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Sample records for 1,3,7-trimethylxanthine

  1. Aggregation of 1,3,7-trimethylxanthine with methylene blue in aqueous solution

    NASA Astrophysics Data System (ADS)

    Baranovskii, S. F.; Bolotin, P. A.; Evstigneev, M. P.

    2006-03-01

    We have studied self-association of aromatic molecules of the thiazine dye methylene blue in aqueous solution, using a dimer model. We have determined the dimerization equilibrium constant for the dye molecules KD = 3900 ± 800 M-1 at T = 293 K. We have decomposed the experimental spectrum into dimer and monomer components. Using the ratio of the molar absorption coefficients for two absorption bands of the dimer spectrum, we obtained the “average” value of the angle between the electronic transition moments of the molecules in the dimers, α = 48°. We have studied heteroassociation of methylene blue (MB) and 1,3,7-trimethylxanthine (caffeine) molecules in aqueous solution. We have calculated the heteroassociation constant as 200 ± 34 M-1. We conclude that heteroassociation of methylene blue and caffeine molecules leads to a lower effective dye concentration in solution, which hypothetically may affect its biological activity. We have determined the values of the Gibbs free energy, the enthalpy, and the entropy for dimerization of methylene blue molecules: ΔG293 = -(20 ± 3) kJ/mol, ΔH = -(25 ± 9) kJ/mol, Δ S293 = -(17 ± 6) J/mol·K; and for methylene blue-caffeine heteroassociation: ΔG293 = -(13 ± 3) kJ/mol, ΔH = -(14 ± 10) kJ/mol, ΔS293 = -(2.4 ± 0.2) J/mol·K, respectively. We have shown that the methylene blue aggregates and the heteroassociates with caffeine are predominantly stabilized by dispersion interactions between the chromophore molecules in the associates.

  2. Absorption spectra of isomeric OH adducts of 1,3,7-trimethylxanthine

    SciTech Connect

    Vinchurkar, M.S.; Rao, B.S.M.; Mohan, H.; Mittal, J.P.; Schmidt, K.H.; Jonah, C.D.

    1997-04-17

    The reactions of OH{sup .}, O{sup .-}, and SO{sub 4}{sup .-} with 1,3,7-trimethylxanthine (caffeine) were studied by pulse radiolysis with optical and conductance detection techniques. The absorption spectra of transients formed in OH{sup .} reaction in neutral solutions exhibited peaks at 310 and 335 nm, as well as a broad absorption maximum at 500 nm, which decayed by first-order kinetics. The rate (k = (4.0 {+-} 0.5) x 10{sup 4} s{sup -1}) of this decay is independent of pH in the range 4-9 and is in agreement with that determined from the conductance detection (k = 4 x 10{sup 4} s{sup -1}). The spectrum in acidic solutions has only a broad peak around 330 nm with no absorption in the higher wavelength region. The intermediates formed in reaction of O{sup .-} absorb around 310 and at 350 nm, and the first-order decay at the latter wavelength was not seen. The OH radical adds to C-4 (X-40H{sup .}) and C-8 (X-80H{sup .}) positions of caffeine in the ratio 1:2 as determined from the redox titration and conductivity measurements. H abstraction from the methyl group is an additional reaction channel in O{sup .-} reaction. Dehydroxylation of the X-40H{sup .} adduct occurs, whereas the X-80H{sup .} adduct does not undergo ring opening. The spectrum obtained for OH{sup .} reaction in oxygenated solutions is similar to that observed in SO{sub 4}{sup .-} reaction in basic solutions. 25 refs., 5 figs., 1 tab.

  3. Caffeine (1, 3, 7-trimethylxanthine) in foods: a comprehensive review on consumption, functionality, safety, and regulatory matters.

    PubMed

    Heckman, Melanie A; Weil, Jorge; Gonzalez de Mejia, Elvira

    2010-04-01

    Caffeine ranks as one of the top most commonly consumed dietary ingredients throughout the world. It is naturally found in coffee beans, cacao beans, kola nuts, guarana berries, and tea leaves including yerba mate. The total daily intake, as well as the major source of caffeine varies globally; however, coffee and tea are the 2 most prominent sources. Soft drinks are also a common source of caffeine as well as energy drinks, a category of functional beverages. Moderate caffeine consumption is considered safe and its use as a food ingredient has been approved, within certain limits, by numerous regulatory agencies around the world. Performance benefits attributed to caffeine include physical endurance, reduction of fatigue, and enhancing mental alertness and concentration. Caffeine has also been recently linked to weight loss and consequent reduction of the overall risks for developing the metabolic syndrome. However, the caloric contribution of caffeine-sweetened beverages needs to be considered in the overall energy balance. Despite all these benefits the potential negative effects of excessive caffeine intake should also be considered, particularly in children and pregnant women.

