing eNOS activity, and by reduction of reactive oxygen species (ROS) levels. Recent studies show that dietary resveratrol is metabolized in the liver and intestine into resveratrol-sulfate and -glucuronide derivatives questioning the relevance of multiple reported mechanistic in vitro data on resveratrol. In this study, we compare side by side different physiologically relevant resveratrol metabolites (resveratrol sulfates- and -glucuronides) and their parent compound in their influence on eNOS enzyme activity, endothelial NO release, and intracellular ROS levels. In contrast to resveratrol, none of the tested resveratrol metabolites elevated eNOS enzyme activity and endothelial NO release or affected intracellular ROS levels, leaving the possibility that not tested metabolites are active and able to explain in vivo findings. PMID:25329867

Ethyl p-nitrophenyl phenylphosphorothioate (EPN)

Integrated Risk Information System (IRIS)

Ethyl p - nitrophenyl phenylphosphorothioate ( EPN ) ; CASRN 2104 - 64 - 5 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 Ha

Icosapent ethyl: Eicosapentaenoic acid concentration and triglyceride-lowering effects across clinical studies.

PubMed

Bays, Harold E; Ballantyne, Christie M; Doyle, Ralph T; Juliano, Rebecca A; Philip, Sephy

2016-09-01

Icosapent ethyl is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester approved at a dose of 4g/day as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500mg/dL) hypertriglyceridemia. This post-hoc exploratory analysis examined the relationship of icosapent ethyl dose with EPA concentrations in plasma and red blood cells (RBCs) across 3 clinical studies-a phase 1 pharmacokinetic study in healthy adult volunteers and 2 pivotal phase 3 studies (MARINE and ANCHOR) in adult patients with hypertriglyceridemia-and examined the relationship between EPA levels and TG-lowering effects in MARINE and ANCHOR. In all 3 studies, icosapent ethyl produced dose-dependent increases in the concentrations of EPA in plasma and RBCs. In both MARINE and ANCHOR, these dose-dependent EPA increases correlated with the degree of TG level lowering (all P<0.01). In patients with high TG levels (≥200mg/dL) and treated with icosapent ethyl 4g/day, the end-of-treatment plasma and RBC EPA concentrations were >170μg/mL and>70μg/mL, respectively. These studies support icosapent ethyl as producing predictable dose-dependent pharmacokinetics/pharmacodynamics, with TG level lowering dependent upon icosapent ethyl dose and EPA concentrations in plasma and RBCs. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

40 CFR 721.9514 - Ethyl silicate, reaction products with modified alkoxysilane salt (generic).

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Ethyl silicate, reaction products with... Significant New Uses for Specific Chemical Substances § 721.9514 Ethyl silicate, reaction products with.... (1) The chemical substance identified generically as Ethyl silicate, reaction products with modified...

40 CFR 721.9514 - Ethyl silicate, reaction products with modified alkoxysilane salt (generic).

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Ethyl silicate, reaction products with... Significant New Uses for Specific Chemical Substances § 721.9514 Ethyl silicate, reaction products with.... (1) The chemical substance identified generically as Ethyl silicate, reaction products with modified...

Behaviour of solid phase ethyl cyanide in simulated conditions of Titan

NASA Astrophysics Data System (ADS)

Couturier-Tamburelli, I.; Toumi, A.; Piétri, N.; Chiavassa, T.

2018-01-01

In order to simulate different altitudes in the atmosphere of Titan, we investigated using infrared spectrometry and mass spectrometry the photochemistry of ethyl cyanide (CH3CH2CN) ices at different temperatures. Heating experiments of the solid phase until complete desorption showed up three phase transitions with a first one appearing to be approximately at the temperature of Titan's surface (94 K), measured by the Huygens probe. Ethyl cyanide, whose presence has been suggested in solid phase in Titan, can be considered as another nitrile for photochemical models of the Titan atmosphere after our first study (Toumi et al., 2016) concerning vinyl cyanide (CH2CHCN). The desorption energy of ethyl cyanide has been calculated to be 36.75 ( ± 0.55) kJ mol-1 using IRTF and mass spectroscopical techniques. High energetic photolysis (λ > 120 nm) have been performed and we identified ethyl isocyanide, vinyl cyanide, cyanoacetylene, ethylene, acetylene, cyanhydric acid and a methylketenimine form as photoproducts from ethyl cyanide. The branching ratios of the primary products were determined at characteristic temperatures of Titan thanks to the value of the νCN stretching band strength of ethyl cyanide that has been calculated to be 4.12 × 10-18 cm molecule-1. We also report here for the first time the values of the photodissociation cross sections of C2H5CN for different temperatures.

Usefulness of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) in Women to Lower Triglyceride Levels (Results from the MARINE and ANCHOR Trials).

PubMed

Mosca, Lori; Ballantyne, Christie M; Bays, Harold E; Guyton, John R; Philip, Sephy; Doyle, Ralph T; Juliano, Rebecca A

2017-02-01

There are limited data on the efficacy and safety of triglyceride (TG)-lowering agents in women. We conducted subgroup analyses of the effects of icosapent ethyl (a high-purity prescription form of the ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid) on TG levels (primary efficacy variable) and other atherogenic and inflammatory parameters in a total of 215 women with a broad range of TG levels (200-2000 mg/dl) enrolled in two 12-week placebo-controlled trials: MARINE (n = 18; placebo, n = 18) and ANCHOR (n = 91; placebo, n = 88). Icosapent ethyl 4 g/day significantly reduced TG levels from baseline to week 12 versus placebo in both MARINE (-22.7%; p = 0.0327) and ANCHOR (-21.5%; p <0.0001) without increasing low-density lipoprotein cholesterol levels. Significant improvements were also observed in non-high-density lipoprotein cholesterol levels in MARINE (-15.7%; p = 0.0082) and ANCHOR (-14.2%; p <0.0001) and total cholesterol levels in MARINE (-14.9%; p = 0.0023) and ANCHOR (-12.1%; p <0.0001), along with significant increases of >500% in eicosapentaenoic acid levels in plasma and red blood cells (all p <0.001). Icosapent ethyl was well tolerated, with adverse-event profiles comparable with findings in the overall studies. In conclusion, icosapent ethyl 4 g/day significantly reduced TG levels and other atherogenic parameters in women without increasing low-density lipoprotein cholesterol levels compared with placebo; the clinical implications of these findings are being evaluated in the REDUCtion of Cardiovascular Events With Eicosapentaenoic Acid [EPA]-Intervention Trial (REDUCE-IT) cardiovascular outcomes study. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Urinary Excretion of Buprenorphine, Norbuprenorphine, Buprenorphine-Glucuronide, and Norbuprenorphine-Glucuronide in Pregnant Women Receiving Buprenorphine Maintenance Treatment

PubMed Central

Kacinko, Sherri L.; Jones, Hendree E.; Johnson, Rolley E.; Choo, Robin E.; Concheiro-Guisan, Marta; Huestis, Marilyn A.

2011-01-01

BACKGROUND Buprenorphine (BUP) is under investigation as a medication therapy for opioid-dependent pregnant women. We investigated BUP and metabolite disposition in urine from women maintained on BUP during the second and third trimesters of pregnancy and postpartum. METHODS We measured BUP, norbuprenorphine (NBUP), buprenorphine glucuronide (BUP-Gluc), and NBUP-Gluc concentrations in 515 urine specimens collected thrice weekly from 9 women during pregnancy and postpartum. Specimens were analyzed using a fully validated liquid chromatography-mass spectrometry method with limits of quantification of 5 µg/L for BUP and BUP-Gluc and 25 µg/L for NBUP and its conjugated metabolite. We examined ratios of metabolites across trimesters and postpartum to identify possible changes in metabolism during pregnancy. RESULTS NBUP-Gluc was the primary metabolite identified in urine and exceeded BUP-Gluc concentrations in 99% of specimens. Whereas BUP-Gluc was identified in more specimens than NBUP, NBUP exceeded BUP-Gluc concentrations in 77.9% of specimens that contained both analytes. Among all participants, the mean BUP-Gluc:NBUP-Gluc ratio was significantly higher in the second trimester compared to the third trimester, and there were significant intrasubject differences between trimesters in 71% of participants. In 3 women, the percent daily dose excreted was higher during pregnancy than postpregnancy, consistent with other data indicating increased renal elimination of drugs during pregnancy. CONCLUSIONS These data are the first to evaluate urinary disposition of BUP and metabolites in a cohort of pregnant women. Variable BUP excretion during pregnancy may indicate metabolic changes requiring dose adjustment during later stages of gestation. PMID:19325013

Utilization of ethyl cellulose polymer and waste materials for roofing tile production

NASA Astrophysics Data System (ADS)

Sam, Suubitaa Spencer; Ng, ChoonAun; Chee, Swee Yong; Habib, NoorZainab; Nadeem, Humayon; Teoh, Wei Ping

2017-05-01

The aim of this study was to utilize ethyl cellulose, mixture of waste engine oil and waste vegetable oil as a binder in the environmental friendly roofing tile production. The waste engine-vegetable oil wasmix together with ethyl cellulose, fly ash, coarse aggregates, fine aggregatesand a catalyst. The Fourier Transform Infrared (FTIR) analysis showed that the oil mixture added with ethyl cellulose has the relatively high binding effect due to the presence of strong carbonyl group especially after being heat cured at 1900C for 24 hours. The mixed proportion of materials with different amount of ethyl cellulose used was studied in the production of tile specimen. The results showed that the ethyl cellulose composed roofing tile specimens passed the transverse breaking strength, durability, permeabilityand the ultraviolet accelerated test. The shrinkage on the tile can be overcome by adding temperature resistance polymer on the exterior of the tile.

An investigation of the stability of free and glucuronidated 11-nor-delta9-tetrahydrocannabinol-9-carboxylic acid in authentic urine samples.

PubMed

Skopp, Gisela; Pötsch, Lucia

2004-01-01

Preanalytical stability of a drug and its major metabolites is an important consideration in pharmacokinetic studies or whenever the analyte pattern is used to estimate drug habits. Firstly, the stability of free and glucuronidated 11-nor-delta9-tetrahydrocannabinol-9-carboxylic acid (THCCOOH, THCCOOglu) in authentic urine samples was investigated. Random urine samples of cannabis users (n = 38) were stored at -20, 4, and 20 degrees C up to 15 days and up to 5 days at 40 degrees C, and alterations of the analyte pattern during storage were followed by liquid chromatography-tandem mass spectrometry. Secondly, the influence of pH (range 5.0-8.0) on the stability of the analytes was studied using spiked urine to elucidate the results obtained from authentic samples. In authentic urine samples, the initial pH ranged from 5.1 to 8.8. The glucuronide was found to be highly labile at a storage temperature of 4 degrees C and above. Initially, 18 urine samples tested positive for THCCOOH. After 2 days storage at 20 degrees C, THCCOOH was detectable in a further 4 samples, and 7 more samples tested positive for THCCOOH (5-81 ng/mL) after 15 days. Depending on time and temperature, the glucuronide concentration decreased, resulting in an increase of THCCOOH concentration. However, a loss in mean total THCCOOH concentration was found, which was significantly higher in deteriorated samples than in samples without signs of deterioration after 15 days of storage at 20 degrees C. In the drug-free urine sample separately spiked with THCCOOglu or THCCOOH, the investigations on the stability of the target analytes at various pH values revealed that THCCOOH was stable at pH 5.0. At higher pH values, its concentration slightly decreased with time, and about 69% of the initial THCCOOH concentration was still present at pH 8.0 on day 5. THCCOOglu concentrations rapidly decreased with increasing pH value. For example, only 72% of the initial THCCOOglu concentration could be detected at p

Physiological basis for isoxadifen-ethyl induction of nicosulfuron detoxification in maize hybrids.

PubMed

Sun, Lanlan; Wu, Renhai; Su, Wangcang; Gao, Zenggui; Lu, Chuantao

2017-01-01

Isoxadifen-ethyl can effectively alleviate nicosulfuron injury in the maize. However, the effects of safener isoxadifen-ethyl on detoxifying enzymes in maize is unknown. The individual and combined effects of the sulfonylurea herbicide nicosulfuron and the safener isoxadifen-ethyl on the growth and selected physiological processes of maize were evaluated. Bioassays showed that the EC50 values of nicosulfuron and nicosulfuron plus isoxadifen-ethyl for maize cultivar Zhengdan958 were 18.87 and 249.28 mg kg-1, respectively, and were 24.8 and 275.51 mg kg-1, respectively, for Zhenghuangnuo No. 2 cultivar. Evaluations of the target enzyme of acetolactate synthase showed that the I50 values of nicosulfuron and nicosulfuron plus isoxadifen-ethyl for the ALS of Zhengdan958 were 15.46 and 28.56 μmol L-1, respectively, and were 0.57 and 2.17 μmol L-1, respectively, for the acetolactate synthase of Zhenghuangnuo No. 2. The safener isoxadifen-ethyl significantly enhanced tolerance of maize to nicosulfuron. The enhanced tolerance of maize to nicosulfuron in the presence of the safener, coupled with the enhanced injury observed in the presence of piperonyl butoxide, 1-aminobenzotriazole, and malathion, suggested cytochrome P450 monooxygenases may be involved in metabolism of nicosulfuron. We proposed that isoxadifen-ethyl increases plant metabolism of nicosulfuron through non-P450-catalyzed routes or through P450 monooxygenases not inhibited by piperonyl butoxide, 1-aminobenzotriazole, and malathion. Isoxadifen-ethyl, at a rate of 33 mg kg-1, completely reversed the effects of all doses (37.5-300 mg kg-1) of nicosulfuron on both of the maize cultivars. When the two compounds were given simultaneously, isoxadifen-ethyl enhanced activity of glutathione S-transferases (GSTs) and acetolactate synthase activity in maize. The free acid 4,5-dihydro-5,5-diphenyl-1,2-oxazole-3-carboxylic was equally effective at inducing GSTs as the parent ester and appeared to be the active safener

Physiological basis for isoxadifen-ethyl induction of nicosulfuron detoxification in maize hybrids

PubMed Central

Sun, Lanlan; Wu, Renhai; Su, Wangcang; Gao, Zenggui; Lu, Chuantao

2017-01-01

Isoxadifen-ethyl can effectively alleviate nicosulfuron injury in the maize. However, the effects of safener isoxadifen-ethyl on detoxifying enzymes in maize is unknown. The individual and combined effects of the sulfonylurea herbicide nicosulfuron and the safener isoxadifen-ethyl on the growth and selected physiological processes of maize were evaluated. Bioassays showed that the EC50 values of nicosulfuron and nicosulfuron plus isoxadifen-ethyl for maize cultivar Zhengdan958 were 18.87 and 249.28 mg kg-1, respectively, and were 24.8 and 275.51 mg kg-1, respectively, for Zhenghuangnuo No. 2 cultivar. Evaluations of the target enzyme of acetolactate synthase showed that the I50 values of nicosulfuron and nicosulfuron plus isoxadifen-ethyl for the ALS of Zhengdan958 were 15.46 and 28.56 μmol L-1, respectively, and were 0.57 and 2.17 μmol L-1, respectively, for the acetolactate synthase of Zhenghuangnuo No. 2. The safener isoxadifen-ethyl significantly enhanced tolerance of maize to nicosulfuron. The enhanced tolerance of maize to nicosulfuron in the presence of the safener, coupled with the enhanced injury observed in the presence of piperonyl butoxide, 1-aminobenzotriazole, and malathion, suggested cytochrome P450 monooxygenases may be involved in metabolism of nicosulfuron. We proposed that isoxadifen-ethyl increases plant metabolism of nicosulfuron through non-P450-catalyzed routes or through P450 monooxygenases not inhibited by piperonyl butoxide, 1-aminobenzotriazole, and malathion. Isoxadifen-ethyl, at a rate of 33 mg kg-1, completely reversed the effects of all doses (37.5–300 mg kg-1) of nicosulfuron on both of the maize cultivars. When the two compounds were given simultaneously, isoxadifen-ethyl enhanced activity of glutathione S-transferases (GSTs) and acetolactate synthase activity in maize. The free acid 4,5-dihydro-5,5-diphenyl-1,2-oxazole-3-carboxylic was equally effective at inducing GSTs as the parent ester and appeared to be the active safener

Metabolic patterns of JWH-210, RCS-4, and THC in pig urine elucidated using LC-HR-MS/MS: Do they reflect patterns in humans?

PubMed

Schaefer, Nadine; Helfer, Andreas G; Kettner, Mattias; Laschke, Matthias W; Schlote, Julia; Ewald, Andreas H; Meyer, Markus R; Menger, Michael D; Maurer, Hans H; Schmidt, Peter H

2017-04-01

The knowledge of pharmacokinetic (PK) properties of synthetic cannabinoids (SCs) is important for interpretation of analytical results found for example in intoxicated individuals. In the absence of human data from controlled studies, animal models elucidating SC PK have to be established. Pigs providing large biofluid sample volumes were tested for prediction of human PK data. In this context, the metabolic fate of two model SCs, namely 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210) and 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4), was elucidated in addition to Δ 9 -tetrahydrocannabinol (THC). After intravenous administration of the compounds, hourly collected pig urine was analyzed by liquid chromatography-high resolution mass spectrometry. The following pathways were observed: for JWH-210, hydroxylation at the ethyl side chain or pentyl chain and combinations of them followed by glucuronidation; for RCS-4, hydroxylation at the methoxyphenyl moiety or pentyl chain followed by glucuronidation as well as O-demethylation followed by glucuronidation or sulfation; for THC, THC glucuronidation, 11-hydroxylation, followed by carboxylation and glucuronidation. For both SCs, parent compounds could not be detected in urine in contrast to THC. These results were consistent with those obtained from human hepatocyte and/or human case studies. Urinary markers for the consumption of JWH-210 were the glucuronide of the N-hydroxypentyl metabolite (detectable for 3-4 h) and of RCS-4 the glucuronides of the N-hydroxypentyl, hydroxy-methoxyphenyl (detectable for at least 6 h), and the O-demethyl-hydroxy metabolites (detectable for 4 h). Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Differential susceptibility of rats and guinea pigs to the ototoxic effects of ethyl benzene.

PubMed

Cappaert, Natalie L M; Klis, Sjaak F L; Muijser, Hans; Kulig, Beverly M; Ravensberg, Luco C; Smoorenburg, Guido F

2002-01-01

The present study was designed to compare the ototoxic effects of volatile ethyl benzene in guinea pigs and rats. Rats showed deteriorated auditory thresholds in the mid-frequency range, based on electrocochleography, after 550-ppm ethyl benzene (8 h/day, 5 days). Outer hair cell (OHC) loss was found in the corresponding cochlear regions. In contrast, guinea pigs showed no threshold shifts and no OHC loss after exposure to much higher ethyl benzene levels (2500 ppm, 6 h/day, 5 days). Subsequently, a limited study (four rats and four guinea pigs) was performed in an attempt to understand these differences in susceptibility. Ethyl benzene concentration in blood was determined in both species after exposure to 500-ppm ethyl benzene (8 h/day, 3 days). At the end of the first day, blood of the rats contained 23.2+/-0.8-microg/ml ethyl benzene, whereas the concentration in guinea pig blood was 2.8+/-0.1 microg/ml. After 3 days, the concentration in both species decreased with respect to the first day, but the ethyl benzene concentration in rat blood was still 4.3 times higher than that in guinea pig blood. Thus, the difference in susceptibility between the species may be related to the ethyl benzene concentration in blood.

Resveratrol glucuronides as the metabolites of resveratrol in humans: characterization, synthesis, and anti-HIV activity.

PubMed

Wang, Lai-Xi; Heredia, Alonso; Song, Haijing; Zhang, Zhaojun; Yu, Biao; Davis, Charles; Redfield, Robert

2004-10-01

Resveratrol is a natural product with diverse biological activities. We have previously reported that resveratrol possesses potent synergistic inhibitory activity against human immunodeficiency virus (HIV)-1 infection in combination with nucleoside analogs (Heredia et al. 2000. J Acquir Immune Defic Syndr 25:246-255). As a part of our program in developing resveratrol as a component for anti-HIV chemotherapy, we describe in this article the characterization, chemical synthesis, and biological effects of the human metabolites of resveratrol. We found that resveratrol was metabolized in humans into two metabolites, which were characterized as resveratrol-3-O- and 4'-O-glucuronides. For further biological studies, we reported two simple, alternative methods for the synthesis of the metabolites. The cytotoxic and antiviral activities of resveratrol and its metabolites were compared in cell culture experiments using human peripheral blood mononuclear cells. Whereas resveratrol was cytotoxic at > or =30 microM, no cytotoxicity was observed for the metabolites at concentrations as high as 300 microM. However, resveratrol showed strong synergistic anti-HIV activity with didanosine at 10 microM, but no synergistic effects were observed for either of the metabolites at up to 300 microM. Nevertheless, the in vitro activity of the metabolites (resveratrol glucuronides) may not necessarily reflect their in vivo function, given the fact that the ubiquitously existing human beta-glucuronidase could convert the metabolites back to resveratrol locally or systematically in vivo. The present studies have implications for future development of resveratrol and/or its derivatives as a chemotherapeutic agent. Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association

Ethyl pyruvate inhibits hypoxic pulmonary vasoconstriction and attenuates pulmonary artery cytokine expression

PubMed Central

Tsai, Ben M.; Lahm, Tim; Morrell, Eric D.; Crisostomo, Paul R.; Markel, Troy; Wang, Meijing; Meldrum, Daniel R.

2009-01-01

Hypoxic pulmonary vasoconstriction is a common consequence of acute lung injury and may be mediated by increased local production of proinflammatory cytokines. Ethyl pyruvate is a novel anti-inflammatory agent that has been shown to downregulate proinflammatory genes following hemorrhagic shock; however, its effects on hypoxic pulmonary vasoconstriction are unknown. We hypothesized that ethyl pyruvate would inhibit hypoxic pulmonary vasoconstriction and downregulate pulmonary artery cytokine expression during hypoxia. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings (n=8/group) during hypoxia (95% N2/5% CO2) with or without prior ethyl pyruvate (10 mM) treatment. Following 60 minutes of hypoxia, pulmonary artery rings were analyzed for TNF-α and IL-1 mRNA via RT-PCR. Ethyl pyruvate inhibited hypoxic pulmonary artery contraction (4.49±2.32% vs. 88.80±5.68% hypoxia alone) and attenuated the hypoxic upregulation of pulmonary artery TNF and IL-1 mRNA (p<0.05). These data indicate that: 1) hypoxia increases pulmonary artery vasoconstriction and proinflammatory cytokine gene expression; 2) ethyl pyruvate decreases hypoxic pulmonary vasoconstriction and downregulates hypoxia-induced pulmonary artery proinflammatory cytokine gene expression; and 3) ethyl pyruvate may represent a novel therapeutic adjunct in the treatment of acute lung injury. PMID:17574585

Kinetic disposition of lorazepam with focus on the glucuronidation capacity, transplacental transfer in parturients and racemization in biological samples.

PubMed

Papini, Olga; da Cunha, Sergio Pereira; da Silva Mathes, Angelo do Carmo; Bertucci, Carlo; Moisés, Elaine Christine Dantas; de Barros Duarte, Luciana; de Carvalho Cavalli, Ricardo; Lanchote, Vera Lucia

2006-02-13

The present study investigates the kinetic disposition with focus on the racemization, glucuronidation capacity and the transplacental transfer of lorazepam in term parturients during labor. The study was conducted on 10 healthy parturients aged 18-37 years with a gestational age of 36-40.1 weeks, treated with a single oral dose of 2 mg racemic lorazepam 2-9 h before delivery. Maternal venous blood and urine samples were obtained over a 0-48 h interval and the umbilical cord sample was obtained immediately after clamping. Lorazepam enantiomers were determined in plasma and urine samples by LC-MS/MS using a Chiralcel OD-R column. In vitro racemization of lorazepam required the calculation of the pharmacokinetic parameters as isomeric mixtures. The data were fitted to two-compartment model and the pharmacokinetic parameters are reported as means (95% CI): t(1/2a) 3.2h (2.6-3.7 h), K(a) 0.23 h(-1) (0.19-0.28 h(-1)), t(1/2) 10.4h (9.4-11.3h), beta 0.068 h(-1) (0.061-0.075h(-1)), AUC(0-infinity) 175.3(ngh)/ml (145.7-204.8(ngh)/ml), Cl/F 2.6 ml/(minkg) (2.3-2.9 ml/(minkg)), Vd/F178.8l (146.5-211.1l), Fel 0.3% (0.1-0.5%), and Cl(R) 0.010 ml/(minkg) (0.005-0.015 ml/(minkg)). Placental transfer of lorazepam evaluated as the ratio of vein umbilical/maternal vein plasma concentrations, obtained as an isomeric mixture, was 0.73 (0.52-0.94). Pregnancy changes the pharmacokinetics of lorazepam, with an increase in the apparent distribution volume, an increase in apparent oral clearance, and a reduction of elimination half-life. The increase in oral clearance may indicate an increase in glucuronidation capacity, with a possible reduction in the plasma concentrations of drugs depending on glucuronidation capacity as the major metabolic pathway.

Spectroscopic characterization of the ethyl radical-water complex.

PubMed

Lin, Chen; Finney, Brian A; Laufer, Allan H; Anglada, Josep M; Francisco, Joseph S

2016-10-14

An ab initio investigation has been employed to determine the structural and spectroscopic parameters, such as rotational constants, vibrational frequencies, vertical excitation energies, and the stability of the ethyl-water complex. The ethyl-water complex has a binding energy of 1.15 kcal⋅mol -1 . The interaction takes place between the hydrogen of water and the unpaired electron of the radical. This interaction is found to produce a red shift in the OH stretching bands of water of ca. 84 cm -1 , and a shift of all UV absorption bands to higher energies.

Methyl Ethyl Ketoxime; Final Test Rule

EPA Pesticide Factsheets

EPA is issuing this final test rule under section 4 of the Toxic Substances Control Act (TSCA), requiring manufacturers and processors of methyl ethyl ketoxime (MEKO, CAS No. 96-29-7) to perform testing for health effects.

Conceptual biotransformation of 4-oxo-all-trans-retinoic acid, 4-oxo-13-cis-retinoic acid and all-trans-retinoyl-beta-glucuronide in rat whole embryo culture.

PubMed

Creech Kraft, J; Juchau, M R

1992-05-28

In cultured rat conceptuses, intraamniotic microinjections of 2500 ng/mL of 4-oxo-13-cis-retinoic acid, 600 ng/mL 4-oxo-all-trans-retinoic acid or 4000 ng/mL all-trans-retinoyl-beta-glucuronide, produce qualitatively and quantitatively similar patterns of dysmorphogenesis as those reported after the intraamniotic microinjection of 250 ng/mL all-trans-retinoic acid [Lee et al., Teratology 44: 313-323, 1991; Creech Kraft et al., Teratology 45: 259-270, 1992]. In the present study, we utilized HPLC techniques to analyze retinoid levels in cultured rat conceptuses, 1.5 hr after intraamniotic microinjections of 4-oxo-13-cis-retinoic acid (2500 ng/mL), 4-oxo-all-trans-retinoic acid (600 ng/mL) or all-trans-retinoyl-beta-glucuronide (4000 ng/mL). Our findings show that, after the microinjections of 4-oxo-all-trans-retinoic acid or 4-oxo-13-cis-retinoic acid (at these selected concentrations), 4-oxo-all-trans-retinoic acid was predominant in the embryos proper at concentrations of about 200 nM. This was roughly equivalent to the levels of all-trans-retinoic acid assayed after microinjections of all-trans-retinoyl-beta-glucuronide (4000 ng/mL). We conclude from these studies that both 4-oxo-all-trans-retinoic acid and all-trans-retinoic acid behave as ultimate or proximate dysmorphogens.