  4. Biosynthesis of caffeine underlying the diversity of motif B' methyltransferase.

    PubMed

    Nakayama, Fumiyo; Mizuno, Kouichi; Kato, Misako

    2015-05-01

    Caffeine (1,3,7-trimethylxanthine) and theobromine (3,7-dimethylxanthine) are well-known purine alkaloids in Camellia, Coffea, Cola, Paullinia, Ilex, and Theobroma spp. The caffeine biosynthetic pathway depends on the substrate specificity of N-methyltransferases, which are members of the motif B' methyl-transferase family. The caffeine biosynthetic pathways in purine alkaloid-containing plants might have evolved in parallel with one another, consistent with different catalytic properties of the enzymes involved in these pathways.

  5. Autopsy report for a caffeine intoxication case and review of the current literature

    PubMed Central

    Yamamoto, Takuma; Yoshizawa, Katsuhiko; Kubo, Shin-ichi; Emoto, Yuko; Hara, Kenji; Waters, Brian; Umehara, Takahiro; Murase, Takehiko; Ikematsu, Kazuya

    2014-01-01

    Caffeine (1,3,7-trimethylxanthine) is a popular mild central nervous system stimulant found in the leaves, seeds and fruits of various plants and in foodstuffs such as coffee, tea, and chocolate, among others. Caffeine is widely used and is not associated with severe side effects when consumed at relatively low doses. Although rarely observed, overdoses can occur. However, only a few fatal caffeine intoxication cases have been reported in the literature. Herein, we report the pathological examination results and information on caffeine concentrations in the blood, urine and main organs in a fatal caffeine intoxication case. Even though high caffeine concentrations were found in the systemic organs, no caffeine-related pathological changes were detected. PMID:26023259

  6. Removal of caffeine from industrial wastewater using Trichosporon asahii.

    PubMed

    Lakshmi, V; Das, Nilanjana

    2013-07-01

    Caffeine (1,3,7-trimethylxanthine), a natural alkaloid present mainly in tea and coffee products has been suggested as an environmental pollutant. Decaffeination is an important process for the removal of caffeine from coffee industrial wastes. In the present study, caffeine removal (through degradation) by yeast isolate, Trichosporon asahii immobilized on various conventional matrices (sodium alginate, carboxymethyl cellulose, chitosan, agar and agarose) was investigated using the method of entrapment. The biofilm forming ability of T. asahii was monitored by atomic force microscopy and scanning electron microscopy. Exopolysaccharide produced by T asahii biofilm was characterized by FT-IR spectroscopy and HPLC analysis. Caffeine removal from coffee processing industrial effluent was found to be 75 and 80 % by alginate immobilized yeast and yeast biofilm formed on gravels over a period of 48 hr in batch mode. Effectiveness of the process was also tested involving the continuous--flow column studies.

  7. Single Ryanodine Receptor Channel Basis of Caffeine's Action on Ca2+ Sparks

    PubMed Central

    Porta, Maura; Zima, Aleksey V.; Nani, Alma; Diaz-Sylvester, Paula L.; Copello, Julio A.; Ramos-Franco, Josefina; Blatter, Lothar A.; Fill, Michael

    2011-01-01

    Caffeine (1, 3, 7-trimethylxanthine) is a widely used pharmacological agonist of the cardiac ryanodine receptor (RyR2) Ca2+ release channel. It is also a well-known stimulant that can produce adverse side effects, including arrhythmias. Here, the action of caffeine on single RyR2 channels in bilayers and Ca2+ sparks in permeabilized ventricular cardiomyocytes is defined. Single RyR2 caffeine activation depended on the free Ca2+ level on both sides of the channel. Cytosolic Ca2+ enhanced RyR2 caffeine affinity, whereas luminal Ca2+ essentially scaled maximal caffeine activation. Caffeine activated single RyR2 channels in diastolic quasi-cell-like solutions (cytosolic MgATP, pCa 7) with an EC50 of 9.0 ± 0.4 mM. Low-dose caffeine (0.15 mM) increased Ca2+ spark frequency ∼75% and single RyR2 opening frequency ∼150%. This implies that not all spontaneous RyR2 openings during diastole are associated with Ca2+ sparks. Assuming that only the longest openings evoke sparks, our data suggest that a spark may result only when a spontaneous single RyR2 opening lasts >6 ms. PMID:21320437

  8. Association of riboflavin, caffeine, and sodium salicylate in aqueous solution

    NASA Astrophysics Data System (ADS)

    Baranovskii, S. F.; Bolotin, P. A.