Sensory reception of the primer pheromone ethyl oleate

NASA Astrophysics Data System (ADS)

Muenz, Thomas S.; Maisonnasse, Alban; Plettner, Erika; Le Conte, Yves; Rössler, Wolfgang

2012-05-01

Social work force distribution in honeybee colonies critically depends on subtle adjustments of an age-related polyethism. Pheromones play a crucial role in adjusting physiological and behavioral maturation of nurse bees to foragers. In addition to primer effects of brood pheromone and queen mandibular pheromone—both were shown to influence onset of foraging—direct worker-worker interactions influence adult behavioral maturation. These interactions were narrowed down to the primer pheromone ethyl oleate, which is present at high concentrations in foragers, almost absent in young bees and was shown to delay the onset of foraging. Based on chemical analyses, physiological recordings from the antenna (electroantennograms) and the antennal lobe (calcium imaging), and behavioral assays (associative conditioning of the proboscis extension response), we present evidence that ethyl oleate is most abundant on the cuticle, received by olfactory receptors on the antenna, processed in glomeruli of the antennal lobe, and learned in olfactory centers of the brain. The results are highly suggestive that the primer pheromone ethyl oleate is transmitted and perceived between individuals via olfaction at close range.

Characterization of [8-ethyl]-chlorophyll c3 from Emiliania huxleyi.

PubMed

Álvarez, Susana; Zapata, Manuel; Garrido, José L; Vaz, Belén

2012-06-04

We report herein the isolation and complete characterization of a member of the chlorophyll c family, designated as [8-ethyl]-chlorophyll c(3) ([8-ethyl]-chl c(3)). Structural elucidation of this pigment rested on the analysis of mono- and bidimensional NMR, UV-VIS spectroscopy and ESI-MS data, and the configuration at the 13(2) position on chiral HPLC analysis.

Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome.

PubMed

Weickert, Martin O; Kaltsas, Gregory; Hörsch, Dieter; Lapuerta, Pablo; Pavel, Marianne; Valle, Juan W; Caplin, Martyn E; Bergsland, Emily; Kunz, Pamela L; Anthony, Lowell B; Grande, Enrique; Öberg, Kjell; Welin, Staffan; Lombard-Bohas, Catherine; Ramage, John K; Kittur, Ashwin; Yang, Qi M; Kulke, Matthew H

2018-04-30

In the placebo-controlled Phase III TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) trial, the oral tryptophan hydroxylase inhibitor telotristat ethyl significantly reduced bowel movement (BM) frequency during a 12-week, double-blind treatment period in 135 patients with metastatic neuroendocrine tumors with carcinoid syndrome and ≥4 BMs per day. Patients (mean [SD] age, 63.5 [8.9] years; mean [SD] body mass index, 24.9 [4.9] kg/m 2 ) received placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day (TID) in addition to somatostatin analogue therapy. Weight loss is associated with uncontrolled carcinoid syndrome and may be associated with reduced survival. Assessment of the occurrence of weight change ≥3% at week 12 was prespecified in the statistical analysis plan. In 120 patients with weight data available, weight gain ≥3% was observed in 2 of 39 patients (5.1%) taking placebo TID, 7 of 41 (17.1%) taking telotristat ethyl 250 mg TID, and 13 of 40 (32.5%) taking telotristat ethyl 500 mg TID (P = 0.0017) at week 12. Weight loss ≥3% was observed in 5 of 39 patients (12.8%) taking placebo TID, 4 of 41 (9.8%) taking telotristat ethyl 250 mg TID, and 6 of 40 (15.0%) taking telotristat ethyl 500 mg TID (P = 0.77). Biochemical and metabolic parameters of serum albumin and cholesterol significantly increased (P = 0.02 and P = 0.001, respectively) in patients gaining weight and decreased in patients who lost weight, suggesting an improvement in overall nutritional status. Up to 32.5% of patients treated with telotristat ethyl experienced significant, dose-dependent weight gain, associated with reduced diarrhea severity and improved biochemical and metabolic parameters. Improved nutritional status could be an additional aspect of telotristat ethyl efficacy among patients with functioning metastatic neuroendocrine tumors. ClinicalTrials.gov identifier: NCT01677910. Copyright © 2018 The

Biomolecules and Biomarkers Used in Diagnosis of Alcohol Drinking and in Monitoring Therapeutic Interventions.

PubMed

Nanau, Radu M; Neuman, Manuela G

2015-06-29

The quantitative, measurable detection of drinking is important for the successful treatment of alcohol misuse in transplantation of patients with alcohol disorders, people living with human immunodeficiency virus that need to adhere to medication, and special occupational hazard offenders, many of whom continually deny drinking. Their initial misconduct usually leads to medical problems associated with drinking, impulsive social behavior, and drunk driving. The accurate identification of alcohol consumption via biochemical tests contributes significantly to the monitoring of drinking behavior. A systematic review of the current methods used to measure biomarkers of alcohol consumption was conducted using PubMed and Google Scholar databases (2010-2015). The names of the tests have been identified. The methods and publications that correlate between the social instruments and the biochemical tests were further investigated. There is a clear need for assays standardization to ensure the use of these biochemical tests as routine biomarkers. Alcohol ingestion can be measured using a breath test. Because alcohol is rapidly eliminated from the circulation, the time for detection by this analysis is in the range of hours. Alcohol consumption can alternatively be detected by direct measurement of ethanol concentration in blood or urine. Several markers have been proposed to extend the interval and sensitivities of detection, including ethyl glucuronide and ethyl sulfate in urine, phosphatidylethanol in blood, and ethyl glucuronide and fatty acid ethyl esters in hair, among others. Moreover, there is a need to correlate the indirect biomarker carbohydrate deficient transferrin, which reflects longer lasting consumption of higher amounts of alcohol, with serum γ-glutamyl transpeptidase, another long term indirect biomarker that is routinely used and standardized in laboratory medicine.

Biomolecules and Biomarkers Used in Diagnosis of Alcohol Drinking and in Monitoring Therapeutic Interventions

PubMed Central

Nanau, Radu M.; Neuman, Manuela G.

2015-01-01

Background: The quantitative, measurable detection of drinking is important for the successful treatment of alcohol misuse in transplantation of patients with alcohol disorders, people living with human immunodeficiency virus that need to adhere to medication, and special occupational hazard offenders, many of whom continually deny drinking. Their initial misconduct usually leads to medical problems associated with drinking, impulsive social behavior, and drunk driving. The accurate identification of alcohol consumption via biochemical tests contributes significantly to the monitoring of drinking behavior. Methods: A systematic review of the current methods used to measure biomarkers of alcohol consumption was conducted using PubMed and Google Scholar databases (2010–2015). The names of the tests have been identified. The methods and publications that correlate between the social instruments and the biochemical tests were further investigated. There is a clear need for assays standardization to ensure the use of these biochemical tests as routine biomarkers. Findings: Alcohol ingestion can be measured using a breath test. Because alcohol is rapidly eliminated from the circulation, the time for detection by this analysis is in the range of hours. Alcohol consumption can alternatively be detected by direct measurement of ethanol concentration in blood or urine. Several markers have been proposed to extend the interval and sensitivities of detection, including ethyl glucuronide and ethyl sulfate in urine, phosphatidylethanol in blood, and ethyl glucuronide and fatty acid ethyl esters in hair, among others. Moreover, there is a need to correlate the indirect biomarker carbohydrate deficient transferrin, which reflects longer lasting consumption of higher amounts of alcohol, with serum γ-glutamyl transpeptidase, another long term indirect biomarker that is routinely used and standardized in laboratory medicine. PMID:26131978

Simulation of Pressure-swing Distillation for Separation of Ethyl Acetate-Ethanol-Water

NASA Astrophysics Data System (ADS)

Yang, Jing; Zhou, Menglin; Wang, Yujie; Zhang, Xi; Wu, Gang

2017-12-01

In the light of the azeotrope of ethyl acetate-ethanol-water, a process of pressure-swing distillation is proposed. The separation process is simulated by Aspen Plus, and the effects of theoretical stage number, reflux ratio and feed stage about the pressure-swing distillation are optimized. Some better process parameters are as follows: for ethyl acetate refining tower, the pressure is 500.0 kPa, theoretical stage number is 16, reflux ratio is 0.6, feed stage is 5; for crude ethanol tower, the pressure is 101.3 kPa, theoretical stage number is 15, reflux ratio is 0.3, feed stage is 4; for ethanol tower, the pressure is 101.3 kPa, theoretical stage number is 25, reflux ratio is 1.2, feed stage is 10. The mass fraction of ethyl acetate in the bottom of the ethyl acetate refining tower reaches 0.9990, the mass fraction of ethanol in the top of the ethanol tower tower reaches 0.9017, the mass fraction of water in the bottom of the ethanol tower tower reaches 0.9622, and there is also no ethyl acetate in the bottom of the ethanol tower. With laboratory tests, experimental results are in good agreement with the simulation results, which indicates that the separation of ethyl acetate ethanol water can be realized by the pressure-swing distillation separation process. Moreover, it has certain practical significance to industrial practice.

Development and validation of an UPLC-MS/MS method for the quantification of irinotecan, SN-38 and SN-38 glucuronide in plasma, urine, feces, liver and kidney: Application to a pharmacokinetic study of irinotecan in rats.

PubMed

Basu, Sumit; Zeng, Min; Yin, Taijun; Gao, Song; Hu, Ming

2016-03-15

The objective of this research is to develop and validate a sensitive and reproducible UPLC-MS/MS method to quantify irinotecan, its active metabolite SN-38 and SN-38 glucuronide (phase II metabolite of SN-38) simultaneously in different bio-matrices (plasma, urine, feces), tissues (liver and kidney) and to use the method to investigate its pharmacokinetic behavior in rats. Irinotecan, SN-38 and SN-38 glucuronide has been resolved and separated by C18 column using acetonitrile and 0.1% formic acid in water used as the mobile phases. Triple quadruple mass spectrometer using multiple reaction monitoring (MRM) with positive scan mode were employed to perform mass analysis. The results showed that the linear response range of irinotecan and SN-38 in plasma, feces, liver and kidney is 4.88-10000 nM, 39-5000 nM, 48.8-6250 nM and 48.8-6250 nM, respectively (R(2)>0.99). In case of SN-38 glucuronide, the standard curves were linear in the concentration range of 6.25-2000 nM, 4.88-1250 nM, 9.8-1250 nM and 9.8-1250 nM in plasma, feces, liver and kidney homogenates, respectively. The lower limit of detection (LLOD) of irinotecan, SN-38 and SN-38 glucuronide was determined to be less than 25 nM in all bio-matrices as well as tissue homogenates. Recoveries of irinotecan, SN-38 and SN-38 glucuronide at three different concentrations (low, medium and high) were not less than 85% at three different concentrations in plasma and feces. The percentage matrix factors in different bio-matrices and tissues were within 20%. The UPLC-MS/MS method was validated with intra-day and inter-day precision of less than 15% in plasma, feces, liver and kidney. Owing to the high sensitivity of this method, only 20 μl of plasma, urine and homogenates of liver, kidney and feces is needed. The validated method has been successfully employed for pharmacokinetic evaluation of irinotecan in male wistar rats to quantify irinotecan, SN-38 and SN-38 glucuronide in plasma, feces, and urine samples. Published

Development and validation of an UPLC-MS/MS method for the quantification of irinotecan, SN 38 and SN-38 glucuronide in plasma, urine, feces, liver and kidney: Application to a pharmacokinetic study of irinotecan in rats

PubMed Central

Basu, Sumit; Zeng, Min; Yin, Taijun; Gao, Song; Hu, Ming

2016-01-01

The objective of this research is to develop and validate a sensitive and reproducible UPLC-MS/MS method to quantify irinotecan, its active metabolite SN-38 and SN-38 glucuronide (phase II metabolite of SN-38) simultaneously in different bio-matrices (plasma, urine, feces), tissues (liver and kidney) and to use the method to investigate its pharmacokinetic behavior in rats. Irinotecan, SN-38 and SN-38 glucuronide has been resolved and separated by C18 column using acetonitrile and 0.1% formic acid in water used as the mobile phases. Triple quadruple mass spectrometer using multiple reaction monitoring (MRM) with positive scan mode were employed to perform mass analysis. The results showed that the linear response range of irinotecan and SN-38 in plasma, feces, liver and kidney is 4.88 –10000 nM, 39 – 5000 nM, 48.8 –6250 nM and 48.8 – 6250 nM, respectively (R2 > 0.99). In case of SN-38 glucuronide, the standard curves were linear in the concentration range of 6.25 – 2000 nM, 4.88 – 1250 nM, 9.8 – 1250 nM and 9.8 – 1250 nM in plasma, feces, liver and kidney homogenates, respectively. The lower limit of detection (LLOD) of irinotecan, SN-38 and SN-38 glucuronide was determined to be less than 25 nM in all bio-matrices as well as tissue homogenates. Recoveries of irinotecan, SN-38 and SN-38 glucuronide at three different concentrations (low, medium and high) were not less than 85% at three different concentrations in plasma and feces. The percentage matrix factors in different bio-matrices and tissues were within 20%. The UPLC-MS/MS method was validated with intra-day and inter-day precision of less than 15% in plasma, feces, liver and kidney. Owing to the high sensitivity of this method, only 20 µl of plasma, urine and homogenates of liver, kidney and feces is needed. The validated method has been successfully employed for pharmacokinetic evaluation of irinotecan in male wistar rats to quantify irinotecan, SN-38 and SN-38 glucuronide in plasma, feces

Oxidative and Non-Oxidative Metabolomics of Ethanol.

PubMed

Dinis-Oliveira, Ricardo Jorge

2016-01-01

It is well known that ethanol can cause significant morbidity and mortality, and much of the related toxic effects can be explained by its metabolic profile. This work performs a complete review of the metabolism of ethanol focusing on both major and minor metabolites. An exhaustive literature search was carried out using textual and structural queries for ethanol and related known metabolizing enzymes and metabolites. The main pathway of metabolism is catalyzed by cytosolic alcohol dehydrogenase, which exhibits multiple isoenzymes and genetic polymorphisms with clinical and forensic implications. Another two oxidative routes, the highly inducible CYP2E1 system and peroxisomal catalase may acquire relevance under specific circumstances. In addition to oxidative metabolism, ethanol also originates minor metabolites such as ethyl glucuronide, ethyl sulfate, ethyl phosphate, ethyl nitrite, phosphatidylethanol and fatty acid ethyl esters. These metabolites represent alternative biomarkers since they can be detected several hours or days after ethanol exposure. It is expected that knowing the metabolomics of ethanol may provide additional insights to better understand the toxicological effects and the variability of dose response.

[Survey and analysis of ethyl carbamate in commercial fermented foods in Hangzhou in 2010].

PubMed

Wu, Ping-Gu; Yang, Da-Jin; Shen, Xiang-Hong; Wang, Li-Yuan; Pan, Xiao-Dong; Zhang, Jing; Zhao, Yong-Xin; Tan, Ying

2011-07-01

To observe the ethyl carbamate concentrations in different commercial fermented foods in Hangzhou in 2010. In 2010, 237 commercial fermented food samples of eight categories, including yellow wine, white spirit, wine, beer, cooking wine, sauce, vinegar and fermented bean curd, were purchased from 3 different size markets respectively in Hangzhou. The ethyl carbamate was measured by gas chromatography-mass spectrometry in selection ion mode, after the samples were coupled with D5-ethyl carbamate, and purified by diatomite solid phase extraction column. The results showed that ethyl carbamate was detected in all samples analyzed (100%) with the range from 2.0 µg/kg to 515.0 µg/kg. The ethyl carbamate average (median) levels in 8 food categories were descending with fermented red bean curd (182.2 µg/kg (161.2 µg/kg)), yellow wine (159.6 µg/kg (121.0 µg/kg)), cooking wine (86.8 µg/kg (95.6 µg/kg)), white spirit (72.0 µg/kg (60.5 µg/kg)), soy sauce (47.2 µg/kg (40.7µg/kg)), vinegar (26.7 µg/kg (31.8 µg/kg)), wine (15.7 µg/kg (16.8 µg/kg)) and beer (2.2 µg/kg (2.3 µg/kg)). The ethyl carbamate was detected in all fermented foods in Hangzhou in 2010, and the levels of ethyl carbamate in red bean curd and yellow wine were higher than others.

Chemical conversion of corticosteroids to 3 alpha,5 alpha-tetrahydro derivatives. Synthesis of 5 alpha-cortol 3-glucuronides and 5 alpha-cortolone 3-glucuronides.

PubMed

Hosoda, H; Osanai, K; Nambara, T

1991-12-01

The synthesis of the 3-glucuronides of 5 alpha-cortol-20 alpha, 5 alpha-cortolone-20 alpha and their 20 beta-epimers is described. The 5 alpha-cortol 20,21-diacetates (12, 17) and 5 alpha-cortolone 20,21-diacetates (14, 19) were the key intermediates. Sodium borohydride reduction of the carbonyl group at C-20 in 5 alpha-tetrahydrocortisol 3-tert-butyldimethylsilyl ether 17,21-acetonide (8) gave the 20 alpha-hydroxy-acetonide (9). Selective removal of the acetonide ring was successful when the 20 alpha-acetoxy-17 alpha,21-acetonide (10) was treated with 50% acetic acid. Subsequent acetylation with acetic anhydride in pyridine, followed by removal of the protecting group at C-3 in the silyl ether-acetate (11) gave the desired 20 alpha-intermediate (12). The 11-ketone (14) was prepared from 11 by oxidation with pyridinium chlorochromate, followed by desilylation. The 20 beta-acetates (17, 19) were synthesized from 21-acetoxy-3 alpha,11 beta,17 alpha-trihydroxy-5 alpha-pregnan-20-one 3-tert-butyldimethylsilyl ether (15). Introduction of the glucuronyl residue at C-3 was carried out by means of the Koenigs-Knorr reaction.

Quantification of phenolic acids and their methylates, glucuronides, sulfates and lactones metabolites in human plasma by LC-MS/MS after oral ingestion of soluble coffee.

PubMed

Marmet, Cynthia; Actis-Goretta, Lucas; Renouf, Mathieu; Giuffrida, Francesca

2014-01-01

Chlorogenic acids and derivatives like phenolic acids are potentially bioactive phenolics, which are commonly found in many foods. Once absorbed, chlorogenic and phenolic acids are highly metabolized by the intestine and the liver, producing glucuronidated and/or sulphated compounds. These metabolites were analyzed in human plasma using a validated liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method. After protein precipitation, phenolic acids and their metabolites were extracted by using ethanol and chromatographic separation was achieved by reversed-phase using an Acquity UPLC BEH C18 column combined with a gradient elution system using 1% acetic acid aqueous solution and 1% acetic acid with 100% acetonitrile. The method was able to quantify 56 different compounds including 24 phenolic acids, 4 lactones, 15 sulfates and 13 glucuronides metabolites between 5 and 1000nM in plasma for most of them, except for m-dihydrocoumaric acid, 5-ferulloylquinic-glucuronide, 4-methoxycinnamic acid, 3-phenylpropionic acid, 3-(4-methoxyphenyl)propionic acid (25 to 1000nM) and p-dihydrocoumaric acid (50-1000nM). Values of repeatability and intermediate reproducibility were below 15% of deviation in general, and maximum 20% for the lowest concentrations. The validated method was successfully applied to quantify phenolic acids and their metabolites in plasma obtained after oral ingestion of soluble coffee. In conclusion, the developed and validated method is proved to be very sensitive, accurate and precise for the quantification of these possible dietary phenols. Copyright © 2013 Elsevier B.V. All rights reserved.

Highly sensitive sites for guanine-O6 ethylation in rat brain DNA exposed to N-ethyl-N-nitrosourea in vivo.

PubMed Central

Nehls, P; Rajewsky, M F; Spiess, E; Werner, D

1984-01-01

Brain chromosomal DNA isolated from fetal BDIX-rats 1 h after i.v. administration of the ethylating N-nitroso carcinogen N-ethyl-N-nitrosourea (75 micrograms/g body weight), statistically contained one molecule of O6-ethyl-2'-deoxyguanosine (O6-EtdGuo) per 81 micron of DNA, as determined in enzymatic DNA hydrolysates by competitive radio-immunoassay using a high-affinity anti-(O6-EtdGuo) monoclonal antibody (ER-6). After fragmentation of the DNA by the restriction enzyme AluI (average fragment length, Lav = 0.28 micron = 970 bp; length range, Lr = 1.87-0.02 micron = 6540 - 60 bp), a small (approximately 2%) fraction of DNA enriched in specific polypeptides tightly associated with DNA was separated from the bulk DNA by a glass fiber binding technique. As analyzed by immune electron microscopy, approximately 1% of the DNA molecules in this fraction contained clusters of 2-10 (O6-EtdGuo)-antibody binding sites (ABS). On the cluster-bearing fragments (Lav, 0.85 micron +/- 0.50 micron S.D.; corresponding to 2970 +/- 1760 bp) the average ABS-ABS interspace distance was 110 nm (= 390 bp; range approximately 9-600 nm), indicating a highly non-random distribution of O6-EtdGuo in target cell DNA. Images Fig. 2. PMID:6370677

40 CFR 721.10109 - Hexanoic acid, 2-ethyl-, mixed triesters with benzoic acid and trimethylolpropane.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Hexanoic acid, 2-ethyl-, mixed... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10109 Hexanoic acid, 2-ethyl-, mixed... to reporting. (1) The chemical substance identified as hexanoic acid, 2-ethyl-, mixed triesters with...

40 CFR 721.10109 - Hexanoic acid, 2-ethyl-, mixed triesters with benzoic acid and trimethylolpropane.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Hexanoic acid, 2-ethyl-, mixed... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10109 Hexanoic acid, 2-ethyl-, mixed... to reporting. (1) The chemical substance identified as hexanoic acid, 2-ethyl-, mixed triesters with...

40 CFR 721.10109 - Hexanoic acid, 2-ethyl-, mixed triesters with benzoic acid and trimethylolpropane.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Hexanoic acid, 2-ethyl-, mixed... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10109 Hexanoic acid, 2-ethyl-, mixed... to reporting. (1) The chemical substance identified as hexanoic acid, 2-ethyl-, mixed triesters with...

40 CFR 721.10109 - Hexanoic acid, 2-ethyl-, mixed triesters with benzoic acid and trimethylolpropane.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Hexanoic acid, 2-ethyl-, mixed... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10109 Hexanoic acid, 2-ethyl-, mixed... to reporting. (1) The chemical substance identified as hexanoic acid, 2-ethyl-, mixed triesters with...

40 CFR 721.10109 - Hexanoic acid, 2-ethyl-, mixed triesters with benzoic acid and trimethylolpropane.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Hexanoic acid, 2-ethyl-, mixed... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10109 Hexanoic acid, 2-ethyl-, mixed... to reporting. (1) The chemical substance identified as hexanoic acid, 2-ethyl-, mixed triesters with...

Merging Features and Optical-Near Infrared Color Gradients of Early-type Galaxies

NASA Astrophysics Data System (ADS)

Kim, Duho; Im, M.

2012-01-01

It has been suggested that merging plays an important role in the formation and the evolution of early-type galaxies (ETGs). Optical-NIR color gradients of ETGs in high density environments are found to be less steep than those of ETGs in low density environments, hinting frequent merger activities in ETGs in high density environments. In order to examine if the flat color gradients are the result of dry mergers, we studied the relations between merging features, color gradient, and environments of 198 low redshift ETGs selected from Sloan Digital Sky Survey (SDSS) Stripe82. Near Infrared (NIR) images are taken from UKIRT Infrared Deep Sky Survey (UKIDSS) Large Area Survey (LAS). Color(r-K) gradients of ETGs with tidal features are a little flatter than relaxed ETGs, but not significant. We found that massive (>1011.3 M⊙) relaxed ETGs have 2.5 times less scattered color gradients than less massive ETGs. The less scattered color gradients of massive ETGs could be evidence of dry merger processes in the evolution of massive ETGs. We found no relation between color gradients of ETGs and their environments.

A field trial of ethyl hexanediol against Aedes dorsalis in Sonoma County, California.

PubMed

Rutledge, L C; Hooper, R L; Wirtz, R A; Gupta, R K

1989-09-01

The repellent ethyl hexanediol (2-ethyl-1,3-hexanediol) was tested against the mosquito Aedes dorsalis in a coastal salt marsh in California. The experimental design incorporated a linear regression model, sequential treatments and a proportional end point (95%) for protection time. The protection time of 0.10 mg/cm2 ethyl hexanediol was estimated at 0.8 h. This time is shorter than that obtained previously for deet (N,N-diethyl-3-methylbenzamide) against Ae. dorsalis (4.4 h).

Furfuryl ethyl ether: important aging flavor and a new marker for the storage conditions of beer.

PubMed

Vanderhaegen, Bart; Neven, Hedwig; Daenen, Luk; Verstrepen, Kevin J; Verachtert, Hubert; Derdelinckx, Guy

2004-03-24

Recently, it was reported that furfuryl ethyl ether is an important flavor compound indicative of beer storage and aging conditions. A study of the reaction mechanism indicates that furfuryl ethyl ether is most likely formed by protonation of furfuryl alcohol or furfuryl acetate followed by S(N)2-substitution of the leaving group by the nucleophilic ethanol. For the reaction in beer, a pseudo-first-order reaction kinetics was derived. A close correlation was found between the values predicted by the kinetic model and the actual furfuryl ethyl ether concentration evolution during storage of beer. Furthermore, 10 commercial beers of different types, aged during 4 years in natural conditions, were analyzed, and it was found that the furfuryl ethyl ether flavor threshold was largely exceeded in each type of beer. In these natural aging conditions, lower pH, darker color, and higher alcohol content were factors that enhanced furfuryl ethyl ether formation. On the other hand, sulfite clearly reduced furfuryl ethyl ether formation. All results show that the furfuryl ethyl ether concentration is an excellent time-temperature integrator for beer storage.

Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial.

PubMed

Pavel, Marianne; Gross, David J; Benavent, Marta; Perros, Petros; Srirajaskanthan, Raj; Warner, Richard R P; Kulke, Matthew H; Anthony, Lowell B; Kunz, Pamela L; Hörsch, Dieter; Weickert, Martin O; Lapuerta, Pablo; Jiang, Wenjun; Kassler-Taub, Kenneth; Wason, Suman; Fleming, Rosanna; Fleming, Douglas; Garcia-Carbonero, Rocio

2018-03-01

Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with <4 BMs/day on SSAs (or ≥1 symptom or ≥4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients ( N  = 76) were randomly assigned (1:1:1) to receive placebo or telotristat ethyl 250 mg or 500 mg 3 times per day (tid); 67 continued receiving telotristat ethyl 500 mg tid during the OLE. Through week 12, TEAEs were generally mild to moderate in severity; 5 (placebo), 1 (telotristat ethyl 250 mg) and 3 (telotristat ethyl 500 mg) patients experienced serious events, and the rate of TEAEs in the OLE was comparable. At week 12, significant reductions in u5-HIAA from baseline were observed, with Hodges-Lehmann estimators of median treatment differences from placebo of -54.0% (95% confidence limits, -85.0%, -25.1%, P  < 0.001) and -89.7% (95% confidence limits, -113.1%, -63.9%, P  < 0.001) for telotristat ethyl 250 mg and 500 mg. These results support the safety and efficacy of telotristat ethyl when added to SSAs in patients with CS diarrhea (ClinicalTrials.gov identifier: Nbib2063659). © 2018 The authors.

Simultaneous extraction of propofol and propofol glucuronide from hair followed by validated LC-MS/MS analyses.

PubMed

Maas, Alexandra; Maier, Christoph; Iwersen-Bergmann, Stefanie; Madea, Burkhard; Hess, Cornelius

2017-11-30

Besides its clinical application, the anaesthetic agent propofol is being increasingly misused, mostly by healthcare professionals, and its abuse potential gained worldwide attention after the tragic death of Michael Jackson in 2009. Due to the short duration of its narcotic effects, propofol abuse is especially easy to hide compared with the use of other recreational drugs. However, propofol possesses a very narrow therapeutic window between the desired effect and potentially fatal toxicity, making abuse of the drug extremely dangerous even in experienced physicians. Consequently, it is important that forensic laboratories possess a sensitive and specific method for the detection of chronic propofol abuse. We present a simple, fast and reliable method to simultaneously extract propofol and its main metabolite propofol glucuronide from hair, followed by sensitive LC-MS/MS analyses, allowing to determine a chronic propofol abuse. Difficulties regarding the detection of propofol using LC-MS/MS were solved by using a derivatization reaction with 2-fluoro-1-methylpyridinium-p-toluene-sulfonate and triethylamine. Reliability of extraction method and subsequent LC-MS/MS analyses was confirmed under consideration of the validation parameters selectivity, linearity, accuracy and precision, analytical limits, processed sample stability, matrix effects and recovery. Appropriate quantification (LLOQ=10pg/mg hair) and detection limits (3.6pg/mg hair for propofol and 7.8 pg/mg hair for propofol glucuronide) could be achieved, enabling to detect even small amounts of both analytes. Applicability of the method was confirmed by analysis of three human hair samples from deceased with suspicion of chronic propofol abuse. Copyright © 2017 Elsevier B.V. All rights reserved.

Production of ethyl levulinate by direct conversion of wheat straw in ethanol media.

PubMed

Chang, Chun; Xu, Guizhuan; Jiang, Xiaoxian

2012-10-01

The production of ethyl levulinate from wheat straw by direct conversion in ethanol media was investigated. Response surface methodology (RSM) was applied to optimize the effects of processing parameters, and the regression analysis was performed on the data obtained. A close agreement between the experimental results and the model predictions was achieved. The optimal conditions for ethyl levulinate production from wheat straw were acid concentration 2.5%, reaction temperature 183°C, mass ratio of liquid to solid 19.8 and reaction time 36 min. Under the optimum conditions, the yield of ethyl levulinate 17.91% was obtained, representing a theoretical yield of 51.0%. The results suggest that wheat straw can be used as potential raw materials for the production of ethyl levulinate by direct conversion in ethanol media. Copyright © 2012 Elsevier Ltd. All rights reserved.

IRIS Toxicological Review of Ethyl Tertiary Butyl Ether (Etbe) ...

EPA Pesticide Factsheets

The IRIS Toxicological Review of Ethyl Tertiary Butyl Ether (ETBE) was released for external peer review in June 2017. EPA’s Science Advisory Board’s (SAB) Chemical Assessment Advisory Committee (CAAC) will conduct a peer review of the scientific basis supporting the ETBE assessment and release a final report of their review. Information regarding the peer review can be found on the SAB website. EPA is conducting an Integrated Risk Information System (IRIS) health assessment for Ethyl Tertiary Butyl Ether (ETBE). The outcome of this project is a Toxicological Review and IRIS Summary for ETBE that will be entered into the IRIS database.

40 CFR 721.10110 - Hexanoic acid, 2-ethyl-, mixed diesters with benzoic acid and neopentlyl glycol.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Hexanoic acid, 2-ethyl-, mixed... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10110 Hexanoic acid, 2-ethyl-, mixed... to reporting. (1) The chemical substance identified as hexanoic acid, 2-ethyl-, mixed diesters with...

40 CFR 721.10111 - Hexanoic acid, 2-ethyl-, mixed diesters with benzoic acid and diethylene glycol.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Hexanoic acid, 2-ethyl-, mixed... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10111 Hexanoic acid, 2-ethyl-, mixed... to reporting. (1) The chemical substance identified as hexanoic acid, 2-ethyl-, mixed diesters with...

40 CFR 721.10111 - Hexanoic acid, 2-ethyl-, mixed diesters with benzoic acid and diethylene glycol.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Hexanoic acid, 2-ethyl-, mixed... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10111 Hexanoic acid, 2-ethyl-, mixed... to reporting. (1) The chemical substance identified as hexanoic acid, 2-ethyl-, mixed diesters with...

40 CFR 721.10110 - Hexanoic acid, 2-ethyl-, mixed diesters with benzoic acid and neopentlyl glycol.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Hexanoic acid, 2-ethyl-, mixed... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10110 Hexanoic acid, 2-ethyl-, mixed... to reporting. (1) The chemical substance identified as hexanoic acid, 2-ethyl-, mixed diesters with...

40 CFR 721.10111 - Hexanoic acid, 2-ethyl-, mixed diesters with benzoic acid and diethylene glycol.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Hexanoic acid, 2-ethyl-, mixed... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10111 Hexanoic acid, 2-ethyl-, mixed... to reporting. (1) The chemical substance identified as hexanoic acid, 2-ethyl-, mixed diesters with...

40 CFR 721.10111 - Hexanoic acid, 2-ethyl-, mixed diesters with benzoic acid and diethylene glycol.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Hexanoic acid, 2-ethyl-, mixed... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10111 Hexanoic acid, 2-ethyl-, mixed... to reporting. (1) The chemical substance identified as hexanoic acid, 2-ethyl-, mixed diesters with...

40 CFR 721.10111 - Hexanoic acid, 2-ethyl-, mixed diesters with benzoic acid and diethylene glycol.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Hexanoic acid, 2-ethyl-, mixed... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10111 Hexanoic acid, 2-ethyl-, mixed... to reporting. (1) The chemical substance identified as hexanoic acid, 2-ethyl-, mixed diesters with...

40 CFR 721.10110 - Hexanoic acid, 2-ethyl-, mixed diesters with benzoic acid and neopentlyl glycol.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Hexanoic acid, 2-ethyl-, mixed... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10110 Hexanoic acid, 2-ethyl-, mixed... to reporting. (1) The chemical substance identified as hexanoic acid, 2-ethyl-, mixed diesters with...

40 CFR 721.10110 - Hexanoic acid, 2-ethyl-, mixed diesters with benzoic acid and neopentlyl glycol.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Hexanoic acid, 2-ethyl-, mixed... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10110 Hexanoic acid, 2-ethyl-, mixed... to reporting. (1) The chemical substance identified as hexanoic acid, 2-ethyl-, mixed diesters with...

40 CFR 721.10110 - Hexanoic acid, 2-ethyl-, mixed diesters with benzoic acid and neopentlyl glycol.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Hexanoic acid, 2-ethyl-, mixed... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10110 Hexanoic acid, 2-ethyl-, mixed... to reporting. (1) The chemical substance identified as hexanoic acid, 2-ethyl-, mixed diesters with...

Copper(II) catalysis in cyanide conversion into ethyl carbamate in spirits and relevant reactions.

PubMed

Aresta, M; Boscolo, M; Franco, D W

2001-06-01

The role of copper(II) species in the oxidation of inorganic cyanide to cyanate and in the conversion of cyanate or urea into ethyl carbamate was investigated. The oxidation process has been shown to be independent from the dissolved oxygen. Elemental analysis and infrared spectroscopy have shown the formation of a mixed copper carbonate/hydroxide in the process of oxidation of cyanide to cyanate in water/ethanol. The complexation to Cu(II) of cyanate formed upon cyanide oxidation makes the former more susceptible to nucleophilic attack from ethanol, with conversion into ethyl carbamate. Comparatively, urea has a minor role with respect to cyanide in the formation of ethyl carbamate. Therefore, the urea present in some samples of Brazilian sugar cane spirit (cachaça) has been shown to have almost no influence on the ethyl carbamate content of cachaças, which comes essentially from cyanide. Fe(II,III) affords results similar to those found with Cu(II). Some suggestions are presented to avoid ethyl carbamate formation in spirits during distillation.

Enzymatic production of biodiesel from microalgal oil using ethyl acetate as an acyl acceptor.

PubMed

Alavijeh, Razieh Shafiee; Tabandeh, Fatemeh; Tavakoli, Omid; Karkhane, Aliasghar; Shariati, Parvin

2015-01-01

Microalgae have become an important source of biomass for biodiesel production. In enzymatic transesterification reaction, the enzyme activity is decreased in presence of alcohols. The use of different acyl acceptors such as methyl/ethyl acetate is suggested as an alternative and effective way to overcome this problem. In this study, ethyl acetate was used for the first time in the enzymatic production of biodiesel by using microalga, Chlorella vulgaris, as a triglyceride source. Enzymatic conversion of such fatty acids to biodiesel was catalyzed by Novozym 435 as an efficient immobilized lipase which is extensively used in biodiesel production. The best conversion yield of 66.71% was obtained at the ethyl acetate to oil molar ratio of 13:1 and Novozym 435 concentration of 40%, based on the amount of oil, and a time period of 72 h at 40℃. The results showed that ethyl acetate have no adverse effect on lipase activity and the biodiesel amount was not decreased even after seven transesterification cycles, so ethyl acetate has a great potential to be substituted for short-chain alcohols in transesterification reaction.

Microbial Community Dynamics during the Bioremediation Process of Chlorimuron-Ethyl-Contaminated Soil by Hansschlegelia sp. Strain CHL1

PubMed Central

Yang, Liqiang; Li, Xinyu; Li, Xu; Su, Zhencheng; Zhang, Chenggang; Zhang, Huiwen

2015-01-01

Long-term and excessive application of chlorimuron-ethyl has led to a series of environmental problems. Strain Hansschlegelia sp. CHL1, a highly efficient chlorimuron-ethyl degrading bacterium isolated in our previous study, was employed in the current soil bioremediation study. The residues of chlorimuron-ethyl in soils were detected, and the changes of soil microbial communities were investigated by phospholipid fatty acid (PLFA) analysis. The results showed that strain CHL1 exhibited significant chlorimuron-ethyl degradation ability at wide range of concentrations between 10μg kg-1 and 1000μg kg-1. High concentrations of chlorimuron-ethyl significantly decreased the total concentration of PLFAs and the Shannon-Wiener indices and increased the stress level of microbes in soils. The inoculation with strain CHL1, however, reduced the inhibition on soil microbes caused by chlorimuron-ethyl. The results demonstrated that strain CHL1 is effective in the remediation of chlorimuron-ethyl-contaminated soil, and has the potential to remediate chlorimuron-ethyl contaminated soils in situ. PMID:25689050

Organic reactions catalyzed by methylrhenium trioxide: Reactions of ethyl diazoacetate and organic azides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Z.; Espenson, J.H.

1996-10-16

Methylrhenium trioxide (CH{sub 3}ReO{sub 3} or MTO) catalyzes several classes of reactions of ethyl diazoacetate, EDA. It is the first high valent oxo complex for carbene transfer. Under mild conditions and in the absence of other substrates, EDA was converted to a 9:1 mixture of diethyl maleate and diethyl fumarate. In the presence of alcohols, {alpha}-alkoxy ethyl acetates were obtained in good yield. The yields dropped for the larger and more branched alcohols, the balance of material being diethyl maleate and fumarate. An electron-donating group in the para position of phenols favors the formation of {alpha}-phenoxy ethyl acetates. The usemore » of EDA to form {alpha}-thio ethyl acetates and N-substituted glycine ethyl esters, on the other hand, is hardly affected by the size or structure of the parent thiol or amine, with all of these reactions proceeding in high yield. MTO-catalyzed cycloaddition reactions occur between EDA and aromatic imines, olefins, and carbonyl compounds. Three-membered ring products are formed: aziridines, cyclopropanes, and epoxides, respectively. The reactions favor the formation of trans products, and provide a convenient route for the preparation of aziridines. Intermediate carbenoid and nitrenoid species have been proposed. In the presence of an oxygen source such as an epoxide, ethyl diazoacetate and azibenzil are converted to an oxalic acid monoethyl ester and to benzil; at the same time the epoxide was converted to an olefin. 75 refs., 1 fig., 7 tabs.« less

Manufacturing Ethyl Acetate From Fermentation Ethanol

NASA Technical Reports Server (NTRS)

Rohatgi, Naresh K.; Ingham, John D.

1991-01-01

Conceptual process uses dilute product of fermentation instead of concentrated ethanol. Low-concentration ethanol, extracted by vacuum from fermentation tank, and acetic acid constitutes feedstock for catalytic reaction. Product of reaction goes through steps that increases ethyl acetate content to 93 percent by weight. To conserve energy, heat exchangers recycle waste heat to preheat process streams at various points.

Simultaneous determination of ezetimibe and its glucuronide metabolite in human plasma by solid phase extraction and liquid chromatography-tandem mass spectrometry.

PubMed

Guo, Lin; Wang, Meng-meng; He, Min; Qiu, Fu-rong; Jiang, Jian

2015-04-01

A liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was developed to quantify ezetimibe (EZM) and its major glucuronide (ezetimibe glucuronide, EZM-G) in human plasma simultaneously. The analytes were purified by solid phase extraction (SPE) without hydrolysis. Separation of the analytes was achieved using acetonitrile-water (0.08% formic acid) (70:30, v/v) as the mobile phase at a flow rate of 0.8 mL/min on an Agilent Extend C18 column. The analytes were detected by LC-MS/MS using negative ionization in multiple reaction monitoring (MRM) mode. The mass transition pairs of m/z 408.4→271.0 and m/z 584.5→271.0 were used to detect EZM and EZM-G, respectively. The analytical method was linear over the concentration range of 0.1-20 ng/mL for EZM and 0.5-200 ng/mL for EZM-G. Within- and between-run precision for EZM was no more than 8.6% and 12.8%; and for EZM-G was no more than 9.0% and 8.7%, respectively. This method was reproducible and reliable, and was successfully used to analyze human plasma samples for application in a bioequivalence study. Copyright © 2015 Elsevier B.V. All rights reserved.

Controlled Degradation of Poly(Ethyl Cyanoacrylate-Co-Methyl Methacrylate)(PECA-Co-PMMA) Copolymers

USDA-ARS?s Scientific Manuscript database

This paper describes a method for modifying poly(ethyl cyanoacrylate) in order to control the degradation and the stability as well as the glass transition temperatures. Copolymers of poly(ethyl cyanoacrylate-co-methyl methacrylate) (PECA-co-PMMA) with various compositions were synthesized by free ...

Morphine Glucuronidation and Elimination in Intensive Care Patients: A Comparison with Healthy Volunteers.

PubMed

Ahlers, Sabine J G M; Välitalo, Pyry A J; Peeters, Mariska Y M; Gulik, Laura van; van Dongen, Eric P A; Dahan, Albert; Tibboel, Dick; Knibbe, Catherijne A J

2015-11-01

Although morphine is used frequently to treat pain in the intensive care unit, its pharmacokinetics has not been adequately quantified in critically ill patients. We evaluated the glucuronidation and elimination clearance of morphine in intensive care patients compared with healthy volunteers based on the morphine and morphine-3-glucuronide (M3G) concentrations. A population pharmacokinetic model with covariate analysis was developed with the nonlinear mixed-effects modeling software (NONMEM 7.3). The analysis included 3012 morphine and M3G concentrations from 135 intensive care patients (117 cardiothoracic surgery patients and 18 critically ill patients), who received continuous morphine infusions adapted to individual pain levels, and 622 morphine and M3G concentrations from a previously published study of 20 healthy volunteers, who received an IV bolus of morphine followed by a 1-hour infusion. For morphine, a 3-compartment model best described the data, whereas for M3G, a 1-compartment model fits best. In intensive care patients with a normal creatinine concentration, a decrease of 76% was estimated in M3G clearance compared with healthy subjects, conditional on the M3G volume of distribution being the same in intensive care patients and healthy volunteers. Furthermore, serum creatinine concentration was identified as a covariate for both elimination clearance of M3G in intensive care patients and unchanged morphine clearance in all patients and healthy volunteers. Under the assumptions in the model, M3G elimination was significantly decreased in intensive care patients when compared with healthy volunteers, which resulted in substantially increased M3G concentrations. Increased M3G levels were even more pronounced in patients with increased serum creatinine levels. Model-based simulations show that, because of the reduction in morphine clearance in intensive care patients with renal failure, a 33% reduction in the maintenance dose would result in morphine

Testosterone and androstanediol glucuronide among men in NHANES III.

PubMed

Duan, Chuan Wei; Xu, Lin

2018-03-09

Most of the androgen replacement therapies were based on serum testosterone and without measurements of total androgen activities. Whether those with low testosterone also have low levels of androgen activity is largely unknown. We hence examined the association between testosterone and androstanediol glucuronide (AG), a reliable measure of androgen activity, in a nationally representative sample of US men. Cross-sectional analysis was based on 1493 men from the Third National Health and Nutrition examination Survey (NHANES III) conducted from 1988 to 1991. Serum testosterone and AG were measured by immunoassay. Kernel density was used to estimate the average density of serum AG concentrations by quartiles of testosterone. Testosterone was weakly and positively correlated with AG (correlation coefficient = 0.18). The kernel density estimates show that the distributions are quite similar between the quartiles of testosterone. After adjustment for age, the distributions of AG in quartiles of testosterone did not change. The correlation between testosterone and AG was stronger in men with younger age, lower body mass index, non-smoking and good self-rated health and health status. Serum testosterone is weakly correlated with total androgen activities, and the correlation is even weaker for those with poor self-rated health. Our results suggest that measurement of total androgen activity in addition to testosterone is necessary in clinical practice, especially before administration of androgen replacement therapy.

Determination of the binding properties of p-cresyl glucuronide to human serum albumin.

PubMed

Yi, Dan; Monteiro, Elisa Bernardes; Chambert, Stéphane; Soula, Hédi A; Daleprane, Julio B; Soulage, Christophe O

2018-04-26

p-Cresyl glucuronide (p-CG) is a by-product of tyrosine metabolism that accumulates in patients with end-stage renal disease. p-CG binding to human serum albumin in physiological conditions (37°C, pH 7.40) was studied by ultrafiltration (MWCO 10 kDa) and data were analyzed assuming one binding site. The estimated value of the association constant was 2.77×10 3  M -1 and a maximal stoichiometry of 3.80 mol per mole. At a concentration relevant for end-stage renal patients, p-CG was 23% bound to albumin. Competition experiments, using fluorescent probes, demonstrated that p-CG did not bind to Sudlow's site I or site II. The p-CG did not interfere with the binding of p-cresyl-sulfate or indoxyl sulfate to serum albumin. Copyright © 2018. Published by Elsevier B.V.

40 CFR 63.61 - Deletion of methyl ethyl ketone from the list of hazardous air pollutants.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 9 2011-07-01 2011-07-01 false Deletion of methyl ethyl ketone from... Designations, Source Category List § 63.61 Deletion of methyl ethyl ketone from the list of hazardous air pollutants. The substance methyl ethyl ketone (MEK, 2-Butanone) (CAS Number 78-93-3) is deleted from the list...

40 CFR 63.61 - Deletion of methyl ethyl ketone from the list of hazardous air pollutants.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 9 2010-07-01 2010-07-01 false Deletion of methyl ethyl ketone from... Designations, Source Category List § 63.61 Deletion of methyl ethyl ketone from the list of hazardous air pollutants. The substance methyl ethyl ketone (MEK, 2-Butanone) (CAS Number 78-93-3) is deleted from the list...

Antiangiogenic effects and mechanisms of trans-ethyl p-methoxycinnamate from Kaempferia galanga L.

PubMed

He, Zhi-Heng; Yue, Grace Gar-Lee; Lau, Clara Bik-San; Ge, Wei; But, Paul Pui-Hay

2012-11-14

Kaempferia galanga L. (Zingiberaceae) is an aromatic herb and a popular spice used as a condiment in Asian cuisine. The ethanol extract of the dried plant and its successive four subfractions were investigated on zebrafish model by quantitative endogenous alkaline phosphatase assay. Both n-hexane and ethyl acetate fractions had antiangiogenic activity, and two major active components (trans-ethyl p-methoxycinnamate and kaempferol) showed potent antiangiogenic effects on wild-type zebrafish. Because of its much stronger effect and no antiangiogenic activity reported, trans-ethyl p-methoxycinnamate was further investigated for its action mechanism. It dose dependently inhibited vessel formation on both wild- and Tg(fli1a:EGFP)y1-type zebrafish embryos. The semiquantitative reverse transcription polymerase chain reaction assay suggested that trans-ethyl p-methoxycinnamate affects multiple molecular targets related to angiogenesis. In vitro, it specifically inhibited the migration and tube formation of human umbilical vein endothelial cells. In vivo, it could block bFGF-induced vessel formation on Matrigel plug assay.

Effects of clofibric acid on the biliary excretion of benoxaprofen glucuronide and taurine conjugate in rats.

PubMed

Okada, K; Kanoh, H; Mohri, K

2011-10-01

Benoxaprofen (BOP) is a 2-methyl propionic acid derivative with anti-inflammatory activity. BOP has an asymmetric carbon, and receives chiral inversion from R to S in vivo. BOP is metabolized to glucuronide (BOP-G) and taurine conjugate (BOP-T). The configuration of BOP-G is mainly S, and that of BOP-T is R. Chiral inversion of R to S of the propionic acid moiety and amino acid conjugation of carboxyl compounds proceed via an acyl CoA intermediate. It is known that fibrates, used in hyperlipidemia, induce acyl CoA synthetase and increase CoA concentration. We administered racemic BOP (10 mg/kg body weight) to rats (CFA+) pre-administered clofibric acid (CFA, 280 mg/kg/day), and studied BOP, BOP-G, and BOP-T enantiomer concentrations in plasma and bile up to 12 h after administration. The findings were compared with those in rats (CFA-) that had not received CFA. Furthermore, we studied the amounts of BOP-G enantiomer produced by glucuronidation in vitro using microsomes pretreated with CFA. The amounts of (S)-BOP-G in CFA+ rats were 2.7-fold larger than that in CFA- rats. Although (R)-BOP-T was excreted in CFA- rats, BOP-T could not be detected in CFA+ rats. Plasma clearance values of racemic BOP and (S)-BOP in CFA+ rats were 5-fold and 6-fold larger than those in CFA- rats, respectively. (S)-BOP-G formation activities were higher than (R)-BOP-G formation activities in both CFA+and CFA- microsomes. These findings suggest that CFA increases biliary excretion of (S)-BOP-G and facilitates plasma elimination of BOP, and further suggests that CFA predominantly induces chiral inversion to S rather than metabolic reaction to (R)-BOP-T, resulting in an increase of (S)-BOP-G.

75 FR 17769 - In the Matter of Certain Products Advertised as Containing Creatine Ethyl Ester; Notice of...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-07

... Advertised as Containing Creatine Ethyl Ester; Notice of Commission Issuance of a Limited Exclusion Order Against the Products Advertised as Containing Creatine Ethyl Ester of Respondents Found in Default... importation of certain products advertised as containing creatine ethyl ester by reason of false advertising...

Randomized controlled trial of ethyl-eicosapentaenoic acid in Huntington disease: the TREND-HD study.

PubMed

2008-12-01

To determine whether ethyl-eicosapentaenoic acid (ethyl-EPA), an omega-3 fatty acid, improves the motor features of Huntington disease. Six-month multicenter, randomized, double-blind, placebo-controlled trial followed by a 6-month open-label phase without disclosing initial treatment assignments. Forty-one research sites in the United States and Canada. Three hundred sixteen adults with Huntington disease, enriched for a population with shorter trinucleotide (cytosine-adenine-guanine) repeat length expansions. Random assignment to placebo or ethyl-EPA, 1 g twice a day, followed by open-label treatment with ethyl-EPA. Six-month change in the Total Motor Score 4 component of the Unified Huntington's Disease Rating Scale analyzed for all research participants and those with shorter cytosine-adenine-guanine repeat length expansions (<45). At 6 months, the Total Motor Score 4 point change for patients receiving ethyl-EPA did not differ from that for those receiving placebo. No differences were found in measures of function, cognition, or global impression. Before public disclosure of the 6-month placebo-controlled results, 192 individuals completed the open-label phase. The Total Motor Score 4 change did not worsen for those who received active treatment for 12 continuous months compared with those who received active treatment for only 6 months (2.0-point worsening; P=.02). Ethyl-EPA was not beneficial in patients with Huntington disease during 6 months of placebo-controlled evaluation. Clinical Trial Registry clinicaltrials.gov Identifier: NCT00146211.

Role of the P-F bond in fluoride-promoted aqueous VX hydrolysis: an experimental and theoretical study.

PubMed

Marciano, Daniele; Columbus, Ishay; Elias, Shlomi; Goldvaser, Michael; Shoshanim, Ofir; Ashkenazi, Nissan; Zafrani, Yossi

2012-11-16

Following our ongoing studies on the reactivity of the fluoride ion toward organophosphorus compounds, we established that the extremely toxic and environmentally persistent chemical warfare agent VX (O-ethyl S-2-(diisopropylamino)ethyl methylphosphonothioate) is exclusively and rapidly degraded to the nontoxic product EMPA (ethyl methylphosphonic acid) even in dilute aqueous solutions of fluoride. The unique role of the P-F bond formation in the reaction mechanism was explored using both experimental and computational mechanistic studies. In most cases, the "G-analogue" (O-ethyl methylphosphonofluoridate, Et-G) was observed as an intermediate. Noteworthy and of practical importance is the fact that the toxic side product desethyl-VX, which is formed in substantial quantities during the slow degradation of VX in unbuffered water, is completely avoided in the presence of fluoride. A computational study on a VX-model, O,S-diethyl methylphosphonothioate (1), clarifies the distinctive tendency of aqueous fluoride ions to react with such organophosphorus compounds. The facility of the degradation process even in dilute fluoride solutions is due to the increased reactivity of fluoride, which is caused by the significant low activation barrier for the P-F bond formation. In addition, the unique nucleophilicity of fluoride versus hydroxide toward VX, in contrast to their relative basicity, is discussed. Although the reaction outcomes were similar, much slower reaction rates were observed experimentally for the VX-model (1) in comparison to VX.

40 CFR 721.1085 - Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Benzenamine,4,4â²-methylenebis[N-ethyl-N-methyl-. 721.1085 Section 721.1085 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.1085 Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-. (a) Chemical...

40 CFR 721.1085 - Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Benzenamine,4,4â²-methylenebis[N-ethyl-N-methyl-. 721.1085 Section 721.1085 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.1085 Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-. (a) Chemical...

21 CFR 172.872 - Methyl ethyl cellulose.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Methyl ethyl cellulose. 172.872 Section 172.872 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR HUMAN...

21 CFR 172.872 - Methyl ethyl cellulose.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Methyl ethyl cellulose. 172.872 Section 172.872 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR HUMAN...

Substoichiometric radiochemical determination of silver with potassium ethyl xanthate in photofilm washings.