    2007-03-01

    We have used UV and visible spectrophotometry to study self-association of aromatic riboflavin molecules (RFN, vitamin B2, 7,8-dimethyl-10-N-(1'-D-ribityl)isoalloxazine) in aqueous solution (pH 6.86) at T = 298 K, using a dimer model. We have determined the equilibrium dimerization constant for riboflavin, KdB = 125 ± 40 M-1. We have studied heteroassociation in the system of molecules of 7,8-dimethyl-10-ribitylisoalloxazine with 1,3,7-trimethylxanthine (caffeine) and sodium salicylate (NAS) in aqueous solution (pH 6.86; T = 298 K). We have determined the heteroassociation constants for RFN-NAS and RFN-caffeine molecules in the absence and in the presence of urea in solutions using a modified Benesi-Hildebrand equation: 25 ± 4, 17 ± 3, and 74 ± 11, 53 ± 7 M-1 respectively. We have determined the dimerization constants for NAS (2.7 ± 0.5 M-1) and caffeine (17.0 ± 1.5 M-1). We conclude that heteroassociation of the aromatic molecules leads to a lower effective riboflavin concentration in solution, and the presence of urea in mixed solutions leads to an decrease in the complexation constants for the RFN-NAS and RFN-caffeine systems.

  9. Mutant quantity and quality in mammalian cells (AL) exposed to cesium-137 gamma radiation: effect of caffeine

    NASA Technical Reports Server (NTRS)

    McGuinness, S. M.; Shibuya, M. L.; Ueno, A. M.; Vannais, D. B.; Waldren, C. A.; Chatterjee, A. (Principal Investigator)

    1995-01-01

    We examined the effect of caffeine (1,3,7-trimethylxanthine) on the quantity and quality of mutations in cultured mammalian AL human-hamster hybrid cells exposed to 137Cs gamma radiation. At a dose (1.5 mg/ml for 16 h) that reduced the plating efficiency (PE) by 20%, caffeine was not itself a significant mutagen, but it increased by approximately twofold the slope of the dose-response curve for induction of S1- mutants by 137Cs gamma radiation. Molecular analysis of 235 S1- mutants using a series of DNA probes mapped to the human chromosome 11 in the AL hybrid cells revealed that 73 to 85% of the mutations in unexposed cells and in cells treated with caffeine alone, 137Cs gamma rays alone or 137Cs gamma rays plus caffeine were large deletions involving millions of base pairs of DNA. Most of these deletions were contiguous with the region of the MIC1 gene at 11p13 that encodes the S1 cell surface antigen. In other mutants that had suffered multiple marker loss, the deletions were intermittent along chromosome 11. These "complex" mutations were rare for 137Cs gamma irradiation (1/63 = 1.5%) but relatively prevalent (23-50%) for other exposure conditions. Thus caffeine appears to alter both the quantity and quality of mutations induced by 137Cs gamma irradiation.

  10. Evaluation of cardiovascular effects of caffeine using telemetric monitoring in the conscious rat.

    PubMed

    Ilbäck, Nils-Gunnar; Siller, Max; Stålhandske, Torbjörn

    2007-05-01

    Caffeine (1,3,7 trimethylxanthine) affects the cardiovascular system, with potential toxic effects ranging from a moderate increase in heart rate to more severe cardiac arrhythmias. Telemetry transmitters were implanted in Wistar rats in the peritoneal cavity with a pressure catheter in the aorta and electrodes for electrocardiogram (ECG) recording subcutaneously. After a single oral administration of saline, each rat was administered single oral doses of 5, 15 and 45 mg/kg b.w. of caffeine. Caffeine was found to induce, to various degrees, a dose-dependent early increase in spontaneous physical activity, heart rate, dp/dt and systolic-diastolic blood pressure. No arrhythmias or visual changes were observed in the ECG complex. High doses induced more strong responses and of longer duration. The increase in systolic blood pressure at the median dose remained in the rats until 20 h after administration. However, the highest dose of caffeine (45 mg/kg b.w.) induced a biphasic response, with an early and pronounced increase in body temperature, spontaneous physical activity, systolic and diastolic blood pressure that later decreased, except for the systolic blood pressure. The results show that the dose level for long-lasting signs of intoxication to develop in the rat, in terms of effects on spontaneous physical activity, body temperature and cardiovascular function, was reached after a single oral dose of caffeine at 45 mg/kg b.w.

  11. Selected C8 two-chain linkers enhance the adenosine A1/A2A receptor affinity and selectivity of caffeine.

    PubMed

    van der Walt, M M; Terre'Blanche, G

    2017-01-05

    Recent research exploring C8 substitution on the caffeine core identified 8-(2-phenylethyl)-1,3,7-trimethylxanthine as a non-selective adenosine receptor antagonist. To elaborate further, we included various C8 two-chain-length linkers to enhance adenosine receptor affinity. The results indicated that the unsubstituted benzyloxy linker (1e A1Ki = 1.52 μM) displayed the highest affinity for the A1 adenosine receptor and the para-chloro-substituted phenoxymethyl (1d A2AKi = 1.33 μM) linker the best A2A adenosine receptor affinity. The position of the oxygen revealed that the phenoxymethyl linker favoured A1 adenosine receptor selectivity over the benzyloxy linker and, by introducing a para-chloro substituent, A2A adenosine receptor selectivity was obtained. Selected compounds (1c, 1e) behaved as A1 adenosine receptor antagonists in GTP shift assays and therefore represent selective and non-selective A1 and A2A adenosine receptor antagonists that may have potential for treating neurological disorders.

  12. Caffeine acutely activates 5'adenosine monophosphate-activated protein kinase and increases insulin-independent glucose transport in rat skeletal muscles.

    PubMed

    Egawa, Tatsuro; Hamada, Taku; Kameda, Naoko; Karaike, Kouhei; Ma, Xiao; Masuda, Shinya; Iwanaka, Nobumasa; Hayashi, Tatsuya

    2009-11-01

    Caffeine (1,3,7-trimethylxanthine) has been implicated in the regulation of glucose and lipid metabolism including actions such as insulin-independent glucose transport, glucose transporter 4 expression, and fatty acid utilization in skeletal muscle. These effects are similar to the exercise-induced and 5'adenosine monophosphate-activated protein kinase (AMPK)-mediated metabolic changes in skeletal muscle, suggesting that caffeine is involved in the regulation of muscle metabolism through AMPK activation. We explored whether caffeine acts on skeletal muscle to stimulate AMPK. Incubation of rat epitrochlearis and soleus muscles with Krebs buffer containing caffeine (> or =3 mmol/L, > or =15 minutes) increased the phosphorylation of AMPKalpha Thr(172), an essential step for full kinase activation, and acetyl-coenzyme A carboxylase Ser(79), a downstream target of AMPK, in dose- and time-dependent manners. Analysis of isoform-specific AMPK activity revealed that both AMPKalpha1 and alpha2 activities increased significantly. This enzyme activation was associated with a reduction in phosphocreatine content and an increased rate of 3-O-methyl-d-glucose transport activity in the absence of insulin. These results suggest that caffeine has similar actions to exercise by acutely stimulating skeletal muscle AMPK activity and insulin-independent glucose transport with a reduction of the intracellular energy status.

  13. Production of Recombinant Caffeine Synthase from Guarana (Paullinia cupana var. sorbilis) in Escherichia coli.

    PubMed

    Schimpl, Flávia Camila; Kiyota, Eduardo; Mazzafera, Paulo

    2016-01-01

    Caffeine synthase (CS) is a methyltransferase responsible for the last two steps of the caffeine biosynthesis pathway in plants. CS is able to convert 7-methylxanthine to theobromine (3,7-dimethylxanthine) and theobromine to caffeine (1,3,7-trimethylxanthine) using S-adenosyl-L-methionine as the methyl donor in both reactions. The production of a recombinant protein is an important tool for the characterization of enzymes, particularly when the enzyme has affinity for different substrates. Guarana has the highest caffeine content among more than a hundred plant species that contain this alkaloid. Different from other plants, in which CS has a higher affinity for paraxanthine (1,7-dimethylxanthine), caffeine synthase from guarana (PcCS) has a higher affinity for theobromine. Here, we describe a method to produce a recombinant caffeine synthase from guarana in Escherichia coli and its purification by affinity chromatography. The recombinant protein retains activity and can be used in enzymatic assays and other biochemical characterization studies.