PubMed

Reddy, P C; Rangamannar, B

1990-05-01

An accurate and rapid radiochemical method has been developed for the determination of microgram amount of silver employing potassium ethyl xanthate as a substoichiometric radiochemical reagent. The light yellow coloured silver ethyl xanthate formed was extracted into nitrobenzene from sulphuric acid media. The effect of foreign ions on the extraction was studied. The method was applied to the determination of silver content in photofilm washings.

40 CFR 721.10401 - Oxirane, 2-ethyl-, polymer with oxirane, mono-C11-15-sec-alkyl ethers.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Oxirane, 2-ethyl-, polymer with... Significant New Uses for Specific Chemical Substances § 721.10401 Oxirane, 2-ethyl-, polymer with oxirane...) The chemical substance identified as oxirane, 2-ethyl-, polymer with oxirane, mono C11-15-sec-alkyl...

40 CFR 721.10400 - Oxirane, 2-ethyl-, polymer with oxirane, mono-C12-14-sec-alkyl ethers.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Oxirane, 2-ethyl-, polymer with... Significant New Uses for Specific Chemical Substances § 721.10400 Oxirane, 2-ethyl-, polymer with oxirane...) The chemical substance identified as oxirane, 2-ethyl-, polymer with oxirane, mono-C12-14-sec-alkyl...

Alkylation of deoxyribonucleic acid by carcinogens dimethyl sulphate, ethyl methanesulphonate, N-ethyl-N-nitrosourea and N-methyl-N-nitrosourea. Relative reactivity of the phosphodiester site thymidylyl(3'-5')thymidine.

PubMed Central

Swenson, D H; Lawley, P D

1978-01-01

1. The ethyl phosphotriester of thymidylyl(3'-5')thymidine, dTp(Et)dT, was identified as a product from reaction of DNA with N-ethyl-N-nitrosourea, by procedures parallel to those reported previously for the methyl homologue produced by N-methyl-N-nitrosourea. 2. Enzymic degradation to yield alkyl phosphotriesters from DNA alkylated by these carcinogens and by dimethyl sulphate and ethyl methanesulphonate was studied quantitatively, and the relative yields of the triesters dTp(Alk)dT were determined. The relative reactivity of the phosphodiester group dTpdT to each of the four carcinogens was thus obtained, and compared with that of DNA overall, or with that of the N-7 atom of guanine in DNA. Relative reactivity of the phosphodiester group was lowest towards dimethyl sulphate, the least electrophilic of the reagents used, and was highest towards N-ethyl-N-nitrosourea, the most electrophilic reagent. 3. The nature of the alkyl group transferred also influenced reactivity of the phosphodiester site, since this site was relatively more reactive towards ethylation than would be predicted simply from the known Swain-Scott s values of the alkylating agents. It was therefore suggested that the steric accessibility of the weakly nucleophilic phosphodiester group on the outside of the DNA macromolecule favours its reaction with ethylating, as opposed to methylating, reagents. 4. Taking a value of the Swain-Scott nucleophilicity (n) of 2.5 for an average DNA nucleotide unit [Walles & Ehrenberg (1969) Acta Chem. Scand. 23, 1080-1084], a value of n of about 1 for the phosphodiester group was deduced, and this value was found to be 2-3 units less than that for the N-7 atom of guanine in DNA. 5. The reactivity of DNA overall was markedly high towards the alkylnitrosoureas, despite their relatively low s values. This was ascribed to an electrostatic factor that favoured reaction of the negatively charged polymer with alkyldiazonium cation intermediates. PMID:208508

77 FR 26456 - Carfentrazone-ethyl; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-04

...: This regulation establishes tolerances for residues of carfentrazone-ethyl in or on crop group 18, non... Registration for Application to the Non-grass Animal Feed Crop Group 18. Human-Health Risk Assessment'' pp. 30...-occupational, non-dietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides...

Evaluation Lactogenic Activity of Ethyl Acetate Fraction of Torbangun (Coleus amboinicus L.) Leaves

NASA Astrophysics Data System (ADS)

Damanik, R. M.; Kustiyah, L.; Hanafi, M.; Iwansyah, A. C.

2017-12-01

This study aimed to assess the lactogenic property of ethyl acetate fraction of torbangun (Coleus amboinicus L.) leaves and to identify the compounds that responsibility as ‘milk booster’ using LC- MS approach. Lactagogue activity was evaluated in terms of quantity of milk produced from the rats treated with commercial milk booster (AF), ethyl acetate fraction of torbangun leaves (EA), water extraction of torbangun (AQ) and kaempferol (KP). The feed was given orally every two days and starting from Day 2 after giving birth until Day 28. The performance of milk production was measured along the experimental period by weight-suckle-weight method. The level of prolactin serum was determined by ELISA methods. Histopathological analysis of mammary gland, liver, intestines and kidney tissues was carried out. Moreover, in order to profiling and identification of compounds of ethyl acetate fraction, ultra-performance liquid chromatography quadrupole time of flight to electrospray ionization mass spectrometry (UPLC-QTOF-ESI-MS) in the positive-ion mode was performed. The ethyl acetate fraction of torbangun leaves (EA) was induced milk production about 17%, and AF 22% and KP 51% compared to the control group. Meanwhile, the EA was not significantly stimulate the synthesis of serum prolactin at Day 14 and Day 28 (p>0.05). Administration of EA did not cause any signs or symptoms of toxicity. In addition, a total of ten compounds was identified by UPLC-QTOF-ESI/MS in the ethyl acetate fraction of the leaves of C. amboinicus, mostly phenolic compounds, flavonols and some of their glycoside derivatives, such as: digiprolatone, and kaempferol-3-7-O-di-rhamnopyranoside. The present study reveals the ethyl acetate fraction of torbangun leaves and its bioactive compounds has the potency as a remedy for stimulating and improving milk production.

Amidation reaction of eugenyl oxyacetate ethyl ester with 1,3 diaminopropane

NASA Astrophysics Data System (ADS)

Suryanti, V.; Wibowo, F. R.; Kusumaningsih, T.; Wibowo, A. H.; Khumaidah, S. A.; Wijayanti, L. A.

2016-04-01

Eugenol having various substituents on the aromatic ring (hydroxy, methoxy and allyl) are useful for starting material in synthesizing of its derivatives. Eugenol derivatives have shown wide future potential applications in many areas, especially as future drugs against many diseases. The aim of this work was to synthesize an amide of eugenol derivative. The starting material used was eugenol from clove oil and the reaction was conducted in 3 step reactions to give the final product. Firstly, eugenol was converted into eugenyl oxyacetate [2-(4-allyl-2-methoxyphenoxy) acetic acid] as a white crystal with 70.5% yield, which was then esterified with ethanol to have eugenyl oxyacetate ethyl ester [ethyl 2-(4-allyl-2-methoxyphenoxy) acetate] as brown liquid in 75.7%. The last step was the reaction between eugenyl oxyacetate ethyl ester and 1,3 diaminopropane to give 2-(4-allyl-2-methoxyphenoxy)-N-(3-aminopropyl) acetamide as a brown powder with 71.6% yield, where the amidation reaction was occurred.

Identification and quantification of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-COOH-glu) in hair by ultra-performance liquid chromatography tandem mass spectrometry as a potential hair biomarker of cannabis use.

PubMed

Pichini, Simona; Marchei, Emilia; Martello, Simona; Gottardi, Massimo; Pellegrini, Manuela; Svaizer, Fiorenza; Lotti, Andrea; Chiarotti, Marcello; Pacifici, Roberta

2015-04-01

We developed and validated an ultra-high-pressure liquid chromatography-tandem mass spectrometry method to identify and quantify 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide in hair of cannabis consumers. After hair washing with methyl alcohol and diethyl ether and subsequent addition of amiodarone as internal standard hair samples were treated with 500 μl VMA-T M3 buffer reagent for 1 h at 100 °C. After cooling, 10 μl VMA-T M3 extract were injected into chromatographic system. Chromatographic separation was carried out on a reversed phase column using a linear gradient elution with two solvents: 5 mM ammonium formate pH 3.0 (solvent A) and 0.1% formic acid in acetonitrile (solvent B). The flow rate was kept constant at 0.4 ml/min during the analysis. The separated analytes were detected with a triple quadrupole mass spectrometer operated in multiple reaction monitoring mode via positive electrospray ionization. Linear calibration curves were obtained for 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide with correlation coefficients (r(2)) of 0.99 and a limit of quantification of 0.25 pg/mg hair. Analytical recovery was between 79.6% and 100.7% and intra- and inter-assay imprecision and inaccuracy were always lower than 15%. Ultra-high-pressure liquid chromatography-tandem mass spectrometry analysis of 20 different hair samples of cannabis consumers disclosed the presence of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide in the range of 0.5-8.6 pg/mg hair. These data provided a good start to consider 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide as alternative hair biomarker of cannabis consumption. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Determination of bilirubin glucuronide and assay of glucuronyltransferase with bilirubin as acceptor

PubMed Central

Van Roy, F. P.; Heirwegh, K. P. M.

1968-01-01

1. Conjugated bilirubin is conveniently determined by coupling with the diazonium salt of ethyl anthranilate. 2. This method has been used in the development of assays for UDP-glucuronyltransferase (EC 2.4.1.17), with bilirubin as substrate, in rat liver homogenates, microsomal preparations and partly purified fractions. 3. Chromatographic analysis suggests that bilirubin monoglucuronide is the product of the enzyme systems studied. PMID:5660631

Bisphenol-A (BPA), BPA glucuronide, and BPA sulfate in mid-gestation umbilical cord serum in a Northern and Central California population

PubMed Central

Gerona, Roy R.; Woodruff, Tracey J.; Dickenson, Carrie A.; Pan, Janet; Schwartz, Jackie M.; Sen, Saunak; Friesen, Matthew M.; Fujimoto, Victor Y.; Hunt, Patricia A.

2013-01-01

Bisphenol-A (BPA) is an endocrine disrupting chemical used in numerous consumer products, resulting in universal exposure in the United States. Prenatal exposure to BPA is associated with numerous reproductive and developmental effects in animals. However, little is known about human fetal exposure or metabolism of BPA during mid-gestation. In the present study, we present a new liquid chromatography-tandem mass spectrometry method to directly measure concentrations of BPA and two predominant metabolic conjugates – BPA glucuronide and BPA sulfate – in umbilical cord serum collected from elective 2nd trimester pregnancy terminations. We detected at least one form of BPA in all umbilical cord serum samples: BPA (GM 0.16; range glucuronide (GM 0.14; range

21 CFR 172.225 - Methyl and ethyl esters of fatty acids produced from edible fats and oils.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Methyl and ethyl esters of fatty acids produced... Methyl and ethyl esters of fatty acids produced from edible fats and oils. Methyl esters and ethyl esters of fatty acids produced from edible fats and oils may be safely used in food, subject to the...

21 CFR 172.225 - Methyl and ethyl esters of fatty acids produced from edible fats and oils.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Methyl and ethyl esters of fatty acids produced... Methyl and ethyl esters of fatty acids produced from edible fats and oils. Methyl esters and ethyl esters of fatty acids produced from edible fats and oils may be safely used in food, subject to the...

Herschel-ATLAS: Dusty early-type galaxies

NASA Astrophysics Data System (ADS)

Rowlands, K.; Dunne, L.; Maddox, S.

2015-03-01

Early-type galaxies (ETGs) are thought to be devoid of dust and star-formation, having formed most of their stars at early epochs. We present the detection of the dustiest ETGs in a large-area blind submillimetre survey with Herschel (H-ATLAS, Eales et al. 2010), where the lack of pre-selection in other bands makes it the first unbiased survey for cold dust in ETGs. The parent sample of 1087 H-ATLAS galaxies in this study have a >= 5σ detection at 250μm, a reliable optical counterpart to the submillimetre source (Smith et al. 2011) and a spectroscopic redshift from the GAMA survey (Driver et al. 2011). Additionally, we construct a control sample of 1052 optically selected galaxies undetected at 250μm and matched in stellar mass to the H-ATLAS parent sample to eliminate selection effects. ETGs were selected from both samples via visual classifications using SDSS images. Further details can be found in Rowlands et al. (2012). Physical parameters are derived for each galaxy using the multiwavelength spectral energy distribution (SED) fitting code of da Cunha, Charlot and Elbaz (2008), Smith et al. 2012, using an energy balance argument. We investigate the differences between the dusty ETGs and the general ETG population, and find that the H-ATLAS ETGs are more than an order of magnitude dustier than the control ETGs. The mean dust mass of the 42 H-ATLAS ETGs is 5.5 × 107M⊙ (comparable to the dust mass of spirals in our sample), whereas the dust mass of the 233 control ETGs inferred from stacking at optical positions on the 250μm map is (0.8 - 4.0) × 106M⊙ for 25-15 K dust. The average star-formation rate of the H-ATLAS ETGs is 1.0 dex higher than that of control ETGs, and the mean r-band light-weighted age of the H-ATLAS ETGs is 1.8 Gyr younger than the control ETGs. The rest-frame NUV - r colours of the H-ATLAS ETGs are 1.0 magnitudes bluer than the control ETGs, and some ETGs may be transitioning from the blue cloud to the red sequence. Some H-ATLAS ETGs

Direct Conversion of Cellulose into Ethyl Lactate in Supercritical Ethanol-Water Solutions.

PubMed

Yang, Lisha; Yang, Xiaokun; Tian, Elli; Lin, Hongfei

2016-01-08

Biomass-derived ethyl lactate is a green solvent with a growing market as the replacement for petroleum-derived toxic organic solvents. Here we report, for the first time, the production of ethyl lactate directly from cellulose with the mesoporous Zr-SBA-15 silicate catalyst in a supercritical mixture of ethanol and water. The relatively strong Lewis and weak Brønsted acid sites on the catalyst, as well as the surface hydrophobicity, were beneficial to the reaction and led to synergy during consecutive reactions, such as depolymerization, retro-aldol condensation, and esterification. Under the optimum reaction conditions, ∼33 % yield of ethyl lactate was produced from cellulose with the Zr-SBA-15 catalyst at 260 °C in supercritical 95:5 (w/w) ethanol/water. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Elevated plasma creatinine due to creatine ethyl ester use.

PubMed

Velema, M S; de Ronde, W

2011-02-01

Creatine is a nutritional supplement widely used in sport, physical fitness training and bodybuilding. It is claimed to enhance performance. We describe a case in which serum creatinine is elevated due to the use of creatine ethyl esther. One week after withdrawal, the plasma creatinine had normalised. There are two types of creatine products available: creatine ethyl esther (CEE) and creatine monohydrate (CM). Plasma creatinine is not elevated in all creatine-using subjects. CEE , but not CM, is converted into creatinine in the gastrointestinal tract. As a result the use of CEE may be associated with elevated plasma creatinine levels. Since plasma creatinine is a widely used marker for renal function, the use of CEE may lead to a false assumption of renal failure.

Free and Glucuronide Whole Blood Cannabinoids' Pharmacokinetics after Controlled Smoked, Vaporized, and Oral Cannabis Administration in Frequent and Occasional Cannabis Users: Identification of Recent Cannabis Intake.

PubMed

Newmeyer, Matthew N; Swortwood, Madeleine J; Barnes, Allan J; Abulseoud, Osama A; Scheidweiler, Karl B; Huestis, Marilyn A

2016-12-01

There is increasing interest in markers of recent cannabis use because following frequent cannabis intake, Δ 9 -tetrahydrocannabinol (THC) may be detected in blood for up to 30 days. The minor cannabinoids cannabidiol, cannabinol (CBN), and THC-glucuronide were previously detected for ≤2.1 h in frequent and occasional smokers' blood after cannabis smoking. Cannabigerol (CBG), Δ 9 -tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-THCV might also be recent use markers, but their blood pharmacokinetics have not been investigated. Additionally, while smoking is the most common administration route, vaporization and edibles are frequently used. We characterized blood pharmacokinetics of THC, its phase I and phase II glucuronide metabolites, and minor cannabinoids in occasional and frequent cannabis smokers for 54 (occasional) and 72 (frequent) hours after controlled smoked, vaporized, and oral cannabis administration. Few differences were observed between smoked and vaporized blood cannabinoid pharmacokinetics, while significantly greater 11-nor-9-carboxy-THC (THCCOOH) and THCCOOH-glucuronide concentrations occurred following oral cannabis. CBG and CBN were frequently identified after inhalation routes with short detection windows, but not detected following oral dosing. Implementation of a combined THC ≥5 μg/L plus THCCOOH/11-hydroxy-THC ratio <20 cutoff produced detection windows <8 h after all routes for frequent smokers; no occasional smoker was positive 1.5 h or 12 h following inhaled or oral cannabis, respectively. Vaporization and smoking provide comparable cannabinoid delivery. CBG and CBN are recent-use cannabis markers after cannabis inhalation, but their absence does not exclude recent use. Multiple, complimentary criteria should be implemented in conjunction with impairment observations to improve interpretation of cannabinoid tests. Clinicaltrials.gov Identifier: NCT02177513. © 2016 American Association for Clinical Chemistry.

Low Cotinine Glucuronidation Results in Higher Serum and Saliva Cotinine in African American Compared to White Smokers.

PubMed

Murphy, Sharon E; Sipe, Christopher J; Choi, Kwangsoo; Raddatz, Leah M; Koopmeiners, Joseph S; Donny, Eric C; Hatsukami, Dorothy K

2017-07-01

Background: Tobacco exposure is often quantified by serum or saliva concentrations of the primary nicotine metabolite, cotinine. However, average cotinine concentrations are higher in African Americans (AA) compared with Whites with similar smoking levels. Cotinine is metabolized by UGT2B10 and CYP2A6, and low UGT2B10 activity is common in AA, due to the prevalence of a UGT2B10 splice variant. Methods: UGT2B10 activity was phenotyped in 1,446 smokers (34% AA) by measuring the percentage of cotinine excreted as a glucuronide. Urinary total nicotine equivalents (TNE), the sum of nicotine and 6 metabolites, were determined to quantify smoking dose, and cotinine and 3'-hydroxycotinine were quantified in saliva (study 1) or serum (study 2). Results: Ninety-seven smokers (78% AA) were null for UGT2B10 activity, and the saliva and serum cotinine levels, after adjustment for TNE and cigarettes per day (CPD), were 68% and 48% higher in these smokers compared with nonnull smokers ( P < 0.001). After adjustment for TNE and CPD, salivary cotinine was 35% higher, and serum cotinine 24% higher in AA versus White smokers, but with additional adjustment for UGT2B10 activity, there were no significant differences in saliva and serum cotinine concentrations between these two groups. Conclusions: UGT2B10 activity significantly influences plasma cotinine levels, and higher cotinine concentrations in AA versus White smokers (after adjustment for smoking dose) result from lower levels of UGT2B10-catalyzed cotinine glucuronidation by AA. Impact: UGT2B10 activity or genotype should be considered when using cotinine as a tobacco exposure biomarker, particularly in populations such as AA with high frequencies of UGT2B10 nonfunctional variants. Cancer Epidemiol Biomarkers Prev; 26(7); 1093-9. ©2017 AACR . ©2017 American Association for Cancer Research.

Polychlorinated Biphenyl Congeners that Increase the Glucuronidation and Biliary Excretion of Thyroxine Are Distinct from the Congeners that Enhance the Serum Disappearance of Thyroxine

PubMed Central

Martin, L. A.; Wilson, D. T.; Reuhl, K. R.; Gallo, M. A.

2012-01-01

Polychlorinated biphenyl (PCB) congeners differentially reduce serum thyroxine (T4) in rats, but little is known about their ability to affect biliary excretion of T4. Thus, male Sprague-Dawley rats were orally administered Aroclor-1254, Aroclor-1242 (32 mg/kg per day), PCB-95, PCB-99, PCB-118 (16 mg/kg per day), PCB-126 (40 μg/kg per day), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (3.9 μg/kg per day), or corn oil for 7 days. Twenty-four hours after the last dose, [125I]T4 was administered intravenously, and blood, bile, and urine samples were collected for quantifying [125I]T4 and in bile [125I]T4 metabolites. Serum T4 concentrations were reduced by all treatments, but dramatic reductions occurred in response to Aroclor-1254, PCB-99 [phenobarbital (PB)-type congener], and PCB-118 (mixed-type congener). None of the treatments increased urinary excretion of [125I]T4. Aroclor-1254, PCB-118, TCDD, and PCB-126 (TCDD-type congener) increased biliary excretion of T4-glucuronide by 850, 756, 710, and 573%, respectively, corresponding to marked induction of hepatic UDP-glucuronosyltransferase (UGT) activity toward T4. PCB-95 and PCB-99 did not induce UGT activity; therefore, the increased biliary excretion of T4-glucuronide was related to the affinity of congeners for the aryl hydrocarbon receptor. The disappearance of [125I]T4 from serum was rapid (within 15-min) and was increased by Aroclor-1254, PCB-99 and PCB-118. Thus, reductions in serum T4 in response to PCBs did not always correspond with UGT activity toward T4 or with increased biliary excretion of T4-glucuronide. The rapid disappearance of [125I]T4 from the serum of rats treated with PB-like PCBs suggests that increased tissue uptake of T4 is an additional mechanism by which PCBs may reduce serum T4. PMID:22187485

IRIS Toxicological Review of Ethyl Tertiary Butyl Ether (Etbe) ...

EPA Pesticide Factsheets

In September 2016, EPA released the draft IRIS Toxicological Review of Ethyl Tertiary Butyl Ether (ETBE) for public comment and discussion. The draft assessment 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 consultation materials provided to other agencies, including interagency review drafts of the IRIS Toxicological Review of Ethyl Tertiary Butyl Ether are posted on this site. EPA is undertaking an new health assessment for ethyl tertiary butyl ether (ETBE) for the Integrated Risk Information System (IRIS). The outcome of this project will be a Toxicological Review and IRIS Summary of ETBE that will be entered on the IRIS database. IRIS is an EPA database containing Agency scientific positions on potential adverse human health effects that may result from chronic (or lifetime) exposure to chemicals in the environment. IRIS contains chemical-specific summaries of qualitative and quantitative health information in support of two steps of the risk assessment process, i.e., hazard identification and dose-response evaluation. IRIS assessments are used nationally and internationally in combination with specific situational exposure assessment infor

Determination of sulfates and glucuronides of endogenic steroids in biofluids by high-performance liquid chromatography/orbitrap mass spectrometry

NASA Astrophysics Data System (ADS)

Semenistaya, E. N.; Virus, E. D.; Rodchenkov, G. M.

2009-04-01

the possibility of selective determination of testosterone and epitestosterone glucuronides in urine by high-performance liquid chromatography/high-resolution mass spectrometry using solid phase microextraction on a meps cartridge was studied. the effect of the biological matrix on the spectra of conjugated steroids can be taken into account by using the spectra of conjugates recorded for urine samples after hydrolysis as reference spectra. the conditions of fragmentation in the ion source were optimized for separate analytes. this method was used for analyzing real samples with different testosterone/epitestosterone ratios. variations in conjugate contents and qualitative changes in the steroid profile of endogenic compounds were observed.

17alpha- and 17beta-boldenone 17-glucuronides: synthesis and complete characterization by 1H and 13C NMR.

PubMed

Casati, Silvana; Ottria, Roberta; Ciuffreda, Pierangela

2009-02-01

Boldenone is an androgenic anabolic steroid intensively used for growth promoting purposes in animals destined for meat production and as a performance enhancer in athletics. Therefore its use is officially banned either in animals intended for consumption or in humans. Because most anabolic steroids are completely metabolized and usually no parent steroid is excreted, metabolite identification is crucial to detect the illegal use of anabolic steroids either in humans or in livestock. 17alpha- and 17beta-boldenone 17-glucuronides were synthesized, purified and characterized in order to provide suitable standards for the identification and quantification of these metabolites.

Infrared spectroscopic studies of the conformation in ethyl alpha-haloacetates in the vapor, liquid and solid phases.

PubMed

Jassem, Naserallah A; El-Bermani, Muhsin F

2010-07-01

Infrared spectra of ethyl alpha-fluoroacetate, ethyl alpha-chloroacetate, ethyl alpha-bromoacetate and ethyl alpha-iodoacetate have been measured in the solid, liquid and vapor phases in the region 4000-200 cm(-1). Vibrational frequency assignment of the observed bands to the appropriate modes of vibration was made. Calculations at DFT B3LYP/6-311+G** level, Job: conformer distribution, using Spartan program '08, release 132 was made to determine which conformers exist in which molecule. The results indicated that the first compound exists as an equilibrium mixture of cis and trans conformers and the other three compounds exist as equilibrium mixtures of cis and gauche conformers. Enthalpy differences between the conformers have been determined experimentally for each compound and for every phase. The values indicated that the trans of the first compound is more stable in the vapor phase, while the cis is the more stable in both the liquid and solid phases. In the other three compounds the gauche is more stable in the vapor and liquid phases, while the cis conformer is the more stable in the solid phase for each of the second and third compound, except for ethyl alpha-iodoacetate, the gauche conformer is the more stable over the three phases. Molar energy of activation Ea and the pseudo-thermodynamic parameters of activation DeltaH(double dagger), DeltaS(double dagger) and DeltaG(double dagger) were determined in the solid phase by applying Arrhenius equation; using bands arising from single conformers. The respective E(a) values of these compounds are 5.1+/-0.4, 6.7+/-0.1, 7.5+/-1.3 and 12.0+/-0.6 kJ mol(-1). Potential energy surface calculations were made at two levels; for ethyl alpha-fluoroacetate and ethyl alpha-chloroacetate; the calculations were established at DFT B3LYP/6-311+G** level and for ethyl alpha-bromoacetate and ethyl alpha-iodoacetate at DFT B3LYP/6-311G* level. The results showed no potential energy minimum exists for the gauche conformer in

Elastic electron scattering by ethyl vinyl ether

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khakoo, M. A.; Hong, L.; Kim, B.

2010-02-15

We report measured and calculated results for elastic scattering of low-energy electrons by ethyl vinyl ether (ethoxyethene), a prototype system for studying indirect dissociative attachment processes that may play a role in DNA damage. The integral cross section displays the expected {pi}{sup *} shape resonance. The agreement between the calculated and measured cross sections is generally good.

46 CFR 151.50-42 - Ethyl ether.

Code of Federal Regulations, 2012 CFR

2012-10-01

... LIQUID HAZARDOUS MATERIAL CARGOES Special Requirements § 151.50-42 Ethyl ether. (a)(1) Gravity tanks... openings shall be in the top of the tank. (2) Pressure vessel type tanks shall be designed for the maximum pressure to which they may be subjected when pressure is used to discharge the cargo, but in no case shall...

Early-type Galaxy Spin Evolution in the Horizon-AGN Simulation

NASA Astrophysics Data System (ADS)

Choi, Hoseung; Yi, Sukyoung K.; Dubois, Yohan; Kimm, Taysun; Devriendt, Julien. E. G.; Pichon, Christophe

2018-04-01

Using the Horizon-AGN simulation data, we study the relative role of mergers and environmental effects in shaping the spin of early-type galaxies (ETGs) after z ≃ 1. We follow the spin evolution of 10,037 color-selected ETGs more massive than {10}10 {M}ȯ that are divided into four groups: cluster centrals (3%), cluster satellites (33%), group centrals (5%), and field ETGs (59%). We find a strong mass dependence of the slow rotator fraction, f SR, and the mean spin of massive ETGs. Although we do not find a clear environmental dependence of f SR, a weak trend is seen in the mean value of the spin parameter driven by the satellite ETGs as they gradually lose their spin as their environment becomes denser. Galaxy mergers appear to be the main cause of total spin changes in 94% of the central ETGs of halos with {M}vir}> {10}12.5 {M}ȯ , but only 22% of satellite and field ETGs. We find that non-merger-induced tidal perturbations better correlate with the galaxy spin down in satellite ETGs than in mergers. Given that the majority of ETGs are not central in dense environments, we conclude that non-merger tidal perturbation effects played a key role in the spin evolution of ETGs observed in the local (z < 1) universe.