  14. Single ryanodine receptor channel basis of caffeine's action on Ca2+ sparks.

    PubMed

    Porta, Maura; Zima, Aleksey V; Nani, Alma; Diaz-Sylvester, Paula L; Copello, Julio A; Ramos-Franco, Josefina; Blatter, Lothar A; Fill, Michael

    2011-02-16

    Caffeine (1, 3, 7-trimethylxanthine) is a widely used pharmacological agonist of the cardiac ryanodine receptor (RyR2) Ca(2+) release channel. It is also a well-known stimulant that can produce adverse side effects, including arrhythmias. Here, the action of caffeine on single RyR2 channels in bilayers and Ca(2+) sparks in permeabilized ventricular cardiomyocytes is defined. Single RyR2 caffeine activation depended on the free Ca(2+) level on both sides of the channel. Cytosolic Ca(2+) enhanced RyR2 caffeine affinity, whereas luminal Ca(2+) essentially scaled maximal caffeine activation. Caffeine activated single RyR2 channels in diastolic quasi-cell-like solutions (cytosolic MgATP, pCa 7) with an EC(50) of 9.0 ± 0.4 mM. Low-dose caffeine (0.15 mM) increased Ca(2+) spark frequency ∼75% and single RyR2 opening frequency ∼150%. This implies that not all spontaneous RyR2 openings during diastole are associated with Ca(2+) sparks. Assuming that only the longest openings evoke sparks, our data suggest that a spark may result only when a spontaneous single RyR2 opening lasts >6 ms. Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  15. Trace determination of caffeine in surface water samples by liquid chromatography--atmospheric pressure chemical ionization--mass spectrometry (LC-APCI-MS).

    PubMed

    Gardinali, Piero R; Zhao, Xu

    2002-12-01

    A new method based on liquid-liquid extraction (LLE) coupled to reverse phase liquid chromatography and atmospheric pressure chemical ionization mass spectrometry (LC-APCI-MS) has been applied to determine trace amounts of caffeine (1,3,7-trimethylxanthine) in surface water samples from a near coastal ecosystem such as Biscayne Bay, Florida. The rational behind the development of such method will be to evaluate the use of unmetabolized caffeine as a potential dissolved phase tracer of human waste contamination. The method allows for the determination of caffeine at levels as low as 4.0 ng/l (ppt) in both salt and freshwater by extracting and concentrating a 1-1 water sample to a final volume of 500 microl and using HPLC separation coupled to an atmospheric pressure chemical ionization mass spectrometry (APCI-MS) system operated in selected ion monitoring (SIM) for the protonated molecular ions (M + H(+)). Samples from different portions of Biscayne Bay and the Miami River, one of its major tributaries, were analyzed and caffeine was detected in those areas previously identified for consistently exceeding the water quality criteria for fecal coliform bacteria contamination. The caffeine concentration in the samples with positive detection was generally low at levels equal or lower than 41 ng/l. However, there is a marked difference between samples collected in open bay areas and those collected from the Miami River.

  16. Fatal caffeine intoxication: a series of eight cases from 1999 to 2009.

    PubMed

    Banerjee, Priya; Ali, Zabiullah; Levine, Barry; Fowler, David R

    2014-05-01

    Caffeine, 1,3,7-trimethylxanthine, is the most widely consumed legal stimulant. The most potent form is over the counter oral tablets. The estimated average daily adult caffeine consumption is 300 mg. Rarely, serious toxicities such as seizure and cardiac arrhythmias have caused death. Caffeine concentrations of 80 mg/L are considered lethal. Cases investigated over 10 years by the Office of the Chief Medical Examiner for the State of Maryland (OCME) whose cause of death was solely or in combination due to caffeine intoxication were reviewed. A total of eight adult cases were identified consisting of two suicides and six undetermined manners. The average postmortem caffeine concentration was 140.4 mg/L. This is the largest case series reported to date of lethal caffeine intoxication. Large doses of prescription medications and/or over the counter medications were abused. No overdoses were from consumption of caffeine-containing foods. Comprehensive postmortem toxicological testing should test for caffeine to capture these rare deaths.