Effect of chlorimuron-ethyl on Bradyrhizobium japonicum and its symbiosis with soybean.

PubMed

Zawoznik, Myriam S; Tomaro, María L

2005-10-01

Possible side-effects of the acetolactate synthase (ALS)-inhibiting herbicide chlorimuron-ethyl on Bradyrhizobium japonicum (Kirchner & Jordan) in pure culture and on inoculated soybean plants growing under controlled conditions were investigated. Growth of B japonicum strain E109 was not affected by this herbicide even when exposed to concentrations 150 times higher than recommended field doses. However, nodulation of soybean plants treated 5 days after emergence with chlorimuron-ethyl at standard application rates was impaired: a 38% decrease in the number of nodules per plant was observed four weeks after treatment. Despite nodule number decrease, no changes in shoot nitrogen content could be detected. Total fresh biomass was diminished by 25% in herbicide-treated plants. Leghemoglobin content in nodules did not vary; nevertheless total nodule protein was diminished by 40% in the herbicide-treated group. ALS activity in different soybean tissues and their relative sensitivity to chlorimuron-ethyl were also investigated. Roots and bacteroids had the greatest specific ALS activities. On a fresh weight basis, the bacteroid fraction displayed the highest ALS activity and was also the most tolerant to in vitro chlorimuron addition: 72% of its activity was retained after including 10 microM chlorimuron-ethyl in the reaction mixture. These results indicate that standard application rates of chlorimuron-ethyl will have limited incidence on B japonicum survival, and effects on nodulation may have little long-term consequences on soybean nitrogen fixation potential. The differences found among soybean tissues not only in intrinsic ALS activity but also in their relative sensitivity to this herbicide suggests that, in leguminous plants living in symbiosis with rhizobia, nodules may contribute to an enhanced tolerance to ALS inhibitors. Copyright (c) 2005 Society of Chemical Industry.

The bioactive compounds and antioxidant activity of ethanol and ethyl ecetate extracts of Candi Banana (Musa paradisiaca)

NASA Astrophysics Data System (ADS)

Laeliocattleya, R. A.; Estiasih, T.; Griselda, G.; Muchlisyiyah, J.

2018-03-01

Banana has various benefits for health. One local variety of banana is candi banana (Musa paradisiaca). The aim of this research was to study the content of the bioactive compounds of phenolics, flavonoids, tannin, carotenoids and the antioxidant activity of extract ethanol and ethyl acetate of candi banana. Powdered candi banana was extracted using ethanol and ethyl acetate in an ultrasonic bath. The results showed that the content of phenolics, flavonoids, tannin and carotenoids in ethanol extract were 58.76 ± 3.19 mg/kg, 416.08 ± 18.79 mg/kg, 209.83 ± 15.87 mg/kg and 74.55 ± 4.31 mg/kg, respectively. The content of phenolics, flavonoids, tannin and carotenoids in ethyl acetate extract were 0.83 ± 0.12 mg/kg, 4.31 ± 0.66 mg/kg, 49.97 ± 2.43 mg/kg and 304.40 ± 16.62 mg/kg. While the antioxidant activity (IC50) of ethanol extract and ethyl acetate were 3374.13 ± 123.46 ppm and 40318.19 ± 1014.90 ppm. This research showed that type of solvents of ethanol and ethyl acetate affected the content of bioactive compounds and antioxidant activity of candi banana. The antioxidant activity of ethanol extract was higher than that of ethyl acetate extract. It showed that ethanol was a better solvent than ethyl acetate to extract bioactive compounds in candi banana.

Correlation between plasma concentration ratios of SN-38 glucuronide and SN-38 and neutropenia induction in patients with colorectal cancer and wild-type UGT1A1 gene

PubMed Central

HIROSE, KOICHI; KOZU, CHIHIRO; YAMASHITA, KOSHIRO; MARUO, EIJI; KITAMURA, MIZUHO; HASEGAWA, JUNICHI; OMODA, KEI; MURAKAMI, TERUO; MAEDA, YORINOBU

2011-01-01

In irinotecan (CPT-11)-based chemotherapy, neutropenia and diarrhea are often induced. In the present study, the clinical significance of the concentration ratios of 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronide (SN-38G) and SN-38 in the plasma in predicting CPT-11-induced neutropenia was examined. A total of 17 patients with colorectal cancer and wild-type UDP-glucuronosyltransferase (UGT)1A1 gene were enrolled and treated with CPT-11 as part of the FOLFIRI regimen [CPT-11 and fluorouracil (5-FU)]. Blood was taken exactly 15 min following a 2-h continuous infusion of CPT-11. Plasma concentrations of SN-38, SN-38G and CPT-11 were determined by a modified high-performance liquid chromatography (HPLC) method. The median, maximum and minimum values of plasma SN-38G/SN-38 ratios were 4.25, 7.09 and 1.03, respectively, indicating that UGT activities are variable among patients with the wild-type UGT1A1 gene. The plasma SN-38G/SN-38 ratios decreased with an increase in the trial numbers of chemotherapy (r=0.741, p=0.000669), suggesting that CPT-11 treatment suppresses UGT activity, and the low plasma SN-38G/SN-38 ratios resulted in the induction of greater neutropenia. However, in this analysis, 2 clearly separated regression lines were observed between plasma SN-38G/SN-38 ratios and neutropenia induction. In conclusion, UGT activity involved in SN-38 metabolism is variable among patients with the wild-type UGT1A1 gene, and each CPT-11 treatment suppresses UGT activity. One-point determination of the plasma SN-38G/SN-38 ratio may provide indications for the prediction of CPT-11-induced neutropenia and adjustment of the optimal dose, although further studies are required. PMID:22740978

40 CFR 721.2465 - Xanthylium, 9-(2-(ethoxycarbonyl)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate.

Code of Federal Regulations, 2013 CFR

2013-07-01

...)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate. 721.2465 Section 721.2465 Protection of...-(ethoxycarbonyl)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate. (a) Chemical substance and significant...-(ethoxycarbonyl)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate (PMN P-00-1195; CAS No. 26694-69-9) is...

40 CFR 721.2465 - Xanthylium, 9-(2-(ethoxycarbonyl)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate.

Code of Federal Regulations, 2012 CFR

2012-07-01

...)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate. 721.2465 Section 721.2465 Protection of...-(ethoxycarbonyl)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate. (a) Chemical substance and significant...-(ethoxycarbonyl)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate (PMN P-00-1195; CAS No. 26694-69-9) is...

40 CFR 721.2465 - Xanthylium, 9-(2-(ethoxycarbonyl)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate.

Code of Federal Regulations, 2011 CFR

2011-07-01

...)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate. 721.2465 Section 721.2465 Protection of...-(ethoxycarbonyl)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate. (a) Chemical substance and significant...-(ethoxycarbonyl)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate (PMN P-00-1195; CAS No. 26694-69-9) is...

40 CFR 721.2465 - Xanthylium, 9-(2-(ethoxycarbonyl)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate.

Code of Federal Regulations, 2014 CFR

2014-07-01

...)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate. 721.2465 Section 721.2465 Protection of...-(ethoxycarbonyl)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate. (a) Chemical substance and significant...-(ethoxycarbonyl)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, ethyl sulfate (PMN P-00-1195; CAS No. 26694-69-9) is...

Transformation of codeine and codeine-6-glucuronide to opioid analogues by urine adulteration with pyridinium chlorochromate: potential issue for urine drug testing.

PubMed

Luong, Susan; Ung, Alison T; Kalman, John; Fu, Shanlin

2014-07-30

Pyridinium chlorochromate (PCC) is the active ingredient of 'Urine Luck', a commercially available in vitro adulterating agent used to conceal the presence of drugs in a urine specimen. The exposure of codeine and its major glucuronide metabolite codeine-6-glucuronide (C6G) to PCC was investigated to determine whether PCC is an effective masking agent for these opiate compounds. Following the addition of PCC to both spiked and authentic codeine and C6G-positive urine specimens, the samples were monitored using liquid chromatography/mass spectrometry (LC/MS). Stable reaction products were identified and characterized using high-resolution MS analysis and, where possible, nuclear magnetic resonance (NMR) analysis. It was determined that PCC effectively oxidizes codeine and C6G, thus altering the original codeine-to-C6G ratio in the urine specimen. Four reaction products were identified for codeine: codeinone, 14-hydroxycodeinone, 6-O-methylcodeine and 8-hydroxy-7,8-dihydrocodeinone. Similarly, three reaction products were identified for C6G: codeinone, codeine and a lactone of C6G (tentative assignment). Besides addressing the complications added to interpretation, more investigation is warranted to further determine their potential for use as markers for monitoring the presence of codeine and C6G in urine specimens adulterated with PCC. Copyright © 2014 John Wiley & Sons, Ltd.

Allergic contact dermatitis from ethyl chloride and benzocaine.

PubMed

Carazo, Juan Luis Anguita; Morera, Blanca Sáenz de San Pedro; Colom, Luis Palacios; Gálvez Lozano, José Manuel

2009-01-01

Ethyl chloride (EC) or chloroethane (C2H5Cl) is a volatile halogenated hydrocarbon. Reports of contact sensitivity to this gas are infrequent considering its widespread use as a local anesthetic, and it may have a relatively low sensitization potential. Benzocaine is another local anesthetic derivative of the ethyl ester of para-aminobenzoic acid, previously reported as a causative agent of delayed hypersensitivity reactions. We present a patient who developed a generalized itching dermatitis after the application of a medical aerosol containing EC, as well as facial angioedema and tongue swelling after the local application of benzocaine. Patch-test results were positive for EC "as is" (++), benzocaine 5% in petrolatum (++), and caine mix (+++) at 96 hours (day 4). The possibility of cross-sensitization between both drugs would not have been chemically plausible. We report the first published clinical case of contact allergic dermatitis from two chemically unrelated local anesthetics (EC and benzocaine) in the same patient.

Antiplasmodial Properties and Bioassay-Guided Fractionation of Ethyl Acetate Extracts from Carica papaya Leaves

PubMed Central

Melariri, Paula; Campbell, William; Etusim, Paschal; Smith, Peter

2011-01-01

We investigated the antiplasmodial properties of crude extracts from Carica papaya leaves to trace the activity through bioassay-guided fractionation. The greatest antiplasmodial activity was observed in the ethyl acetate crude extract. C. papaya showed a high selectivity for P. falciparum against CHO cells with a selectivity index of 249.25 and 185.37 in the chloroquine-sensitive D10 and chloroquine-resistant DD2 strains, respectively. Carica papaya ethyl acetate extract was subjected to bioassay-guided fractionation to ascertain the most active fraction, which was purified and identified using high-pressure liquid chromatography (HPLC) and GC-MS (Gas chromatography-Mass spectrometry) methods. Linoleic and linolenic acids identified from the ethyl acetate fraction showed IC50 of 6.88 μg/ml and 3.58 μg/ml, respectively. The study demonstrated greater antiplasmodial activity of the crude ethyl acetate extract of Carica papaya leaves with an IC50 of 2.96 ± 0.14 μg/ml when compared to the activity of the fractions and isolated compounds. PMID:22174990

Pseudoendogenous presence of β-boldenone sulphate and glucuronide in untreated young bulls from the food chain.

PubMed

Chiesa, Luca; Pasquale, Elisa; Panseri, Sara; Cannizzo, Francesca T; Biolatti, Bartolomeo; Pavlovic, Radmila; Arioli, Francesco

2015-01-01

The administration of boldenone (bold) to bovines, either for growth promotion or therapeutic purposes, has been banned in the EU since 1981. It is, however, a pseudoendogenous hormone, thus its detection in bovine urine, in the form of α-boldenone conjugates, is considered fully compliant up to 2 ng ml(-1). Greater attention has been placed on β-boldenone, the anabolic active epimer, whose conjugated form must be absent in urine. Recently, the identification of a biomarker representing unquestionable evidence of illicit treatment with bold or its precursor androstadienedione has been a major topic in the literature regarding the detection of residues in bovine urine, and β-boldenone sulphate is a candidate molecule. In this study, we used a method previously validated according to the European Commission Decision 2002/657/EC for the determination of sulphate and glucuronide conjugates of β-boldenone. We assessed the occurrence of these molecules in young bull urine, with the aim of understanding whether they could be of endogenous origin, and to check for a possible relationship with particular environmental and stress conditions. Urine samples from 56 young bulls were collected after transport stress, under non-stressful conditions and after transport and slaughter stress. Histopathological investigation of the hormone target organs, i.e. the bulbourethral and prostate glands, was also performed. The results indicate an inverse relationship between the presence and concentration of β-boldenone sulpho- and gluco-conjugates in urine, and stress conditions, expressed by the absence of detection at the slaughterhouse. No significant macroscopic and histologic lesions were detected. Our study indicates that β-boldenone sulphate could be a biomarker of treatment only at the slaughterhouse, while at the farm, in untreated animals (i.e. after a five-month period under the control of Official Veterinarians), sulphate and glucuronide metabolites were found with a

Branchial and renal pathology in the fish exposed chronically to methoxy ethyl mercuric chloride

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gill, T.S.; Pant, J.C.; Tewari, H.

1988-08-01

Pathological manifestations causally related to pesticide poisoning have been described in both surficial and internal tissues of the fishes. Among the various organomercurials are phenyl mercuric acetate, methyl mercuric dicyanidiamide, methoxy ethyl mercuric chloride, methoxy ethyl mercuric silicate etc. Of these, the methoxy ethyl mercuric chloride (MEMC) is used in agriculture as an antifungal seed dressing, and its toxicity is primarily manifest in the Hg/sup 2 +/ ion. This report describes pathogenesis of branchial and renal lesions in the common freshwater fish, Puntius conchonius exposed chronically to sublethal levels of MEMC. Prior to this, alterations in the peripheral blood andmore » metabolite levels in response to experimental MEMC poisoning have been demonstrated in this species.« less

40 CFR 721.4468 - 1H-Imidazole, 2-ethyl-4,5-dihydro-4-methyl-.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false 1H-Imidazole, 2-ethyl-4,5-dihydro-4... Specific Chemical Substances § 721.4468 1H-Imidazole, 2-ethyl-4,5-dihydro-4-methyl-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as 1H-imidazole...

Characterization of argon dielectric barrier discharges applied to ethyl lactate plasma polymerization

NASA Astrophysics Data System (ADS)

Laurent, Morgane; Desjardins, Edouard; Meichelboeck, Maximilian; Naudé, Nicolas; Stafford, Luc; Gherardi, Nicolas; Laroche, Gaétan

2017-11-01

The influence of the input voltage frequency (35 and 150 kHz), interelectrode gap (1 and 2 mm) and precursor concentration (250, 350, and 450 ppm) on the electron temperature (T e), number density of metastable Ar atoms (n(Ar m )), and discharge current density (proportional to the electron density ne) is studied in an argon-ethyl lactate dielectric barrier discharge (DBD). An argon-ammonia Penning mixture is also considered as reference. These results are correlated to the chemistry (XPS, IR) and topography (AFM) of the ethyl-lactate-based plasma polymer coatings. Low T e values from 0.3 to 0.5 eV were obtained for all discharges. This observation, in addition to resemblances with the Ar-NH3 mixture, suggested that the ionization kinetics of ethyl lactate-based discharges is driven by Penning reactions. Among the investigated parameters, the dissipated power obtained through changes of the excitation frequency had the largest impact on both the coatings properties and the discharge behavior.

Human Metabolite Lamotrigine-N(2)-glucuronide Is the Principal Source of Lamotrigine-Derived Compounds in Wastewater Treatment Plants and Surface Water.

PubMed

Zonja, Bozo; Pérez, Sandra; Barceló, Damià

2016-01-05

Wastewater and surface water samples, extracted with four solid-phase extraction cartridges of different chemistries, were suspect-screened for the anticonvulsant lamotrigine (LMG), its metabolites, and related compounds. LMG, three human metabolites, and a LMG synthetic impurity (OXO-LMG) were detected. Preliminary results showed significantly higher concentrations of OXO-LMG in wastewater effluent, suggesting its formation in the wastewater treatment plants (WWTPs). However, biodegradation experiments with activated sludge demonstrated that LMG is resistant to degradation and that its human metabolite lamotrigine-N(2)-glucuronide (LMG-N2-G) is the actual source of OXO-LMG in WWTPs. In batch reactors, LMG-N2-G was transformed, following pseudo-first-order kinetics to OXO-LMG and LMG, but kinetic experiments suggested an incomplete mass balance. A fragment ion search applied to batch-reactor and environmental samples revealed another transformation product (TP), formed by LMG-N2-G oxidation, which was identified by high-resolution mass spectrometry. Accounting for all TPs detected, a total mass balance at two concentration levels in batch reactors was closed at 86% and 102%, respectively. In three WWTPs, the total mass balance of LMG-N2-G ranged from 71 to 102%. Finally, LMG-N2-G and its TPs were detected in surface water samples with median concentration ranges of 23-139 ng L(-1). The results of this study suggest that glucuronides of pharmaceuticals might also be sources of yet undiscovered, but environmentally relevant, transformation products.

77 FR 41346 - Trinexapac-ethyl; Proposed Pesticide Tolerance

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-13

.... SUMMARY: This document proposes to amend the existing trinexapac-ethyl tolerance levels for wheat, forage and wheat, middlings as well as change the commodity definition for hog, kidney. Additionally the EPA..., molasses; and wheat, bran under the Federal Food, Drug, and Cosmetic Act (FFDCA). DATES: Comments must be...

Wet in situ transesterification of microalgae using ethyl acetate as a co-solvent and reactant.

PubMed

Park, Jeongseok; Kim, Bora; Chang, Yong Keun; Lee, Jae W

2017-04-01

This study addresses wet in situ transesterification of microalgae for the production of biodiesel by introducing ethyl acetate as both reactant and co-solvent. Ethyl acetate and acid catalyst are mixed with wet microalgae in one pot and the mixture is heated for simultaneous lipid extraction and transesterification. As a single reactant and co-solvent, ethyl acetate can provide higher FAEE yield and more saccharification of carbohydrates than the case of binary ethanol and chloroform as a reactant and a co-solvent. The optimal yield was 97.8wt% at 114°C and 4.06M catalyst with 6.67mlEtOAC/g dried algae based on experimental results and response surface methodology (RSM). This wet in situ transesterification of microalgae using ethyl acetate doesn't require an additional co-solvent and it also promises more economic benefit as combining extraction and transesterification in a single process. Copyright © 2017 Elsevier Ltd. All rights reserved.

Qualitative in vitro NMR analysis of creatine ethyl ester pronutrient in human plasma.

PubMed

Giese, M W; Lecher, C S

2009-10-01

There are a number of forms of creatine available that attempt to improve the solubility and permeability, with the anticipation this will result in an improved pharmacokinetic profile and ultimately an enhanced ergogenic response. Previous research has shown that the different salt forms can improve solubility resulting in slightly altered pharmacokinetic profiles, however specific data exploring the conversion of esterified derivatives to creatine is lacking. The purpose of this study was to examine the assertion that creatine ethyl ester undergoes enzymatic conversion to creatine in human tissues. The IN VITRO response of creatine ethyl ester to incubation in human plasma was examined by H-NMR analysis. Lyophilized human plasma was reconstituted in D2O and phosphate-buffered saline and 1.5 mg of the analyte was added. Following incubation at 37 degrees C for 4 h and subsequent protein precipitation, the supernatant was analyzed by NMR, utilizing the diagnostic chemical shift of the methylene signal to determine the species present in solution, I.E. creatine ethyl ester, creatine, or creatinine. Both creatine and creatinine were run in parallel as control experiments and each assay was run in triplicate. As expected both creatine and creatinine remained unchanged. However, conversion of creatine ethyl ester to creatine by the esterases in human plasma was not observed to any detectable extent and the only species detected after the incubation period was creatinine. While not a definitive characterization of the IN VIVO behavior, these results strongly warrant a complete IN VIVO pharmacokinetic analysis of creatine ethyl ester since it appears these "pronutrients" may actually provide large exogenous sources of pharmacologically inactive creatinine rather than ergogenic creatine.

Protective Effect of Ethyl Acetate Fraction of Stereospermum Suaveolens Against Hepatic Oxidative Stress in STZ Diabetic Rats.

PubMed

Balasubramanian, Thirumalaiswamy; Senthilkumar, G P; Karthikeyan, M; Chatterjee, Tapan Kumar

2013-07-01

Stereospermum suaveolens is a folk remedy for the treatment of diabetes and liver disorders in southern parts of India. In the present study, the protective effect of the ethyl acetate fraction of ethanol extract from S. suaveolens against hepatic oxidative stress was evaluated in streptozotocin (STZ)-induced diabetic rats for 14 days. The ethyl acetate fraction was administered orally to the STZ diabetic rats at the doses of 200 and 400 mg/kg. Blood glucose level was measured according to glucose oxidase method. In order to determine hepatoprotective activity, changes in the levels of serum biomarker enzymes such as aspartate transaminase (AST), alanine transaminase (ALT), and serum alkaline phosphatase (SALP) were assessed in the ethyl acetate fraction treated diabetic rats and were compared with the levels in diabetic control rats. In addition, the antioxidant activity of ethyl acetate fraction was evaluated using various hepatic parameters such as thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). It was found that administration of ethyl acetate fraction (200 and 400 mg/kg) produced a significant (P < 0.001) fall in fasting blood glucose level, TBARS, bilirubin, AST, ALT, and SALP, while elevating the GSH levels, and SOD and CAT activities in diabetic rats. Histopathologic studies also revealed the protective effect of ethyl acetate fraction on the liver tissues of diabetic rats. It was concluded from this study that the ethyl acetate fraction from ethanol extract of S. suaveolens modulates the activity of enzymatic and nonenzymatic antioxidants and enhances the defense against hepatic oxidative stress in STZ-induced diabetic rats.

Ethyl carbamate levels in wine and spirits from markets in Hebei Province, China.

PubMed

Liu, Y P; Dong, B; Qin, Z S; Yang, N J; Lu, Y; Yang, L X; Chang, F Q; Wu, Y N

2011-01-01

Ethyl carbamate (EC) in wine, grain spirits and wine sauce (145 samples) was analysed using solid-phase extraction and stable isotope dilution GC/MS. Samples were obtained from markets in eight areas (Shijiazhuang, Baoding, Handan, Qinhuangdao, Langfang, Zhangjiakou, Xingtai and Cangzhou) of Hebei Province, China. The method had a limit of detection of 2 µg kg⁻¹, with recoveries varying from 95.7 to 102% and RSD ranging 2.3-5.6%. The average concentrations of ethyl carbamate in wines, grain spirits and wine sauce were 14.7 (<2.0-44.5) µg kg⁻¹, 33.8 (2.9-129) µg kg⁻¹ and 8.7 (<2.0-63.3) µg kg⁻¹, respectively. The results led to the development of limit standards that can be used to predict the concentration of ethyl carbamate in Chinese fermented wines.

Synthesis of Ethyl Nalidixate: A Medicinal Chemistry Experiment

ERIC Educational Resources Information Center

Leslie, Ray; Leeb, Elaine; Smith, Robert B.

2012-01-01

A series of laboratory experiments that complement a medicinal chemistry lecture course in drug design and development have been developed. The synthesis of ethyl nalidixate covers three separate experimental procedures, all of which can be completed in three, standard three-hour lab classes and incorporate aspects of green chemistry such as…

Ethyl Formate: A Potential Disinfestation Treatment for Eucalyptus Weevil (Gonipterus platensis) (Coleoptera: Curculionidae) in Apples.

PubMed

Agarwal, Manjree; Ren, Yonglin; Newman, James; Learmonth, Stewart

2015-12-01

Export of Pink Lady apples from Australia has been significantly affected by infestations of adult eucalyptus weevils (Gonipterus platensis Marelli). These weevils cling tenaciously to the pedicel of apple fruit when selecting overwintering sites. As a result, apples infested with live G. platensis adults lead to rejection for export. Since the Montreal Protocol restricted use of methyl bromide as postharvest treatment, it was necessary to consider alternative safer fumigants for disinfestation of eucalyptus weevil. Laboratory experiments were conducted using concentrations of 5, 10, 15, 20, 25, 30, 40, and 80 mg/liter of ethyl formate. Complete control (100% mortality) was achieved at 25-30 mg/liter of ethyl formate at 22-24°C for 24-h exposure without apples. However, with 90-95% of the volume full of apples, complete control was achieved at 40 mg/liter of ethyl formate at 22-24°C for 24-h exposure. No phytotoxicity was observed and after one day aeration, residue of ethyl formate declined to natural levels (0.05-0.2 mg/kg). Five ethyl formate field trials were conducted in cool storages (capacity from 250-900 tons) and 100% kill of eucalyptus weevils were achieved at 50-55 mg/liter at 7-10°C for 24 h. Ethyl formate has great potential for preshipment treatment of apples. Its use is considerably cheaper and safer than already existing fumigants like methyl bromide and phosphine. © The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan.

PubMed

van Erp, Nielka P H; Baker, Sharyn D; Zhao, Ming; Rudek, Michelle A; Guchelaar, Henk-Jan; Nortier, Johan W R; Sparreboom, Alex; Gelderblom, Hans

2005-11-01

Milk thistle (Silybum marianum) is one of the most commonly used herbal therapies, and its principal constituent silybin significantly inhibits cytochrome P450 isoform 3A4 (CYP3A4) and UDP glucuronosyltransferase isoform 1A1 (UGT1A1) in vitro. Here, we investigated whether milk thistle affects the pharmacokinetics of irinotecan, a substrate for CYP3A4 and UGT1A1, in humans. Six cancer patients were treated with irinotecan (dose, 125 mg/m(2)) given as a 90-minute infusion once every week. Four days before the second dose, patients received 200 mg milk thistle, thrice a day, for 14 consecutive days. Pharmacokinetic studies of irinotecan and its metabolites 7-ethyl-10-hydroxycamptothecin (SN-38), 7-ethyl-10-[3,4,5-trihydroxy-pyran-2-carboxylic acid]-camptothecin (SN-38-glucuronide), and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin were done during the first three irinotecan administrations. Short-term (4 days) or more prolonged intake of milk thistle (12 days) had no significant effect on irinotecan clearance (mean, 31.2 versus 25.4 versus 25.6 L/h; P = 0.16). The area under the curve ratio of SN-38 and irinotecan was slightly decreased by milk thistle (2.58% versus 2.23% versus 2.17%; P = 0.047), whereas the relative extent of glucuronidation of SN-38 was similar (10.8 versus 13.5 versus 13.1; P = 0.64). Likewise, the area under the curve ratio of 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin and irinotecan was unaffected by milk thistle (0.332 versus 0.285 versus 0.337; P = 0.53). The maximum plasma concentrations of silybin ranged between 0.0249 and 0.257 micromol/L. Silybin concentrations after intake of milk thistle are too low to significantly affect the function of CYP3A4 and UGT1A1 in vivo, indicating that milk thistle is unlikely to alter the disposition of anticancer drugs metabolized by these enzymes.