  17. Caffeine and the kidney: what evidence right now?

    PubMed

    Bolignano, Davide; Coppolino, Giuseppe; Barillà, Antonio; Campo, Susanna; Criseo, Manila; Tripodo, Donatella; Buemi, Michele

    2007-07-01

    Caffeine, or 1, 3, 7-trimethylxanthine, is one of the most frequently consumed active drugs worldwide. Its main mechanisms of action include inhibiting the phosphodiesteratic enzyme and adenosine receptors and activating the ryanodine receptors with several actions on all organs. What effect does caffeine have on the kidney? Is caffeine beneficial or dangerous? A review of the current literature reveals conflicting opinions regarding the prolithiasic effect of this substance, whereas its diuretic action is least disputed and more easily observed. Caffeine may have a toxic or preventive effect in some physiologic or pathologic conditions. Some of these incongruences may depend on several factors, such as dosage, prior chronic exposure, genetic-enzymatic axes, and concomitant drug consumption. While awaiting further insight from forthcoming studies on the issue, we may reach a preliminary conclusion that, as yet, there is no evidence contraindicating the consumption of the equivalent of 3 to 4 cups of coffee per day in healthy or nephropathic subjects. However, particular attention should be paid to the elderly, children, and patients on concomitant treatment with analgesics or diuretics, whereas in subjects with a family or clinical history of calcium lithiasis a moderate caffeine consumption should be associated with an adequate fluid intake. Further in-depth studies are required to investigate whether this beverage is beneficial to patients on hemodialysis.

  18. Automated reference region extraction and population-based input function for brain [11C]TMSX PET image analyses

    PubMed Central

    Rissanen, Eero; Tuisku, Jouni; Luoto, Pauliina; Arponen, Eveliina; Johansson, Jarkko; Oikonen, Vesa; Parkkola, Riitta; Airas, Laura; Rinne, Juha O

    2015-01-01

    [11C]TMSX ([7-N-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine) is a selective adenosine A2A receptor (A2AR) radioligand. In the central nervous system (CNS), A2AR are linked to dopamine D2 receptor function in striatum, but they are also important modulators of inflammation. The golden standard for kinetic modeling of brain [11C]TMSX positron emission tomography (PET) is to obtain arterial input function via arterial blood sampling. However, this method is laborious, prone to errors and unpleasant for study subjects. The aim of this work was to evaluate alternative input function acquisition methods for brain [11C]TMSX PET imaging. First, a noninvasive, automated method for the extraction of gray matter reference region using supervised clustering (SCgm) was developed. Second, a method for obtaining a population-based arterial input function (PBIF) was implemented. These methods were created using data from 28 study subjects (7 healthy controls, 12 multiple sclerosis patients, and 9 patients with Parkinson's disease). The results with PBIF correlated well with original plasma input, and the SCgm yielded similar results compared with cerebellum as a reference region. The clustering method for extracting reference region and the population-based approach for acquiring input for dynamic [11C]TMSX brain PET image analyses appear to be feasible and robust methods, that can be applied in patients with CNS pathology. PMID:25370856

  19. Long-term caffeine consumption reverses tumor-induced suppression of the innate immune response in adult mice.

    PubMed

    Mandal, Anup; Poddar, Mrinal K

    2008-12-01

    Caffeine (1,3,7-trimethylxanthine), the active principle alkaloid of coffee ( Coffea arabica) and tea ( Camellia sinensis) possesses a restraining effect on tumor-induced suppression of the specific immune response in adult mice. The present study deals with the effect of long-term consumption of caffeine in the development of Ehrlich ascites carcinoma (EAC) cells in adult Swiss female mice, in relation to the innate immune response and tumor growth. Although the consumption of caffeine alone for more than 12 consecutive days did not affect the innate immune response parameters, continuation of its treatment following intraperitoneal EAC cell inoculation not only reduced the IN VIVO tumor growth but also reduced/restored the EAC cell-induced suppression of the innate immune response. These results suggest that caffeine may inhibit IN VIVO tumor growth through reduction of the cancer cell-induced suppression of the innate immune response. CNS:central nervous system EAC:Ehrlich ascites carcinoma ESR:erythrocyte sedimentation rate GABA:gamma-aminobutyric acid Hb:hemoglobin HPA:hypothalamic-pituitary-adrenal HPG:hypothalamic-pituitary-gonadal PCV:packed cell volume RBC:red blood cell WBC:white blood cell.

  20. Decaffeination and measurement of caffeine content by addicted Escherichia coli with a refactored N-demethylation operon from Pseudomonas putida CBB5.