[Ethyl 4-methyloctanoate, major component of male pherome in Oryctes rhinoceros (L.) (Coleoptera, Dynastidae)].

PubMed

Morin, J P; Rochat, D; Malosse, C; Lettere, M; de Chenon, R D; Wibwo, H; Descoins, C

1996-07-01

Ethyl 4-methyloctanoate, which has already been described in Oryctes monoceros, has been identified, using extracts of effluvia collected from males, as being a major component of the male pheromone of O. rhinoceros. Field trials have been carried out in North Sumatra, Indonesia. Ethyl 4-methyloctanoate synthesized in the laboratory and released at 10 mg/d resulted in the capture of 6.8 insects per week per trap, whereas ethyl chrysanthemate (40 mg/d), an allelochemical compound once used as an attractant, only led to the capture of 0.3 insects, and the control none at all. The insects captured with the pheromone were 81% females, the majority being sexually mature. Discovery of this compound opens up new prospects for O. rhinoceros control.

Reactions of NO 3 with the man-made emissions 2-methylpent-2-ene, ( Z)-3-methylpent-2-ene, ethyl vinyl ether, and the stress-induced plant emission ethyl vinyl ketone

NASA Astrophysics Data System (ADS)

Pfrang, Christian; Tooze, Christopher; Nalty, Andrew; Canosa-Mas, Carlos E.; Wayne, Richard P.

Rate coefficients for reactions of nitrate radicals (NO 3) with the anthropogenic emissions 2-methylpent-2-ene, ( Z)-3-methylpent-2-ene, ethyl vinyl ether, and the stress-induced plant emission ethyl vinyl ketone (pent-1-en-3-one) were determined to be (9.3±1.1)×10 -12, (9.3±3.2)×10 -12, (1.7±1.3)×10 -12 and (9.4±2.7)×10 -17 cm 3 molecule -1 s -1. We performed kinetic experiments at room temperature and atmospheric pressure using a relative-rate technique with GC-FID analysis. Experiments with ethyl vinyl ether required a modification of our established procedure that might introduce additional uncertainties, and the errors suggested reflect these difficulties. Rate coefficients are discussed in terms of electronic and steric influences. Atmospheric lifetimes with respect to important oxidants in the troposphere were calculated. NO 3-initiated oxidation is found to be the strongly dominating degradation route for 2-methylpent-2-ene, ( Z)-3-methylpent-2-ene and ethyl vinyl ether. Atmospheric concentrations of the alkenes and their relative contribution to the total NMHC emissions from trucks can be expected to increase if plans for the introduction of particle filters for diesel engines are implemented on a global scale. Thus more kinetic data are required to better evaluate the impact of these emissions.

[Intravenous ethyl alcohol in metabolic resuscitation].

PubMed

Agolini, G; Lipartiti, T; Zaffiri, O; Musso, L; Belloni, G P

1980-11-01

Intravenously administered ethyl alcohol may be effective as analgesic and hypotensive peripheric vasoactive drug. In the Intensive Care Departments parenteral ethanol administration is infrequent because no "sure dosage" can be suggested in adults and children. Liver, kidney and C.N.S. diseases can worsen; foetopathy can follow. Drug-ethanol interaction may be particularly important for some patients admitted in Intensive Care Departments. Often the potential caloric support cannot be fully utilized ("empty" calories) and seldom hyperventilation, hyperlactacidemia and impaired protein synthesis can follow.

Protective Effect of Ethyl Acetate Fraction of Stereospermum Suaveolens Against Hepatic Oxidative Stress in STZ Diabetic Rats

PubMed Central

Balasubramanian, Thirumalaiswamy; Senthilkumar, G. P; Karthikeyan, M.; Chatterjee, Tapan Kumar

2013-01-01

Stereospermum suaveolens is a folk remedy for the treatment of diabetes and liver disorders in southern parts of India. In the present study, the protective effect of the ethyl acetate fraction of ethanol extract from S. suaveolens against hepatic oxidative stress was evaluated in streptozotocin (STZ)-induced diabetic rats for 14 days. The ethyl acetate fraction was administered orally to the STZ diabetic rats at the doses of 200 and 400 mg/kg. Blood glucose level was measured according to glucose oxidase method. In order to determine hepatoprotective activity, changes in the levels of serum biomarker enzymes such as aspartate transaminase (AST), alanine transaminase (ALT), and serum alkaline phosphatase (SALP) were assessed in the ethyl acetate fraction treated diabetic rats and were compared with the levels in diabetic control rats. In addition, the antioxidant activity of ethyl acetate fraction was evaluated using various hepatic parameters such as thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). It was found that administration of ethyl acetate fraction (200 and 400 mg/kg) produced a significant (P < 0.001) fall in fasting blood glucose level, TBARS, bilirubin, AST, ALT, and SALP, while elevating the GSH levels, and SOD and CAT activities in diabetic rats. Histopathologic studies also revealed the protective effect of ethyl acetate fraction on the liver tissues of diabetic rats. It was concluded from this study that the ethyl acetate fraction from ethanol extract of S. suaveolens modulates the activity of enzymatic and nonenzymatic antioxidants and enhances the defense against hepatic oxidative stress in STZ-induced diabetic rats. PMID:24716175

40 CFR 180.1323 - Ethyl-2E,4Z-decadienoate (Pear Ester); exemption from the requirement of a tolerance.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 24 2014-07-01 2014-07-01 false Ethyl-2E,4Z-decadienoate (Pear Ester... RESIDUES IN FOOD Exemptions From Tolerances § 180.1323 Ethyl-2E,4Z-decadienoate (Pear Ester); exemption... for residues of the biochemical pesticide, ethyl-2E,4Z-decadienoate (pear ester), in or on all food...

Observations of reduced electron Gyroscale fluctuations in national spherical torus experiment H-mode plasmas with large ExB flow shear.

PubMed

Smith, D R; Kaye, S M; Lee, W; Mazzucato, E; Park, H K; Bell, R E; Domier, C W; Leblanc, B P; Levinton, F M; Luhmann, N C; Menard, J E; Yuh, H

2009-06-05

Electron gyroscale fluctuation measurements in National Spherical Torus Experiment H-mode plasmas with large toroidal rotation reveal fluctuations consistent with electron temperature gradient (ETG) turbulence. Large toroidal rotation in National Spherical Torus Experiment plasmas with neutral beam injection generates ExB flow shear rates comparable to ETG linear growth rates. Enhanced fluctuations occur when the electron temperature gradient is marginally stable with respect to the ETG linear critical gradient. Fluctuation amplitudes decrease when the ExB flow shear rate exceeds ETG linear growth rates. The observations indicate that ExB flow shear can be an effective suppression mechanism for ETG turbulence.

[Complex application 2-ethyl-6-methyl-3-hydroxypyridine-succinate and vinpocetine in cerebrovascular disorder.

PubMed

Solovyeva, E Yu; Karneev, A N; Chekanov, A V; Baranova, O A; Choi, I V

Developing brain ischemia due to cerebral vascularization leads to disruption of brain metabolism. Chronic cerebral hypoperfusion leads to irreversible brain damage and plays an important role in the development of some types of dementia. Early use of antioxidants such as ethyl ether apovincamine acid (vinpocetine) and 2-ethyl-6-methyl-3-hydroxypyridine-succinate in the treatment of this pathology is seen as a real pathogenetically based method of correction of cerebral metabolism with cerebral vascular disorders, demonstrating the increase in cerebral blood flow and also neuroprotective effects. Clinical studies and studies on biological models show that the main mechanisms of action of vinpocetine and 2-ethyl-6-methyl-3-hydroxypyridine-succinate, although have a similar focus, but implementing neuroprotective and nootropic effects via various links in the pathogenesis of ischemic brain damage.

Effects of ethyl chloride spray on pain and parameters of needle electromyography in the upper extremity.

PubMed

Moon, Young-Eun; Kim, Sang-Hyun

2014-10-01

The aim of this study was to compare the effects of ethyl chloride and placebo sprays for reducing pain induced by needle electromyography and changes in parameters of the motor unit action potential during needle electromyography of the upper extremity. Sixty patients were randomized into the ethyl chloride or placebo spray groups. In both groups, spray was applied just before needle electromyography of the flexor carpi radialis, and a visual analog scale to evaluate the pain of needle electromyography and a five-point Likert scale for patient satisfaction and preference for reexamination were compared between the two groups. Then, changes in the amplitude, phases, turns, and duration of the motor unit action potential during needle electromyography of the biceps brachii were compared before and after spraying in each group. The visual analog scale was significantly lower, and patient satisfaction and preference for reexamination were significantly higher in the ethyl chloride spray group. Among the parameters of the motor unit action potential, there were no significant changes except for an increased duration after spraying with ethyl chloride. Ethyl chloride spray can effectively reduce pain, but it must be used with caution because it may affect parameters of the motor unit action potential during needle electromyography.

A semisynthesis of 3'-O-ethyl-5,6-dihydrospinosyn J based on the spinosyn A aglycone.

PubMed

Zhang, Kai; Liu, Shenglan; Liu, Anjun; Chai, Hongxin; Li, Jiarong; A, Lamusi

2017-01-01

Spinetoram, a mixture of 3'- O -ethyl-5,6-dihydrospinosyn J (XDE-175-J, major component) and 3'- O -ethylspinosyn L (XDE-175-L, minor component), is a novel kind of green and efficient insecticide with a broad range of action against various insects. Nowadays, spinetoram is widely used in agriculture and food storage. This work reports a 7-step semisynthesis of 3'- O -ethyl-5,6-dihydrospinosyn J from spinosyn A aglycone. The C9-OH and C17-OH of the aglycone are successively connected to 3- O -ethyl-2,4-di- O -methylrhamnose and D-forosamine after selective protection and deprotection steps. Then, with 10% Pd/C as catalyst, the 5,6-double bond of the macrolide was selectively reduced to afford 3'- O -ethyl-5,6-dihydrospinosyn J. In addition, the 3- O -ethyl-2,4-di- O -methylrhamnose is synthesized from rhamnose which is available commercially, while the D-forosamine and aglycone are obtained via the hydrolysis of spinosyn A. High yields were obtained in each step, and all intermediates in the synthesis were characterized by 1 H NMR, 13 C NMR and MS techniques. This study can be helpful for developing an efficient chemical synthesis of spinetoram, and it also offers opportunities to synthesize spinosyn analogues and rhamnose derivatives.

21 CFR 177.1320 - Ethylene-ethyl acrylate copolymers.

Code of Federal Regulations, 2014 CFR

2014-04-01

... content. The ethyl acrylate can be determined by the infrared spectra. Prepare a scan from 10.5 microns to 12.5 microns. Obtain a baseline absorbance at 11.6 microns and divide by the plaque thickness to... less than 0.920 nor more than 0.935, as determined by ASTM method D1505-68 (Reapproved 1979), “Standard...

Mixture Toxicity of SN2-Reactive Soft Electrophiles: 2—Evaluation of Mixtures Containing Ethyl α-Halogenated Acetates

PubMed Central

Mooneyham, T.; Jeyaratnam, J.; Schultz, T. W.; Pöch, G.

2011-01-01

Four ethyl α-halogenated acetates were tested in (1) sham and (2) nonsham combinations and (3) with a nonreactive nonpolar narcotic. Ethyl iodoacetate (EIAC), ethyl bromoacetate (EBAC), ethyl chloroacetate (ECAC), and ethyl fluoroacetate (EFAC), each considered to be an SN2-H-polar soft electrophile, were selected for testing based on their differences in electro(nucleo)philic reactivity and time-dependent toxicity (TDT). Agent reactivity was assessed using the model nucleophile glutathione, with EIAC and EBAC showing rapid reactivity, ECAC being less reactive, and EFAC lacking reactivity at ≤250 mM. The model nonpolar narcotic, 3-methyl-2-butanone (3M2B), was not reactive. Toxicity of the agents alone and in mixture was assessed using the Microtox acute toxicity test at three exposure durations: 15, 30 and 45 min. Two of the agents alone (EIAC and EBAC) had TDT values >100%. In contrast, ECAC (74 to 99%) and EFAC (9 to 12%) had partial TDT, whereas 3M2B completely lacked TDT (<0%). In mixture testing, sham combinations of each agent showed a combined effect consistent with predicted effects for dose-addition at each time point, as judged by EC50 dose-addition quotient values. Mixture toxicity results for nonsham ethyl acetate combinations were variable, with some mixtures being inconsistent with the predicted effects for dose-addition and/or independence. The ethyl acetate–3M2B combinations were somewhat more toxic than predicted for dose-addition, a finding differing from that observed previously for α-halogenated acetonitriles with 3M2B. PMID:21452006

Two new Ni(II) supramolecular complexes based on ethyl isonicotinate and ethyl nicotinate for removal of acid blue 92 dye

NASA Astrophysics Data System (ADS)

Etaiw, Safaa El-din H.; Marie, Hassan

2018-03-01

Two new luminescent supramolecular complexes (SC); [Ni(EIN)4(NCS)2] SC1 and [Ni2(EN)8(NCS)4] SC2, (EIN = ethyl isonicotinate, EN = ethyl nicotinate), have been synthesized by self-assembly method and structurally characterized by X-ray single crystal, FT-IR and UV-Vis spectra, PXRD, elemental and thermogravimetric analyses. Both SC1 and SC2 are monoclinic crystals however, they have different asymmetric units. Ni(II) atoms in both SC are isostructural and have similar hexa-coordinate environment. The structures of SC1 and SC2 consist of parallel polymeric 1D-chains, extended in two and three dimensional supramolecular frameworks by intermolecular hydrogen bonding interactions. SC1 and SC2 are luminescent materials which can be used in applications as molecular sensing systems. SC1 and SC2 were used as heterogeneous catalysts for degradation of acid blue 92 (AB-92) under sun light irradiation. The fluorescence measurements of terephthalic acid technique as a probe molecule were used to determine the •OH radicals. Also the radicals trapping experiments using isopropanol alcohol (IPA) as radical scavenger were discussed. In addition a mechanism of degradation was proposed and discussed.

Evaluating Micrometeorological Estimates of Groundwater Discharge from Great Basin Desert Playas

NASA Astrophysics Data System (ADS)

Jackson, T.; Halford, K. J.; Gardner, P.

2017-12-01

Groundwater availability studies in the arid southwestern United States traditionally have assumed that groundwater discharge by evapotranspiration (ETg) from desert playas is a significant component of the groundwater budget. This result occurs because desert playa ETg rates are poorly constrained by Bowen Ratio energy budget (BREB) and eddy-covariance (EC) micrometeorological measurement approaches. Best attempts by previous studies to constrain ETg from desert playas have resulted in ETg rates that are below the detection limit of micrometeorological approaches. This study uses numerical models to further constrain desert playa ETg rates that are below the detection limit of EC (0.1 mm/d) and BREB (0.3 mm/d) approaches, and to evaluate the effect of hydraulic properties and salinity-based groundwater-density contrasts on desert playa ETg rates. Numerical models simulated ETg rates from desert playas in Death Valley, California and Dixie Valley, Nevada. Results indicate that actual ETg rates from desert playas are significantly below the upper detection limits provided by the BREB- and EC-based micrometeorological measurements. Discharge from desert playas contribute less than 2 percent of total groundwater discharge from Dixie and Death Valleys, which suggests discharge from desert playas is negligible in other basins. Numerical simulation results also show that ETg from desert playas primarily is limited by differences in hydraulic properties between alluvial fan and playa sediments and, to a lesser extent, by salinity-based groundwater density contrasts.

Multicomponent Synthesis of a N-Protected Alpha-Amino Ester: Ethyl 2-((4-Methoxyphenyl)Amino)-3-Phenylpropanoate

ERIC Educational Resources Information Center

Le Gall, Erwan; Pignon, Antoine

2012-01-01

This laboratory experiment describes the preparation of a N-protected phenylalanine ethyl ester by a zinc-mediated Mannich-like multicomponent reaction between benzyl bromide, "p"-anisidine, and ethyl glyoxylate. The one-step reaction involves the in situ metallation of benzyl bromide into a benzylzinc reagent and its addition onto imine (Barbier…

Probing the interaction of 1-ethyl-3-methylimidazolium ethyl sulfate ([Emim][EtSO4]) with alcohols and water by solvent and rotational relaxation.

PubMed

Sarkar, Souravi; Pramanik, Rajib; Ghatak, Chiranjib; Setua, Palash; Sarkar, Nilmoni

2010-03-04

The effect of the addition of cosolvents in the room temperature ionic liquid (RTIL) 1-ethyl-3-methylimidazolium ethyl sulfate ([Emim][EtSO(4)]) was probed by the solvent and rotational relaxation studies of coumarin 153 in neat ionic liquid [Emim][EtSO(4)] and [Emim][EtSO(4)]-cosolvent mixtures by using steady-state and time-resolved fluorescence spectroscopy. With gradual addition of cosolvents in the RTIL, both the average solvation time and rotational relaxation times gradually decrease. Addition of cosolvents in the IL decreases the viscosity of the medium. We have optimized the geometry of [Emim][EtSO(4)] and [Emim][EtSO(4)]-cosolvent mixtures by using quantum chemical calculations using density functional theory methods, which show the formation of hydrogen bond between cosolvents with [Emim][EtSO(4)]. With addition of the same amount of alcohols in neat [Emim][EtSO(4)], the rotational relaxation time decreases more compared to the addition of the same amount of water.

40 CFR 721.8100 - Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy...

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. 721.8100...-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. (a) Chemical substances and significant new use subject to...

40 CFR 721.8100 - Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy...

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. 721.8100...-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. (a) Chemical substances and significant new use subject to...

40 CFR 721.8100 - Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy...

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. 721.8100...-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. (a) Chemical substances and significant new use subject to...

40 CFR 721.8100 - Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy...

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. 721.8100...-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. (a) Chemical substances and significant new use subject to...

40 CFR 721.8100 - Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy...

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. 721.8100...-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. (a) Chemical substances and significant new use subject to...

40 CFR 180.441 - Quizalofop ethyl; tolerances for residues.

Code of Federal Regulations, 2010 CFR

2010-07-01

... combined residues of the herbicide quizalofop (2-[4-(6-chloroquinoxalin-2-yl oxy)phenoxy]propanoic acid... combined residues of the herbicide quizalofop (2-[4-(6-chloroquinoxalin-2-yl oxy)phenoxy]propanoic acid... byproducts 0.05 (3) Tolerances are established for the combined residues of the herbicide quizalofop-p ethyl...

40 CFR 180.441 - Quizalofop ethyl; tolerances for residues.

Code of Federal Regulations, 2011 CFR

2011-07-01

... combined residues of the herbicide quizalofop (2-[4-(6-chloroquinoxalin-2-yl oxy)phenoxy]propanoic acid... combined residues of the herbicide quizalofop (2-[4-(6-chloroquinoxalin-2-yl oxy)phenoxy]propanoic acid... byproducts 0.05 (3) Tolerances are established for the combined residues of the herbicide quizalofop-p ethyl...

Attraction of Mosquitoes to Diethyl Methylbenzamide and Ethyl Hexanediol

DTIC Science & Technology

1990-09-01

tant to the biting midges Culicoides pulicaris that 8% ethyl acetate was attractant to the Linn. and Culicoides puncticoUis Becker (Cera- vinegar fly...Drosoph- finding by mosquitoes (Diptera: Culcidae): a review. ila melanogaster Meigen to the products of ferment - Bull. Entomol. Res. 70:525-532. ing banana

Acetic acid removal from corn stover hydrolysate using ethyl acetate and the impact on Saccharomyces cerevisiae bioethanol fermentation.

PubMed

Aghazadeh, Mahdieh; Ladisch, Michael R; Engelberth, Abigail S

2016-07-08

Acetic acid is introduced into cellulose conversion processes as a consequence of composition of lignocellulose feedstocks, causing significant inhibition of adapted, genetically modified and wild-type S. cerevisiae in bioethanol fermentation. While adaptation or modification of yeast may reduce inhibition, the most effective approach is to remove the acetic acid prior to fermentation. This work addresses liquid-liquid extraction of acetic acid from biomass hydrolysate through a pathway that mitigates acetic acid inhibition while avoiding the negative effects of the extractant, which itself may exhibit inhibition. Candidate solvents were selected using simulation results from Aspen Plus™, based on their ability to extract acetic acid which was confirmed by experimentation. All solvents showed varying degrees of toxicity toward yeast, but the relative volatility of ethyl acetate enabled its use as simple vacuum evaporation could reduce small concentrations of aqueous ethyl acetate to minimally inhibitory levels. The toxicity threshold of ethyl acetate, in the presence of acetic acid, was found to be 10 g L(-1) . The fermentation was enhanced by extracting 90% of the acetic acid using ethyl acetate, followed by vacuum evaporation to remove 88% removal of residual ethyl acetate along with 10% of the broth. NRRL Y-1546 yeast was used to demonstrate a 13% increase in concentration, 14% in ethanol specific production rate, and 11% ethanol yield. This study demonstrated that extraction of acetic acid with ethyl acetate followed by evaporative removal of ethyl acetate from the raffinate phase has potential to significantly enhance ethanol fermentation in a corn stover bioethanol facility. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:929-937, 2016. © 2016 American Institute of Chemical Engineers.

In vitro inhibitory effects of major bioactive constituents of Andrographis paniculata, Curcuma longa and Silybum marianum on human liver microsomal morphine glucuronidation: A prediction of potential herb-drug interactions arising from andrographolide, curcumin and silybin inhibition in humans.

PubMed

Uchaipichat, Verawan

2018-02-01

This study aimed to investigate the liver microsomal inhibitory effects of silybin, silychristin, andrographolide, and curcumin by using morphine as an in vitro UGT2B7 probe substrate, and predict the magnitude of the herb-drug interaction arising from these herbal constituents' inhibition in vivo. Studies were performed in the incubation with and without bovine serum albumin (BSA). Andrographolide and curcumin showed a marked inhibition on morphine 3- and 6-glucuronidation with IC 50 of 50&87 and 96&111 μM, respectively. In the presence of 2%BSA, andrographolide also showed a strong inhibition on morphine 3- and 6-glucuronidation (IC 50 4.4&21.6 μM) whereas curcumin showed moderate inhibition (IC 50 338&333 μM). In the absence and presence of 2%BSA, morphine 3- and 6-glucuronidation was moderately inhibited by silybin (IC 50 583&862 and 1252&1421 μM, respectively), however was weakly inhibited by silychristin (IC 50 3527&3504 and 1124&1530 μM, respectively). The K i of andrographolide, curcumin and silybin on morphine 3- and 6-glucuronidation were 7.1&9.5, 72.7&65.2, and 224.5&159.7 μM, respectively, while the respective values generated from the system containing 2%BSA were 2.4&3.1, 96.4&108.8, and 366.3&394.5 μM. Using the in vitro and in vivo extrapolation approach, andrographolide was herbal component that may have had a potential interaction in vivo when it was co-administered with morphine. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Wound healing properties of ethyl acetate fraction of Moringa oleifera in normal human dermal fibroblasts.

PubMed

Gothai, Sivapragasam; Arulselvan, Palanisamy; Tan, Woan Sean; Fakurazi, Sharida

2016-01-01

Wounds are the outcome of injuries to the skin that interrupt the soft tissue. Healing of a wound is a complex and long-drawn-out process of tissue repair and remodeling in response to injury. A large number of plants are used by folklore traditions for the treatment of cuts, wounds and burns. Moringa oleifera (MO) is an herb used as a traditional folk medicine for the treatment of various skin wounds and associated diseases. The underlying mechanisms of wound healing activity of ethyl acetate fraction of MO leaves extract are completely unknown. In the current study, ethyl acetate fraction of MO leaves was investigated for its efficacy on cell viability, proliferation and migration (wound closure rate) in human normal dermal fibroblast cells. Results revealed that lower concentration (12.5 µg/ml, 25 µg/ml, and 50 µg/ml) of ethyl acetate fraction of MO leaves showed remarkable proliferative and migratory effect on normal human dermal fibroblasts. This study suggested that ethyl acetate fraction of MO leaves might be a potential therapeutic agent for skin wound healing by promoting fibroblast proliferation and migration through increasing the wound closure rate corroborating its traditional use.

Hepatic and intestinal glucuronidation of mono(2-ethylhexyl) phthalate, an active metabolite of di(2-ethylhexyl) phthalate, in humans, dogs, rats, and mice: an in vitro analysis using microsomal fractions.

PubMed

Hanioka, Nobumitsu; Isobe, Takashi; Kinashi, Yu; Tanaka-Kagawa, Toshiko; Jinno, Hideto

2016-07-01

Mono(2-ethylhexyl) phthalate (MEHP) is an active metabolite of di(2-ethylhexyl) phthalate (DEHP) and has endocrine-disrupting effects. MEHP is metabolized into glucuronide by UDP-glucuronosyltransferase (UGT) enzymes in mammals. In the present study, the hepatic and intestinal glucuronidation of MEHP in humans, dogs, rats, and mice was examined in an in vitro system using microsomal fractions. The kinetics of MEHP glucuronidation by liver microsomes followed the Michaelis-Menten model for humans and dogs, and the biphasic model for rats and mice. The K m and V max values of human liver microsomes were 110 µM and 5.8 nmol/min/mg protein, respectively. The kinetics of intestinal microsomes followed the biphasic model for humans, dogs, and mice, and the Michaelis-Menten model for rats. The K m and V max values of human intestinal microsomes were 5.6 µM and 0.40 nmol/min/mg protein, respectively, for the high-affinity phase, and 430 µM and 0.70 nmol/min/mg protein, respectively, for the low-affinity phase. The relative levels of V max estimated by Eadie-Hofstee plots were dogs (2.0) > mice (1.4) > rats (1.0) ≈ humans (1.0) for liver microsomes, and mice (8.5) > dogs (4.1) > rats (3.1) > humans (1.0) for intestinal microsomes. The percentages of the V max values of intestinal microsomes to liver microsomes were mice (120 %) > rats (57 %) > dogs (39 %) > humans (19 %). These results suggest that the metabolic abilities of UGT enzymes expressed in the liver and intestine toward MEHP markedly differed among species, and imply that these species differences are strongly associated with the toxicity of DEHP.

Human beta-glucuronidase. Measurement of its activity in gallbladder bile devoid of intrinsic interference.

PubMed

Ho, Y C; Ho, K J

1988-04-01

Our purpose is to develop a standard method for preparing the bile for beta-glucuronidase determination by removal of bile acids and conjugated bilirubin which interfere with its activity. The bile acids and conjugated bilirubin in their purified solutions and in the diluted gallbladder biles could be extracted completely with cholestyramine in powder form or tetrahexylammonium chloride (THAC) in chloroform or ethyl acetate. The enzyme was, however, partially precipitated with cholestyramine and denatured by chloroform but not by ethyl acetate. A standard procedure, therefore, includes extraction of the diluted gallbladder bile with THAC in ethyl acetate, followed by determination of the maximal velocity (Vmax) of the enzyme by a kinetic method employing phenolphthalein glucuronide as the substrate. The average Vmax of beta-glucuronidase in the 20 normal gallbladder biles was 165 +/- 86 nmol/min/ml (mean +/- SD), a 23.5-fold increase over the activity before extraction. The measured activity represented the true activity of the enzyme in the bile for recovery of activity of the enzyme added to the bile was practically complete.