    PubMed

    Quandt, Erik M; Hammerling, Michael J; Summers, Ryan M; Otoupal, Peter B; Slater, Ben; Alnahhas, Razan N; Dasgupta, Aurko; Bachman, James L; Subramanian, Mani V; Barrick, Jeffrey E

    2013-06-21

    The widespread use of caffeine (1,3,7-trimethylxanthine) and other methylxanthines in beverages and pharmaceuticals has led to significant environmental pollution. We have developed a portable caffeine degradation operon by refactoring the alkylxanthine degradation (Alx) gene cluster from Pseudomonas putida CBB5 to function in Escherichia coli. In the process, we discovered that adding a glutathione S-transferase from Janthinobacterium sp. Marseille was necessary to achieve N 7 -demethylation activity. E. coli cells with the synthetic operon degrade caffeine to the guanine precursor, xanthine. Cells deficient in de novo guanine biosynthesis that contain the refactored operon are ″addicted″ to caffeine: their growth density is limited by the availability of caffeine or other xanthines. We show that the addicted strain can be used as a biosensor to measure the caffeine content of common beverages. The synthetic N-demethylation operon could be useful for reclaiming nutrient-rich byproducts of coffee bean processing and for the cost-effective bioproduction of methylxanthine drugs.

  1. Mutant quantity and quality in mammalian cells (AL) exposed to cesium-137 gamma radiation: effect of caffeine

    NASA Technical Reports Server (NTRS)

    McGuinness, S. M.; Shibuya, M. L.; Ueno, A. M.; Vannais, D. B.; Waldren, C. A.; Chatterjee, A. (Principal Investigator)

    1995-01-01

    We examined the effect of caffeine (1,3,7-trimethylxanthine) on the quantity and quality of mutations in cultured mammalian AL human-hamster hybrid cells exposed to 137Cs gamma radiation. At a dose (1.5 mg/ml for 16 h) that reduced the plating efficiency (PE) by 20%, caffeine was not itself a significant mutagen, but it increased by approximately twofold the slope of the dose-response curve for induction of S1- mutants by 137Cs gamma radiation. Molecular analysis of 235 S1- mutants using a series of DNA probes mapped to the human chromosome 11 in the AL hybrid cells revealed that 73 to 85% of the mutations in unexposed cells and in cells treated with caffeine alone, 137Cs gamma rays alone or 137Cs gamma rays plus caffeine were large deletions involving millions of base pairs of DNA. Most of these deletions were contiguous with the region of the MIC1 gene at 11p13 that encodes the S1 cell surface antigen. In other mutants that had suffered multiple marker loss, the deletions were intermittent along chromosome 11. These "complex" mutations were rare for 137Cs gamma irradiation (1/63 = 1.5%) but relatively prevalent (23-50%) for other exposure conditions. Thus caffeine appears to alter both the quantity and quality of mutations induced by 137Cs gamma irradiation.

  2. Pathogen resistance of transgenic tobacco plants producing caffeine.

    PubMed

    Kim, Yun-Soo; Sano, Hiroshi

    2008-02-01

    Caffeine (1,3,7-trimethylxanthine) is a typical purine alkaloid, and produced by a variety of plants such as coffee and tea. Its physiological function, however, is not completely understood, but chemical defense against pathogens and herbivores, and allelopathic effects against competing plant species have been proposed. Previously, we constructed transgenic tobacco plants, which produced caffeine up to 5 microg per gram fresh weight of leaves, and showed them to repel caterpillars of tobacco cutworms (Spodoptera litura). In the present study, we found that these transgenic plants constitutively expressed defense-related genes encoding pathogenesis-related (PR)-1a and proteinase inhibitor II under non-stressed conditions. We also found that they were highly resistant against pathogens, tobacco mosaic virus and Pseudomonas syringae. Expression of PR-1a and PR-2 was higher in transgenic plants than in wild-type plants during infection. Exogenously applied caffeine to wild-type tobacco leaves exhibited the similar resistant activity. These results suggested that caffeine stimulated endogenous defense system of host plants through directly or indirectly activating gene expression. This assumption is essentially consistent with the idea of chemical defense, in which caffeine may act as one of signaling molecules to activate defense response. It is thus conceivable that the effect of caffeine is bifunctional; direct interference with pest metabolic pathways, and activation of host defense systems.