Stable dye-sensitized solar cells based on a gel electrolyte with ethyl cellulose as the gelator

NASA Astrophysics Data System (ADS)

Vasei, Maryam; Tajabadi, Fariba; Jabbari, Ali; Taghavinia, Nima

2015-09-01

A simple gelating process is developed for the conventional acetonitrile-based electrolyte of dye solar cells, based on ethyl cellulose as the gelator. The electrolyte becomes quasi-solid-state upon addition of an ethanolic solution of ethyl cellulose to the conventional acetonitrile-based liquid electrolyte. The photovoltaic conversion efficiency with the new gel electrolyte is only slightly lower than with the liquid electrolyte, e.g., 6.5 % for liquid electrolyte versus 5.9 % for gel electrolyte with 5.8 wt% added ethyl cellulose. Electrolyte gelation has small effect on the ionic diffusion coefficient of iodide, and the devices are remarkably stable for at least 550 h under irradiation at 55 °C.

Fourier transform millimeter-wave spectroscopy of the ethyl radical in the electronic ground state.

PubMed

Kim, Eunsook; Yamamoto, Satoshi

2004-02-15

The pure rotational spectrum of the ethyl radical (C2H5) has been detected for the first time with the Fourier transform millimeter-wave spectrometer. The ethyl radical is produced by discharging the C2H5I gas diluted in Ar. The 1(01)-0(00) rotational transition of the ethyl radical is observed in the frequency range from 43,680 to 43,780 MHz. The observed spectrum shows a very complicated pattern of the fine and hyperfine structures of a doublet radical with the nuclear spins of five protons. The fine and hyperfine components are assigned with the aid of measurements of the Zeeman splittings. As a result, the 22 lines are ascribed to the transitions in the ground vibronic state (A2"). The rotational constant, the spin-rotation interaction constant, and hyperfine interaction constants are determined by the least-squares fit. The Fermi contact term of the alpha-proton is determined to be -64.1654 MHz in the gas phase, indicating that the structure of the -CH2 is essentially planar. The present rotational spectroscopic study further supports that the methyl group of the ethyl radical can be regarded as a nearly free internal rotor with a low energy barrier. A few unassigned lines still remain, which may be vibrational satellites of the internal rotation mode. Copyright 2004 American Institute of Physics

Biomarkers of alcohol consumption in body fluids - possibilities and limitations of application in toxicological analysis.

PubMed

Woźniak, Mateusz K; Wiergowski, Marek; Namieśnik, Jacek; Biziuk, Marek

2017-10-05

Ethyl alcohol is the most popular legal drug, but its excessive consumption causes social problems. Despite many public campaigns against alcohol use, car accidents, instances of aggressive behaviour, sexual assaults and deterioration in labor productivity caused by inebriated people is still commonplace. Fast and easy diagnosis of alcohol consumption is required in order to introduce proper and effective therapy, and is crucial in forensic toxicology analysis. The easiest method to prove alcohol intake is determination of ethanol in body fluids or in breath. However, since ethanol is rapidly metabolized in the human organism, only recent consumption can be detected using this method. Because of that, the determination of alcohol biomarkers was introduced for monitoring alcohol consumption over a wider range of time. The markers described in this article are ethanol, its non-oxidative metabolites (ethyl glucuronide, ethyl sulfate, phosphatidylethanol, ethyl phosphate, fatty acid ethyl esters) and oxidative metabolites (acetaldehyde and acetaldehyde adducts). The objective of this study is to review published studies focusing on the sample preparation methods and chromatographic or biochemical techniques for the determination of alcohol biomarkers in whole blood, plasma, serum and urine. Authors also described issues concerning the detection window of these biomarkers, and possibilities and limitations of their use in routine analytical toxicology for monitoring alcohol consumption or sobriety during alcohol therapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

In Vitro Effects of Bisphenol A β-D-Glucuronide (BPA-G) on Adipogenesis in Human and Murine Preadipocytes

PubMed Central

Boucher, Jonathan G.; Boudreau, Adèle; Ahmed, Shaimaa

2015-01-01

Background Exposure to common environmental substances, such as bisphenol A (BPA), has been associated with a number of negative health outcomes. In vivo, BPA is rapidly converted to its predominant metabolite, BPA-glucuronide (BPA-G), which has long been believed to be biologically inactive because it lacks estrogenic activity. However, the effects of BPA-G on cellular metabolism have not been characterized. In the present study we examined the effect of BPA-G on adipogenesis. Methods The effect of BPA-G on the differentiation of human and 3T3L1 murine preadipocytes was evaluated in vitro by quantifying lipid accumulation and the expression of adipogenic markers. Results Treatment of 3T3L1 preadipocytes with 10 μM BPA-G induced a significant increase in lipid accumulation, mRNA expression of the adipogenic markers sterol regulatory element binding factor 1 (SREBF1) and lipoprotein lipase (LPL), and protein levels of LPL, aP2, and adipsin. Treatment of primary human preadipocytes with BPA-G also induced adipogenesis as determined by aP2 levels. Co-treatment of cells with the estrogen receptor (ER) antagonist fulvestrant (ICI) significantly inhibited the BPA-G–induced increase in LPL and aP2 levels, whereas treatment with ICI alone had no effect. Moreover, BPA-G did not display any significant estrogenic activity. Conclusions To our knowledge, this study is the first to report that BPA-G induces adipocyte differentiation and is not simply an inactive metabolite. The fact that BPA-G induced adipogenesis and was inhibited by an ER antagonist yet showed no estrogenic activity suggests that it has no classical ER transcriptional activation function and acts through a pathway that remains to be determined. Citation Boucher JG, Boudreau A, Ahmed S, Atlas E. 2015. In vitro effects of bisphenol A β-D-glucuronide (BPA-G) on adipogenesis in human and murine preadipocytes. Environ Health Perspect 123:1287–1293; http://dx.doi.org/10.1289/ehp.1409143 PMID:26018136

Isophote Shapes Of Early-Type Galaxies In Massive Clusters At Z 1 And 0

NASA Astrophysics Data System (ADS)

Mitsuda, Kazuma; Doi, Mamoru; Morokuma, Tomoki; Suzuki, Nao; Yasuda, Naoki; Perlmutter, Saul; Aldering, Greg; Meyers, Joshua

2017-06-01

Dynamics of early-type galaxies (ETGs), whether they are supported by rotation or dispersion, is a clue to understand their assembly history. We compare the isophote shape parameter a4 between z ˜ 1 and 0 as a proxy for dynamics to investigate the epoch at which the dynamical properties are established. We create cluster ETG samples with stellar masses of log(M✽/M⦿) ≥ 10.5 with spectroscopic redshifts. We have 130 ETGs from the Hubble Space Telescope Cluster Supernova Survey for z ˜ 1 and 355 ETGs from the Sloan Digital Sky Survey for z ˜ 0. We find similar dependence of the a4 parameter on the mass at z ˜ 1 and 0; the main population changes from disky (a4 > 0) to boxy (a4 ≤ 0) at a critical mass of log(M✽/M⦿) 11.5 with the massive end dominated by boxy ETGs. The disky ETG fraction is consistent between these redshifts. Although uncertainties are large, the results suggest that the isophote shapes and probably dynamical properties of cluster ETGs are already in place at z > 1 and do not significantly evolve in z < 1, despite significant size evolution. The constant disky fraction imply that the processes responsible for the size evolution is not enough violent to convert the dynamical properties of ETGs.

Implications for the Origin of Early-type Dwarf Galaxies: A Detailed Look at the Isolated Rotating Early-type Dwarf Galaxy LEDA 2108986 (CG 611), Ramifications for the Fundamental Plane’s {S}_{K}^{2} Kinematic Scaling, and the Spin-Ellipticity Diagram

NASA Astrophysics Data System (ADS)

Graham, Alister W.; Janz, Joachim; Penny, Samantha J.; Chilingarian, Igor V.; Ciambur, Bogdan C.; Forbes, Duncan A.; Davies, Roger L.

2017-05-01

Selected from a sample of nine, isolated, dwarf early-type galaxies (ETGs) with the same range of kinematic properties as dwarf ETGs in clusters, we use LEDA 2108986 (CG 611) to address the nature versus nurture debate regarding the formation of dwarf ETGs. The presence of faint disk structures and rotation within some cluster dwarf ETGs has often been heralded as evidence that they were once late-type spiral or dwarf irregular galaxies prior to experiencing a cluster-induced transformation into an ETG. However, CG 611 also contains significant stellar rotation (≈20 km s-1) over its inner half-light radius ({R}{{e},{maj}}=0.71 kpc), and its stellar structure and kinematics resemble those of cluster ETGs. In addition to hosting a faint young nuclear spiral within a possible intermediate-scale stellar disk, CG 611 has accreted an intermediate-scale, counter-rotating gas disk. It is therefore apparent that dwarf ETGs can be built by accretion events, as opposed to disk-stripping scenarios. We go on to discuss how both dwarf and ordinary ETGs with intermediate-scale disks, whether under (de)construction or not, are not fully represented by the kinematic scaling {S}0.5=\\sqrt{0.5 {V}{rot}2+{σ }2}, and we also introduce a modified spin-ellipticity diagram λ (R)-ɛ (R) with the potential to track galaxies with such disks.

Subchronic Toxicity Study in Rats of Two New Ethyl-Carbamates with Ixodicidal Activity

PubMed Central

Prado-Ochoa, María Guadalupe; Abrego-Reyes, Víctor Hugo; Velázquez-Sánchez, Ana María; Muñoz-Guzmán, Marco Antonio; Ramírez-Noguera, Patricia; Angeles, Enrique; Alba-Hurtado, Fernando

2014-01-01

Female and male Wistar rats were used to determine the subchronic oral toxicities of two new ethyl-carbamates with ixodicidal activities (ethyl-4-bromphenyl-carbamate and ethyl-4-chlorphenyl-carbamate). The evaluated carbamates were administered in the drinking water (12.5, 25 and 50 mg/kg/day) for 90 days. Exposure to the evaluated carbamates did not cause mortality or clinical signs and did not affect food consumption or weight gain. However, exposure to these carbamates produced alterations in water consumption, hematocrit, percentages of reticulocytes, plasma proteins, some biochemical parameters (aspartate aminotransferase, gamma-glutamyl transpeptidase, cholinesterase, and creatinine activities), thiobarbituric acid reactive substances, and the relative weight of the spleen. Histologically, slight pathological alterations were found in the liver that were consistent with the observed biochemical alterations. The nonobserved adverse effect levels (NOAELs) of the evaluated carbamates were 12.5 mg/kg/day for both the female and male rats. The low severity and reversibility of the majority of the observed alterations suggest that the evaluated carbamates have low subchronic toxicity. PMID:24818142

Metabolism of oral 9-cis-retinoic acid in the human. Identification of 9-cis-retinoyl-beta-glucuronide and 9-cis-4-oxo-retinoyl-beta-glucuronide as urinary metabolites.

PubMed

Sass, J O; Masgrau, E; Saurat, J H; Nau, H

1995-09-01

Data from a number of investigators suggest that the 9-cis-isomer of RA1 (9-cis-RA) may be a promising agent in chemoprevention and treatment of certain types of cancer. Therefore, clinical studies on this retinoid have been initiated. However, up to now, no information has been published on the metabolism of 9-cis-RA in the human. Herein, we report the first data on retinoid metabolism after multiple administration of 9-cis-RA (20 mg/day po) to human volunteers. After 2 and 12-13 hr, plasma concentrations of 9-cis-RA and its metabolites 9,13-dicis-RA, 13-cis-RA, and all-trans-RA were low. In contrast, dosing with 13-cis-RA yielded much higher plasma retinoid levels. Effects on plasma retinol concentrations did not become obvious after any drug treatment. Several retinoid metabolites were found in the urine of 9-cis-RA-treated individuals, and 9-cis-RAG, as well as 9-cis-4-oxo-RAG, could be identified. After treatment with 9-cis-RA, high concentrations of the administered drug were found in the feces, along with comparably low concentrations of 13-cis-RA, 9,13-dicis-RA, and all-trans-RA. Our report indicates that 9-cis-RA is either eliminated much more rapidly than 13-cis-RA, or it is poorly absorbed, and presents the characterization of two urinary glucuronides.

Convenient Route to Di- and Triorganosilyl Ethyl Ethers and the Corresponding Di- and Triorganosilanes

DTIC Science & Technology

1993-11-22

example R2 R’SiH. Early reports indicated that formation of R3SiCI or R2SiCI 2 compounds by the addition of organolithium or Grignard reagents to...corresponding Grignard reagents are far less effective for the substiution reactions. 7 3 Table I. Conversion of (CH3 CH20) 4Si to Organosilyl Ethyl Ethers (X...ABSTRACT (Maximum 200 words) Tetraethoxysilane was treated with alkyl- and aryllithium reagents for the preparation of organosilyl ethyl ethers of the

[Ethyl chloride aerosol spray for local anesthesia before arterial puncture: randomized placebo-controlled trial].

PubMed

Ballesteros-Peña, Sendoa; Fernández-Aedo, Irrintzi; Vallejo-De la Hoz, Gorka

2017-06-01

To compare the efficacy of an ethyl chloride aerosol spray to a placebo spray applied in the emergency department to the skin to reduce pain from arterial puncture for blood gas analysis. Single-blind, randomized placebo-controlled trial in an emergency department of Hospital de Basurto in Bilbao, Spain. We included 126 patients for whom arterial blood gas analysis had been ordered. They were randomly assigned to receive application of the experimental ethyl chloride spray (n=66) or a placebo aerosol spray of a solution of alcohol in water (n=60). The assigned spray was applied just before arterial puncture. The main outcome variable was pain intensity reported on an 11-point numeric rating scale. The median (interquartile range) pain level was 2 (1-5) in the experimental arm and 2 (1-4.5) in the placebo arm (P=.72). Topical application of an ethyl chloride spray did not reduce pain caused by arterial puncture.

Mus308 Processes Oxygen and Nitrogen Ethylation DNA Damage in Germ Cells of Drosophila

PubMed Central

Díaz-Valdés, Nancy; Comendador, Miguel A.; Sierra, L. María

2010-01-01

The D. melanogaster mus308 gene, highly conserved among higher eukaryotes, is implicated in the repair of cross-links and of O-ethylpyrimidine DNA damage, working in a DNA damage tolerance mechanism. However, despite its relevance, its possible role on the processing of different DNA ethylation damages is not clear. To obtain data on mutation frequency and on mutation spectra in mus308 deficient (mus308−) conditions, the ethylating agent diethyl sulfate (DES) was analysed in postmeiotic male germ cells. These data were compared with those corresponding to mus308 efficient conditions. Our results indicate that Mus308 is necessary for the processing of oxygen and N-ethylation damage, for the survival of fertilized eggs depending on the level of induced DNA damage, and for an influence of the DNA damage neighbouring sequence. These results support the role of mus308 in a tolerance mechanism linked to a translesion synthesis pathway and also to the alternative end-joinig system. PMID:20936147

Removal of chloropyrifos ethyl, tetradifon and chlorothalonil pesticide residues from citrus by using ozone.

PubMed

Kusvuran, Erdal; Yildirim, Deniz; Mavruk, Funda; Ceyhan, Mehmet

2012-11-30

The removal of chloropyrifos ethyl, tetradifon and chlorothalonil pesticide residues from the lemon, orange and grapefruit matrices were achieved by ozonation. All of chlorothalonil residues adsorbed onto the orange matrix were completely removed after 5 min ozonation. The highest removal percentages of tetradifon and chloropyrifos ethyl were achieved as 98.6 and 94.2%, respectively for the lemon and grapefruit matrices. All of diffused chlorothalonil and chloropyrifos ethyl residues were completely removed from both orange and grapefruit matrices after 5 min ozonation. Increasing of applied ozone dosage was not significantly effect on the removal percentages of pesticides whereas increasing of ozonation temperature caused a negative effect on the removal percentages of pesticides. The washing of the matrices with tap water was not as effective as ozonation in the removal of residual pesticides. Our results show that ozone treatment has a great potential for removing of residual pesticides from lemon, orange and grapefruit matrices. Copyright © 2012 Elsevier B.V. All rights reserved.

Kinetics of Ethyl Acetate Synthesis Catalyzed by Acidic Resins

ERIC Educational Resources Information Center

Antunes, Bruno M.; Cardoso, Simao P.; Silva, Carlos M.; Portugal, Ines

2011-01-01

A low-cost experiment to carry out the second-order reversible reaction of acetic acid esterification with ethanol to produce ethyl acetate is presented to illustrate concepts of kinetics and reactor modeling. The reaction is performed in a batch reactor, and the acetic acid concentration is measured by acid-base titration versus time. The…

Wound healing properties of ethyl acetate fraction of Moringa oleifera in normal human dermal fibroblasts

PubMed Central

Gothai, Sivapragasam; Arulselvan, Palanisamy; Tan, Woan Sean; Fakurazi, Sharida

2016-01-01

Background/Aim: Wounds are the outcome of injuries to the skin that interrupt the soft tissue. Healing of a wound is a complex and long-drawn-out process of tissue repair and remodeling in response to injury. A large number of plants are used by folklore traditions for the treatment of cuts, wounds and burns. Moringa oleifera (MO) is an herb used as a traditional folk medicine for the treatment of various skin wounds and associated diseases. The underlying mechanisms of wound healing activity of ethyl acetate fraction of MO leaves extract are completely unknown. Materials and Methods: In the current study, ethyl acetate fraction of MO leaves was investigated for its efficacy on cell viability, proliferation and migration (wound closure rate) in human normal dermal fibroblast cells. Results: Results revealed that lower concentration (12.5 µg/ml, 25 µg/ml, and 50 µg/ml) of ethyl acetate fraction of MO leaves showed remarkable proliferative and migratory effect on normal human dermal fibroblasts. Conclusion: This study suggested that ethyl acetate fraction of MO leaves might be a potential therapeutic agent for skin wound healing by promoting fibroblast proliferation and migration through increasing the wound closure rate corroborating its traditional use. PMID:27069722

Inert Reassessment Document for Ethyl Alcohol - CAS No. 64-17-5

EPA Pesticide Factsheets

The main use of ethyl alcohol is in the consumption of alcoholic beverage and as a solvent in the laboratory and industry, and in the manufacture of denatured alcohol, pharmaceuticals, perfumes, and organic synthesis.

Synthesis of 10-Ethyl Flavin: A Multistep Synthesis Organic Chemistry Laboratory Experiment for Upper-Division Undergraduate Students

ERIC Educational Resources Information Center

Sichula, Vincent A.

2015-01-01

A multistep synthesis of 10-ethyl flavin was developed as an organic chemistry laboratory experiment for upper-division undergraduate students. Students synthesize 10-ethyl flavin as a bright yellow solid via a five-step sequence. The experiment introduces students to various hands-on experimental organic synthetic techniques, such as column…

21 CFR 172.225 - Methyl and ethyl esters of fatty acids produced from edible fats and oils.

Code of Federal Regulations, 2013 CFR

2013-04-01

... from edible fats and oils. 172.225 Section 172.225 Food and Drugs FOOD AND DRUG ADMINISTRATION... Methyl and ethyl esters of fatty acids produced from edible fats and oils. Methyl esters and ethyl esters of fatty acids produced from edible fats and oils may be safely used in food, subject to the...

21 CFR 172.225 - Methyl and ethyl esters of fatty acids produced from edible fats and oils.

Code of Federal Regulations, 2012 CFR

2012-04-01

... from edible fats and oils. 172.225 Section 172.225 Food and Drugs FOOD AND DRUG ADMINISTRATION... Methyl and ethyl esters of fatty acids produced from edible fats and oils. Methyl esters and ethyl esters of fatty acids produced from edible fats and oils may be safely used in food, subject to the...

Chemodynamics of Methyl Parathion and Ethyl Parathion: Adsorption Models for Sustainable Agriculture

PubMed Central

Rafique, Uzaira; Balkhair, Khaled S.; Ashraf, Muhammad Aqeel

2014-01-01

The toxicity of organophosphate insecticides for nontarget organism has been the subject of extensive research for sustainable agriculture. Pakistan has banned the use of methyl/ethyl parathions, but they are still illegally used. The present study is an attempt to estimate the residual concentration and to suggest remedial solution of adsorption by different types of soils collected and characterized for physicochemical parameters. Sorption of pesticides in soil or other porous media is an important process regulating pesticide transport and degradation. The percentage removal of methyl parathion and ethyl parathion was determined through UV-Visible spectrophotometer at 276 nm and 277 nm, respectively. The results indicate that agricultural soil as compared to barren soil is more efficient adsorbent for both insecticides, at optimum batch condition of pH 7. The equilibrium between adsorbate and adsorbent was attained in 12 hours. Methyl parathion is removed more efficiently (by seven orders of magnitude) than ethyl parathion. It may be attributed to more available binding sites and less steric hindrance of methyl parathion. Adsorption kinetics indicates that a good correlation exists between distribution coefficient (Kd) and soil organic carbon. A general increase in Kd is noted with increase in induced concentration due to the formation of bound or aged residue. PMID:24689059

In vitro protection of biological macromolecules against oxidative stress and in vivo toxicity evaluation of Acacia nilotica (L.) and ethyl gallate in rats

PubMed Central

2014-01-01

Background Recently, enormous research has been focused on natural bioactive compounds possessing potential antioxidant and anticancer properties using cell lines and animal models. Acacia nilotica (L.) is widely distributed in Asia, Africa, Australia and Kenya. The plant is traditionally used to treat mouth, ear and bone cancer. However, reports on Acacia nilotica (L.) Wild. Ex. Delile subsp. indica (Benth.) Brenan regarding its toxicity profile is limited. Hence in this study, we investigated the antioxidant capacity and acute toxicity of ethyl gallate, a phenolic antioxidant present in the A. nilotica (L.) leaf extract. Methods The antioxidant activity of ethyl gallate against Fenton’s system (Fe3+/H2O2/ascorbic acid) generated oxidative damage to pBR322 DNA and BSA was investigated. We also studied the interaction of ethyl gallate to CT-DNA by wave scan and FTIR analysis. The amount of ethyl gallate present in the A. nilotica (L.) leaf extract was calculated using HPLC and represented in gram equivalence of ethyl gallate. The acute toxicity profile of ethyl gallate in the A. nilotica (L.) leaf extract was analyzed in albino Wistar rats. Measurement of liver and kidney function markers, total proteins and glucose were determined in the serum. Statistical analysis was done using statistical package for social sciences (SPSS) tool version 16.0. Results Ethyl gallate was found to be effective at 100 μg/mL concentration by inhibiting the free radical mediated damage to BSA and pBR322 DNA. We also found that the interaction of ethyl gallate and A. nilotica (L.) leaf extract to CT-DNA occurs through intercalation. One gram of A. nilotica (L.) leaf extract was found to be equivalent to 20 mg of ethyl gallate through HPLC analysis. Based on the acute toxicity results, A. nilotica (L.) leaf extract and ethyl gallate as well was found to be non-toxic and safe. Conclusions Results revealed no mortality or abnormal biochemical changes in vivo and the protective effect

Preparation and Antioxidant Activity of Ethyl-Linked Anthocyanin-Flavanol Pigments from Model Wine Solutions.

PubMed

Li, Lingxi; Zhang, Minna; Zhang, Shuting; Cui, Yan; Sun, Baoshan

2018-05-03

Anthocyanin-flavanol pigments, formed during red wine fermentation and storage by condensation reactions between anthocyanins and flavanols (monomers, oligomers, and polymers), are one of the major groups of polyphenols in aged red wine. However, knowledge of their biological activities is lacking. This is probably due to the structural diversity and complexity of these molecules, which makes the large-scale separation and isolation of the individual compounds very difficult, thus restricting their further study. In this study, anthocyanins (i.e., malvidin-3-glucoside, cyanidin-3-glucoside, and peonidin-3-glucoside) and (⁻)-epicatechin were first isolated at a preparative scale by high-speed counter-current chromatography. The condensation reaction between each of the isolated anthocyanins and (⁻)-epicatechin, mediated by acetaldehyde, was conducted in model wine solutions to obtain ethyl-linked anthocyanin-flavanol pigments. The effects of pH, molar ratio, and temperature on the reaction rate were investigated, and the reaction conditions of pH 1.7, molar ratio 1:6:10 (anthocyanin/(⁻)-epicatechin/acetaldehyde), and reaction temperature of 35 °C were identified as optimal for conversion of anthocyanins to ethyl-linked anthocyanin-flavanol pigments. Six ethyl-linked anthocyanin-flavanol pigments were isolated in larger quantities and collected under optimal reaction conditions, and their chemical structures were identified by HPLC-QTOF-MS and ECD analyses. Furthermore, DPPH, ABTS, and FRAP assays indicate that ethyl-linked anthocyanin-flavanol pigments show stronger antioxidant activities than their precursor anthocyanins.

Dissociation of the Ethyl Radical: An Exercise in Computational Chemistry

ERIC Educational Resources Information Center

Nassabeh, Nahal; Tran, Mark; Fleming, Patrick E.

2014-01-01

A set of exercises for use in a typical physical chemistry laboratory course are described, modeling the unimolecular dissociation of the ethyl radical to form ethylene and atomic hydrogen. Students analyze the computational results both qualitatively and quantitatively. Qualitative structural changes are compared to approximate predicted values…

Correlations between conceptal concentrations of all-trans-retinoic acid and dysmorphogenesis after microinjections of all-trans-retinoic acid, 13-cis-retinoic acid, all-trans-retinoyl-beta-glucuronide, or retinol in cultured whole rat embryos.

PubMed

Kraft, J C; Juchau, M R

1992-01-01

Retinol (4,000 ng/ml), all-trans-retinoyl-beta-glucuronide (4,000 ng/ml), and 13-cis-retinoic acid (1,500 ng/ml) each produced dysmorphogenic effects qualitatively similar to those elicited by 250 ng/ml of all-trans-retinoic acid after microinjections of the respective individual retinoids into the amniotic cavities of cultured whole rat embryos. Subsequent HPLC analyses of the cultured whole conceptuses, embryos proper, yolk sacs, and culture media (24 hr after microinjections) indicated that conceptal biotransformation of each of the retinoids had occurred during the culture period. All-trans-retinoic acid was present in the embryos proper at quantitatively similar concentrations (20-100 nM) after microinjections of the selected quantities of each of the microinjected retinoids: retinol, all-trans-retinoyl-beta-glucuronide, 13-cis-retinoic acid, or all-trans-retinoic acid. The results suggested that all-trans-retinoic acid acted as an ultimate dysmorphogen for the retinoids tested with respect to the anomalies monitored in the embryo culture system.

Phytochemical screening and antioxidant activity of ethanolic extract and ethyl acetate fraction from basil leaf (Ocimum basilicum L.) by DPPH radical scavenging method

NASA Astrophysics Data System (ADS)

Warsi; Sholichah, A. R.

2017-11-01

Basil leaf (Ocimum basilicum L.) contains various compounds such as flavonoid, alkaloid, phenol and essential oil, so it needs to be fractionated to find out the flavonoid compound with the greatest potential as an antioxidant. This research was aimed to know the chemical compound, antioxidant potential of ethanolic extract and ethyl acetate fraction from basil leaf. The basil leaf was extracted by maceration using ethanol 70 %. The crude extract was fractionated with ethyl acetate. The ethanolic extract and ethyl acetate fraction were screened of phytochemical content including identification of flavonoids, alkaloids and polyphenolics. The antioxidant activity of the ethanolic extract and ethyl acetate fraction were tested qualitatively with 2,2-diphenyl-1-picrylhydrazyl (DPPH) and phosphomolybdate. Its antioxidant activity was determined quantitatively using DPPH radical scavenging method. Phytochemical screening test showed that ethanolic extract and ethyl acetate fraction from basil leaf contain flavonoids, polyphenolics, and alkaloids. The qualitative analysis of antioxidant activity of ethanolic extract and ethyl acetate fraction from basil leaf showed an antioxidant activity. The IC50 value of ethanolic extract, ethyl acetate fraction and quercetin were 1,374.00±6.20 389.00±1.00 2.10±0.01μg/mL, respectively. The research showed that antioxidant activity of the ethyl acetate fraction more potential than the ethanol extract of the basil leaf, but less than quercetin.

40 CFR 721.10130 - Quino[2,3-b]acridine-7,14-dione, 5,12-dihydro-ar-[4-[[2-(sulfooxy)ethyl]substituted]phenyl...

Code of Federal Regulations, 2010 CFR

2010-07-01

...-dihydro-ar-[4-[[2-(sulfooxy)ethyl]substituted]phenyl]-, monosodium salt (generic). 721.10130 Section 721... Quino[2,3-b]acridine-7,14-dione, 5,12-dihydro-ar-[4-[[2-(sulfooxy)ethyl]substituted]phenyl]-, monosodium... substance identified generically as quino[2,3-b]acridine-7,14-dione, 5,12-dihydro-ar-[4-[[2-(sulfooxy)ethyl...

Benzylic oxidation of gemfibrozil-1-O-beta-glucuronide by P450 2C8 leads to heme alkylation and irreversible inhibition.

PubMed

Baer, Brian R; DeLisle, Robert Kirk; Allen, Andrew

2009-07-01

Gemfibrozil-1-O-beta-glucuronide (GEM-1-O-gluc), a major metabolite of the antihyperlipidemic drug gemfibrozil, is a mechanism-based inhibitor of P450 2C8 in vitro, and this irreversible inactivation may lead to clinical drug-drug interactions between gemfibrozil and other P450 2C8 substrates. In light of this in vitro finding and the observation that the glucuronide conjugate does not contain any obvious structural alerts, the current study was conducted to determine the potential site of GEM-1-O-gluc bioactivation and the subsequent mechanism of P450 2C8 inhibition (i.e., modification of apoprotein or heme). LC/MS analysis of a reaction mixture containing recombinant P450 2C8 and GEM-1-O-gluc revealed that the substrate was covalently linked to the heme prosthetic heme group during catalysis. A combination of mass spectrometry and deuterium isotope effects revealed that a benzylic carbon on the 2',5'-dimethylphenoxy group of GEM-1-O-gluc was covalently bound to the heme of P450 2C8. The regiospecificity of substrate addition to the heme group was not confirmed experimentally, but computational modeling experiments indicated that the gamma-meso position was the most likely site of modification. The metabolite profile, which consisted of two benzyl alcohol metabolites and a 4'-hydroxy-GEM-1-O-gluc metabolite, indicated that oxidation of GEM-1-O-gluc was limited to the 2',5'-dimethylphenoxy group. These results are consistent with an inactivation mechanism wherein GEM-1-O-gluc is oxidized to a benzyl radical intermediate, which evades oxygen rebound, and adds to the gamma-meso position of heme. Mechanism-based inhibition of P450 2C8 can be rationalized by the formation of the GEM-1-O-gluc-heme adduct and the consequential restriction of additional substrate access to the catalytic iron center.

The effect of fluorine atom on the synthesis and composition of gametocidal ethyl oxanilates.

PubMed

Iskra, Jernej; Titan, Primož; Meglič, Vladimir

2013-01-01

Three derivatives of ethyl oxanilate were synthesized in order to test their application as gametocides on the hermaphrodite plants like common wheat (Triticum aestivum L.). A substituent at para position (F, Br, CN) of aniline defined its reactivity towards diethyl oxalate 2. Classical reaction in toluene was not selective and amidation occurred also at the second carbonyl groups of 2. Alternative synthesis under solvent-free conditions with application of low pressure for removal of EtOH provided selectively with ethyl oxanilate 3a and 3b. 4-Cyanoaniline did not react selectively and the corresponding ethyl oxanilate 3c was prepared from mono acid chloride of oxalic acid. Fluoro derivative 3a was found to be the only one that gives stable aqueous suspension for its application as chemical hybridizing agent for common wheat, while bromo- 3b and cyano- 3c analogues were not soluble enough and suspension was stable for less than 2 hours. Fluoro derivative had shown the best induction of male sterility, while in comparison with standard chemical hybridizing agent they were substantially less toxic for plant.

Miscibility of ethyl cellulose/copolyamide6/66/1010 blends by viscometry and refractive index method

NASA Astrophysics Data System (ADS)

Zhang, Xiuzhen; Shen, Yuhua; Xie, Anjian; Gao, Sulian; Xing, Zhiying

2011-04-01

The miscibility of ethyl cellulose (EC)/copolyamide6/66/1010 (PA-130) in formic acid is studied by viscometry and refractive index techniques at 25°C. Using viscosity data, the criteria Δ b, Δ b', Δ[η]m, interaction parameter μ, β and thermodynamic parameter α are calculated. These investigations indicate that blend of EC/PA-130 is miscible when the ethyl cellulose content is more than 50 wt % in the blend. Further the result was also confirmed by refractive index measurements.

40 CFR 721.9672 - Amides, tall-oil fatty, N-[2-[2-hydroxyethyl)amino]ethyl], reaction products with sulfur dioxide...

Code of Federal Regulations, 2013 CFR

2013-07-01

...-hydroxyethyl)amino]ethyl], reaction products with sulfur dioxide; fatty acids, tall-oil, reaction products with 1-piperazineethanamine and sulfur dioxide; fatty acids, tall-oil reaction products with sulfur...)amino]ethyl], reaction products with sulfur dioxide; fatty acids, tall-oil, reaction products with 1...

40 CFR 721.9672 - Amides, tall-oil fatty, N-[2-[2-hydroxyethyl)amino]ethyl], reaction products with sulfur dioxide...

Code of Federal Regulations, 2011 CFR

2011-07-01

...-hydroxyethyl)amino]ethyl], reaction products with sulfur dioxide; fatty acids, tall-oil, reaction products with 1-piperazineethanamine and sulfur dioxide; fatty acids, tall-oil reaction products with sulfur...)amino]ethyl], reaction products with sulfur dioxide; fatty acids, tall-oil, reaction products with 1...

40 CFR 721.9672 - Amides, tall-oil fatty, N-[2-[2-hydroxyethyl)amino]ethyl], reaction products with sulfur dioxide...

Code of Federal Regulations, 2010 CFR

2010-07-01

...-hydroxyethyl)amino]ethyl], reaction products with sulfur dioxide; fatty acids, tall-oil, reaction products with 1-piperazineethanamine and sulfur dioxide; fatty acids, tall-oil reaction products with sulfur...)amino]ethyl], reaction products with sulfur dioxide; fatty acids, tall-oil, reaction products with 1...

Optimisation of Croton gratissimus Oil Extraction by n-Hexane and Ethyl Acetate Using Response Surface Methodology.

PubMed

Jiyane, Phiwe Charles; Tumba, Kaniki; Musonge, Paul

2018-04-01

The extraction of oil from Croton gratissimus seeds was studied using the three-factor five-level full-factorial central composite rotatable design (CCRD) of the response surface methodology (RSM). The effect of the three factors selected, viz., extraction time, extraction temperature and solvent-to-feed ratio on the extraction oil yield was investigated when n-hexane and ethyl acetate were used as extraction solvents. The coefficients of determination (R 2 ) of the models developed were 0.98 for n-hexane extraction and 0.97 for ethyl acetate extraction. These results demonstrated that the models developed adequately represented the processes they described. From the optimized model, maximum extraction yield obtained from n-hexane and ethyl acetate extraction were 23.88% and 23.25%, respectively. In both cases the extraction temperature and solvent-to-feed ratio were 35°C and 5 mL/g, respectively. In n-hexane extraction the maximum conditions were reached only after 6 min whereas in ethyl acetate extraction it took 20 min to get the maximum extraction oil yield. Oil extraction of Croton gratissimus seeds, in this work, favoured the use of n-hexane as an extraction solvent as it offered higher oil yields at low temperatures and reduced residence times.

IRIS Toxicological Review of Ethyl Tertiary Butyl Ether (Etbe) ...

EPA Pesticide Factsheets

In August 2013, EPA released the draft literature searches and associated search strategies, evidence tables, and exposure response arrays for ETBE to obtain input from stakeholders and the public prior to developing the draft IRIS assessment. Specifically, EPA was interested in comments on the following: Draft literature search strategies The approach for identifying studies The screening process for selecting pertinent studies The resulting list of pertinent studies Preliminary evidence tables The process for selecting studies to include in evidence tables The quality of the studies in the evidence tables The literature search strategy, which describes the processes for identifying scientific literature, contains the studies that EPA considered and selected to include in the evidence tables. The preliminary evidence tables and exposure-response arrays present the key study data in a standardized format. The evidence tables summarize the available critical scientific literature. The exposure-response figures provide a graphical representation of the responses at different levels of exposure for each study in the evidence table. The draft Toxicological Review of Ethyl Tertiary Butyl Ether provides scientific support and rationale for the hazard and dose-response assessment pertaining to chronic exposure to ethyl tertiary butyl ether.

Dissolved Massive Metal-rich Globular Clusters Can Cause the Range of UV Upturn Strengths Found among Early-type Galaxies

NASA Astrophysics Data System (ADS)

Goudfrooij, Paul

2018-04-01

I discuss a scenario in which the ultraviolet (UV) upturn of giant early-type galaxies (ETGs) is primarily due to helium-rich stellar populations that formed in massive metal-rich globular clusters (GCs), which subsequently dissolved in the strong tidal field in the central regions of the massive host galaxy. These massive GCs are assumed to show UV upturns similar to those observed recently in M87, the central giant elliptical galaxy in the Virgo cluster of galaxies. Data taken from the literature reveal a strong correlation between the strength of the UV upturn and the specific frequency of metal-rich GCs in ETGs. Adopting a Schechter function parameterization of GC mass functions, simulations of long-term dynamical evolution of GC systems show that the observed correlation between UV upturn strength and GC specific frequency can be explained by variations in the characteristic truncation mass {{ \\mathcal M }}{{c}} such that {{ \\mathcal M }}{{c}} increases with ETG luminosity in a way that is consistent with observed GC luminosity functions in ETGs. These findings suggest that the nature of the UV upturn in ETGs and the variation of its strength among ETGs are causally related to that of helium-rich populations in massive GCs, rather than intrinsic properties of field stars in massive galactic spheroids. With this in mind, I predict that future studies will find that [N/Fe] decreases with increasing galactocentric radius in massive ETGs, and that such gradients have the largest amplitudes in ETGs with the strongest UV upturns.

77 FR 75859 - Pyraflufen-Ethyl; Extension of Time-Limited Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-26

... residues of pyraflufen-ethyl in or on cattle, meat byproducts; goat, meat byproducts; horse, meat byproducts; sheep, meat byproducts; and milk. Nichino America, Inc. requested the tolerance extensions under... on: Cattle, meat byproducts; goat, meat byproducts; horse, meat byproducts; sheep, meat byproducts...

Solid dispersions of the penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA): Formulation design and optimization studies

PubMed Central

Yang, Yu-Tsai; Di Pasqua, Anthony J.; Zhang, Yong; Sueda, Katsuhiko; Jay, Michael

2015-01-01

The penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA), which exists as an oily liquid, was incorporated into a solid dispersion for oral administration by the solvent evaporation method using blends of polyvinylpyrrolidone (PVP), Eudragit® RL PO and α-tocopherol. D-optimal mixture design was used to optimize the formulation. Formulations that had a high concentration of both Eudragit® RL PO and α-tocopherol exhibited low water absorption and enhanced stability of the DTPA prodrug. Physicochemical properties of the optimal formulation were evaluated using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). In vitro release of the prodrug was evaluated using the USP Type II apparatus dissolution method. DSC studies indicated that the matrix had an amorphous structure, while FTIR spectrometry showed that DTPA penta-ethyl ester and excipients did not react with each other during formation of the solid dispersion.. Dissolution testing showed that the optimized solid dispersion exhibited a prolonged release profile, which could potentially result in a sustained delivery of DTPA penta-ethyl to enhance bioavailability. In conclusion, DTPA penta-ethyl ester was successfully incorporated into a solid matrix with high drug loading and improved stability compared to prodrug alone. PMID:24047113

Understanding the Patient Experience with Carcinoid Syndrome: Exit Interviews from a Randomized, Placebo-controlled Study of Telotristat Ethyl.

PubMed

Anthony, Lowell; Ervin, Claire; Lapuerta, Pablo; Kulke, Matthew H; Kunz, Pamela; Bergsland, Emily; Hörsch, Dieter; Metz, David C; Pasieka, Janice; Pavlakis, Nick; Pavel, Marianne; Caplin, Martyn; Öberg, Kjell; Ramage, John; Evans, Emily; Yang, Qi Melissa; Jackson, Shanna; Arnold, Karie; Law, Linda; DiBenedetti, Dana B

2017-11-01

Telotristat ethyl, an oral tryptophan hydroxylase inhibitor, is intended to treat carcinoid syndrome by reducing serotonin production. Telotristat ethyl was evaluated in TELESTAR, a Phase III study for patients who had carcinoid syndrome with at least 4 bowel movements (BMs) per day and who were receiving somatostatin analogue therapy. This interview substudy was conducted to provide insight into the patient experience in TELESTAR and to help understand whether reductions in BM frequency (the primary end point) and other symptoms were clinically meaningful. Participating sites were asked to invite (before randomization) all eligible patients to telephone interviews scheduled at the end of the double-blind treatment period. Patients and interviewers were blinded to treatment. All 35 interviewed participants reported diarrhea and/or excessive BMs at baseline. Patients reported that these symptoms negatively affected emotional, social, physical, and occupational well-being. Prespecified criteria for treatment response (achieving ≥30% reduction in BM frequency for at least 50% of the days) were met by 8 of 26 patients taking telotristat ethyl and 1 of 9 patients taking placebo. All 8 patients taking telotristat ethyl described clinically meaningful reductions in BM frequency and were very satisfied with the ability of the study drug to control their carcinoid syndrome symptoms. Overall, reports of being very satisfied were observed in 12 patients taking telotristat ethyl and 0 taking placebo. Patient interviews revealed that TELESTAR patients, at baseline, were significantly affected by their high BM frequency. Patient reports of their clinical trial experience supported the significance of the primary end point and clinical responder analysis in TELESTAR, helping identify and understand clinically meaningful change produced by telotristat ethyl. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The Herschel Virgo Cluster Survey. XIII. Dust in early-type galaxies

NASA Astrophysics Data System (ADS)

di Serego Alighieri, S.; Bianchi, S.; Pappalardo, C.; Zibetti, S.; Auld, R.; Baes, M.; Bendo, G.; Corbelli, E.; Davies, J. I.; Davis, T.; De Looze, I.; Fritz, J.; Gavazzi, G.; Giovanardi, C.; Grossi, M.; Hunt, L. K.; Magrini, L.; Pierini, D.; Xilouris, E. M.

2013-04-01

Aims: We study the dust content of a large optical input sample of 910 early-type galaxies (ETG) in the Virgo cluster, also extending to the dwarf ETG, and examine the results in relation to those on the other cold ISM components. Methods: We have searched for far-infrared emission in all galaxies in the input sample using the 250 μm image of the Herschel Virgo Cluster Survey (HeViCS). This image covers a large fraction of the cluster with an area of ~55 square degrees. For the detected ETG we measured fluxes in five bands from 100 to 500 μm, and estimated the dust mass and temperature with modified black-body fits. Results: Dust is detected above the completeness limit of 25.4 mJy at 250 μm in 46 ETG, 43 of which are in the optically complete part of the input sample. In addition, dust is present at fainter levels in another six ETG. We detect dust in the four ETG with synchrotron emission, including M 87. Dust appears to be much more concentrated than stars and more luminous ETG have higher dust temperatures. Considering only the optically complete input sample and correcting for the contamination by background galaxies, dust detection rates down to the 25.4 mJy limit are 17% for ellipticals, about 40% for lenticulars (S0 + S0a), and around 3% for dwarf ETG. Dust mass does not correlate clearly with stellar mass and is often much greater than expected for a passive galaxy in a closed-box model. The dust-to-stars mass ratio anticorrelates with galaxy luminosity, and for some dwarf ETG reaches values as high as for dusty late-type galaxies. In the Virgo cluster slow rotators appear more likely to contain dust than fast ones. Comparing the dust results with those on Hi there are only eight ETG detected both in dust and in Hi in the HeViCS area; 39 have dust but only an upper limit on Hi, and eight have Hi but only an upper limit on dust. The locations of these galaxies in the cluster are different, with the dusty ETG concentrated in the densest regions, while the

NEWLY QUENCHED GALAXIES AS THE CAUSE FOR THE APPARENT EVOLUTION IN AVERAGE SIZE OF THE POPULATION

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carollo, C. M.; Bschorr, T. J.; Lilly, S. J.

2013-08-20

We use the large COSMOS sample of galaxies to study in an internally self-consistent way the change in the number densities of quenched early-type galaxies (Q-ETGs) of a given size over the redshift interval 0.2 < z < 1 in order to study the claimed size evolution of these galaxies. In a stellar mass bin at 10{sup 10.5} < M{sub galaxy} < 10{sup 11} M{sub Sun }, we see no change in the number density of compact Q-ETGs over this redshift range, while in a higher mass bin at >10{sup 11} M{sub Sun }, where we would expect merging tomore » be more significant, we find a small decrease, by {approx}30%. In both mass bins, the increase of the median sizes of Q-ETGs with time is primarily caused by the addition to the size function of larger and more diffuse Q-ETGs. At all masses, compact Q-ETGs become systematically redder toward later epochs, with a (U - V) color difference which is consistent with a passive evolution of their stellar populations, indicating that they are a stable population that does not appreciably evolve in size. We find furthermore, at all epochs, that the larger Q-ETGs (at least in the lower mass bin) have average rest-frame colors that are systematically bluer than those of the more compact Q-ETGs, suggesting that the former are indeed younger than the latter. The idea that new, large, Q-ETGs are responsible for the observed growth in the median size of the population at a given mass is also supported by analysis of the sizes and number of the star-forming galaxies that are expected to be the progenitors of the new Q-ETGs over the same period. In the low mass bin, the new Q-ETGs appear to have {approx}30% smaller half-light radii than their star-forming progenitors. This is likely due to the fading of their disks after they cease star formation. Comparison with higher redshifts shows that the median size of newly quenched galaxies roughly scales, at constant mass, as (1 + z){sup -1}. We conclude that the dominant cause of the size evolution seen

Synthesis and molecular docking against dihydrofolate reductase of novel pyridin-N-ethyl-N-methylbenzenesulfonamides as efficient anticancer and antimicrobial agents

NASA Astrophysics Data System (ADS)

Debbabi, Khaled F.; Bashandy, Mahmoud S.; Al-Harbi, Sami A.; Aljuhani, Enas H.; Al-Saidi, Hamed M.

2017-03-01

This article describes the synthesis of some novel sulfonamides having biologically active pyridine 21-28. Starting with 4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)-N-ethyl-N-methylbenzenesulfonamide (2), which was prepared from condensation of acetophenone derivative 1 with 2-cyanoacetohydrazide. Interaction of compound 2 with different aldehydes namely 4-fluorobenzaldehyde, 4-hydroxybenzaldehyde and 4-N,N-dimethylbenzaldehyde afforded the corresponding hydrazono-ethyl-N-ethyl-N-methylbenzene sulfonamides 18-20 respectively, which when reacted with malononitrile and ethyl cyanoacetate afforded compounds 21-26 respectively. These compounds 21-26 can be prepared by another reaction route by interaction of compounds 2 with arylidine malononitrile and arylidine ethyl cyanoacetate in refluxing dioxane in the presence of trimethylamine as catalyst. Interaction of compound 2 with malononitrile and ethyl cyanoacetate afforded oxopyridine derivatives 27 and 28 respectively. All the new prepared compounds were evaluated for their antitumor activities against the cell lines MCF-7 in comparison with the reference drug Doxorubicin using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) colorimetric assay. Compounds 25, 21, 23 with SI values of 9.72, 9.71, 8.81 respectively, exhibited better activity than doxorubicin (Dox) as a reference drug with SI value of 8.49. In addition, compounds 25, 27 and 22 exhibited anti-bacterial activity against gram-negative bacteria (Klebsiella pneumoniae) with inhibition zones 22.6, 20.3 and 19.3 mm respectively, which were more active than gentamicin as a reference drug with inhibition zone 17.3 mm. Molecular Operating Environment (MOE) performed virtual screening using molecular docking studies of the synthesized compounds. The results indicated that some synthesized compounds suitable inhibitor against dihydrofolate reductase (DHFR) enzyme (PDB SD: 4DFR) with further modification.

Vasodilatory effects and underlying mechanisms of the ethyl acetate extracts from Gastrodia elata.

PubMed

Dai, Rong; Wang, Ting; Si, Xiaoqin; Jia, Yuanyuan; Wang, Lili; Yuan, Yan; Lin, Qing; Yang, Cui

2017-05-01

The objective of this study was to assess the ethyl acetate extracts of Gastrodia elata Blume (GEB) on vascular tone and the mechanisms involved. GEB was extracted with 95% EtOH followed by a further extraction with ethyl acetate. The effects of GEB and its ingredients on the isometric tensions of the aortic rings from rats were measured. The ethyl acetate extract of GEB induced a vasodilatory effect on rat aorta, which was partially dependent on endothelium. Four chemical compounds isolated from GEB were identified as 3,4-dihydroxybenzaldehyde (DB), 4-hydroxybenzaldehyde (HB), 4-methoxybenzyl alcohol (MA), and 4,4'-dihydroxydiphenyl methane (DM), respectively. All of these compounds induced vasodilatations, which were dependent on the endothelium to different degrees. After pretreatment with N ω -nitro-l-arginine methyl ester, indomethacin, or methylene blue, the vasodilatations induced by DB, HB, and MA were significantly decreased. In addition, the contractions of the rat aortic rings due to Ca 2+ influx and intracellular Ca 2+ release were also inhibited by DM. Furthermore, the administration of DB significantly enhanced the productions of nitric oxide (NO) and the activities of the endothelial NO synthase in aorta and in endothelial cells. Thus, GEB may play an important role in the amelioration of hypertension by modulating vascular tones.

Experimental studies of Debye-like process and structural relaxation in mixtures of 2-ethyl-1-hexanol and 2-ethyl-1-hexyl bromide

NASA Astrophysics Data System (ADS)

Preuß, M.; Gainaru, C.; Hecksher, T.; Bauer, S.; Dyre, J. C.; Richert, R.; Böhmer, R.

2012-10-01

Binary solutions of 2-ethyl-1-hexanol (2E1H) with 2-ethyl-1-hexyl bromide (2E1Br) are investigated by means of dielectric, shear mechanical, near-infrared, and solvation spectroscopy as well as dielectrically monitored physical aging. For moderately diluted 2E1H the slow Debye-like process, which dominates the dielectric spectra of the neat monohydroxy alcohol, separates significantly from the α-relaxation. For example, the separation in equimolar mixtures amounts to four decades in frequency. This situation of highly resolved processes allows one to demonstrate unambiguously that physical aging is governed by the α-process, but even under these ideal conditions the Debye process remains undetectable in shear mechanical experiments. Furthermore, the solvation experiments show that under constant charge conditions the microscopic polarization fluctuations take place on the time scale of the structural process. The hydrogen-bond populations monitored via near-infrared spectroscopy indicate the presence of a critical alcohol concentration, xc ≈ 0.5-0.6, thereby confirming the dielectric data. In the pure bromide a slow dielectric process of reduced intensity is present in addition to the main relaxation. This is taken as a sign of intermolecular cooperativity probably mediated via halogen bonds.

Direct measurement of Bisphenol A (BPA), BPA glucuronide and BPA sulfate in a diverse and low-income population of pregnant women reveals high exposure, with potential implications for previous exposure estimates: a cross-sectional study.

PubMed

Gerona, Roy R; Pan, Janet; Zota, Ami R; Schwartz, Jackie M; Friesen, Matthew; Taylor, Julia A; Hunt, Patricia A; Woodruff, Tracey J

2016-04-12

Bisphenol A (BPA) is a ubiquitous, endocrine-disrupting environmental contaminant that increases risk of some adverse developmental effects. Thus, it is important to characterize BPA levels, metabolic fate and sources of exposure in pregnant women. We used an improved liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytic method to directly and simultaneously measure unconjugated BPA (uBPA), BPA glucuronide and BPA sulfate in the urine of a population of ethnically and racially diverse, and predominately low-income pregnant women (n = 112) in their second trimester. We also administered a questionnaire on dietary and non-dietary sources of exposure to BPA. We found universal and high exposure to uBPA and its metabolites: median concentrations were 0.25, 4.67, and 0.31 μg/g creatinine for uBPA, BPA glucuronide, and BPA sulfate, respectively. The median Total BPA (uBPA + BPA in glucuronide and sulfate forms) level was more than twice that measured in U.S. pregnant women in NHANES 2005-2006, while 30 % of the women had Total BPA levels above the 95th percentile. On average, Total BPA consisted of 71 % BPA in glucuronide form, 15 % BPA in sulfate form and 14 % uBPA, however the proportion of BPA in sulfate form increased and the proportion of uBPA decreased with Total BPA levels. Occupational and non-occupational contact with paper receipts was positively associated with BPA in conjugated (glucuronidated + sulfated) form after adjustment for demographic characteristics. Recent consumption of foods and beverages likely to be contaminated with BPA was infrequent among participants and we did not observe any positive associations with BPA analyte levels. The high levels of BPA analytes found in our study population may be attributable to the low-income status of the majority of participants and/or our direct analytic method, which yields a more complete evaluation of BPA exposure. We observed near-universal exposure to BPA among pregnant women, as

Colonization on Cucumber Root and Enhancement of Chlorimuron-ethyl Degradation in the Rhizosphere by Hansschlegelia zhihuaiae S113 and Root Exudates.

PubMed

Zhang, Hao; Chen, Feng; Zhao, Hua-Zhu; Lu, Jia-Sen; Zhao, Meng-Jun; Hong, Qing; Huang, Xing

2018-05-09

The colonization of Hansschlegelia zhihuaiae S113 and its degradation of the herbicide chlorimuron-ethyl in the cucumber rhizosphere was investigated. The results reveal that S113 colonized the cucumber roots (2.14 × 10 5 cells per gram of roots) and were able to survive in the rhizosphere (maintained for 20 d). The root exudates promoted colonization on roots and increased the degradation of chlorimuron-ethyl by S113. Five organic acids in cucumber-root exudates were detected and identified by HPLC. Citric acid and fumaric acid significantly stimulated S113 colonization on cucumber roots, with 18.4 and 15.5% increases, respectively, compared with the control. After irrigation with an S113 solution for 10 days, chlorimuron-ethyl could not be detected in the roots, seedlings, or rhizosphere soil, which allowed for improved cucumber growth. Therefore, the degradation mechanism of chlorimuron-ethyl residues by S113 in the rhizosphere could be applied in situ for the bioremediation of chlorimuron-ethyl contaminated soil to ensure crop safety.

Increase of medium-chain fatty acid ethyl ester content in mixed H. uvarum/S. cerevisiae fermentation leads to wine fruity aroma enhancement.