  3. Monkey liver cytochrome P450 2C9 is involved in caffeine 7-N-demethylation to form theophylline.

    PubMed

    Utoh, Masahiro; Murayama, Norie; Uno, Yasuhiro; Onose, Yui; Hosaka, Shinya; Fujino, Hideki; Shimizu, Makiko; Iwasaki, Kazuhide; Yamazaki, Hiroshi

    2013-12-01

    Caffeine (1,3,7-trimethylxanthine) is a phenotyping substrate for human cytochrome P450 1A2. 3-N-Demethylation of caffeine is the main human metabolic pathway, whereas monkeys extensively mediate the 7-N-demethylation of caffeine to form pharmacological active theophylline. Roles of monkey P450 enzymes in theophylline formation from caffeine were investigated using individual monkey liver microsomes and 14 recombinantly expressed monkey P450 enzymes, and the results were compared with those for human P450 enzymes. Caffeine 7-N-demethylation activity in microsomes from 20 monkey livers was not strongly inhibited by α-naphthoflavone, quinidine or ketoconazole, and was roughly correlated with diclofenac 4'-hydroxylation activities. Monkey P450 2C9 had the highest activity for caffeine 7-N-demethylation. Kinetic analysis revealed that monkey P450 2C9 had a high Vmax/Km value for caffeine 7-N-demethylation, comparable to low Km value for monkey liver microsomes. Caffeine could dock favorably with monkey P450 2C9 modeled for 7-N-demethylation and with human P450 1A2 for 3-N-demethylation. The primary metabolite theophylline was oxidized to 8-hydroxytheophylline in similar ways by liver microsomes and by recombinant P450s in both humans and monkeys. These results collectively suggest a high activity for monkey liver P450 2C9 toward caffeine 7-N-demethylation, whereas, in humans, P450 1A2-mediated caffeine 3-N-demethylation is dominant.

  4. The perspective of caffeine and caffeine derived compounds in therapy.

    PubMed

    Pohanka, M

    2015-01-01

    Caffeine (1,3,7-trimethylxanthine) is a plant secondary metabolite with a significant impact on multiple processes and regulatory pathways in the body. Though major part of the population meets caffeine via coffee, tea or chocolate, it has also an important role in pharmacology and it is used as a supplementary substance in medicaments. Currently, the ability of caffeine to ameliorate some neurodegenerative disorders is proved in some studies. This review describes basic data about caffeine including toxicity, pharmacokinetics, biological mechanism of the action, and metabolism. Beside this, promising applications of caffeine, new medicaments and derivatives are discussed. Relevant papers and inventions are depicted in the manuscript. Caffeine is a pharmacologically promising substance that deserves big consideration in the current research and development. The compound has several reasons to be an object of scientific interest and to be used for pharmacology purposes. Despite an extensive research for a long time, no significantly negative effects on human health were proved hence caffeine can be considered as a completely safe compound. The recent data about amelioration of neurodegenerative and other disorders are promising and deserving more work on the issue. ARTICLE HIGHLIGHTS: Caffeine is a purine alkaloid from plants and it has a broad use in current pharmacology. Caffeine is a competitive antagonist of neurotransmitter adenosine on adenosine receptors. The substance is added as a supplementary to drugs and food.Besides interfering on adenosine receptors, caffeine interacts with acetylcholinesterase, monoamine oxidase, phosphodiesterase, ryanodine receptors and others.Current research is devoted to the role of caffeine in neurodegenerative diseases and immunity alteration. New chemical compounds based on caffeine moiety are prepared (Tab. 4, Fig. 6, Ref. 149).

  5. Molecular and biochemical characterization of caffeine synthase and purine alkaloid concentration in guarana fruit.

    PubMed

    Schimpl, Flávia Camila; Kiyota, Eduardo; Mayer, Juliana Lischka Sampaio; Gonçalves, José Francisco de Carvalho; da Silva, José Ferreira; Mazzafera, Paulo

    2014-09-01

    Guarana seeds have the highest caffeine concentration among plants accumulating purine alkaloids, but in contrast with coffee and tea, practically nothing is known about caffeine metabolism in this Amazonian plant. In this study, the levels of purine alkaloids in tissues of five guarana cultivars were determined. Theobromine was the main alkaloid that accumulated in leaves, stems, inflorescences and pericarps of fruit, while caffeine accumulated in the seeds and reached levels from 3.3% to 5.8%. In all tissues analysed, the alkaloid concentration, whether theobromine or caffeine, was higher in young/immature tissues, then decreasing with plant development/maturation. Caffeine synthase activity was highest in seeds of immature fruit. A nucleotide sequence (PcCS) was assembled with sequences retrieved from the EST database REALGENE using sequences of caffeine synthase from coffee and tea, whose expression was also highest in seeds from immature fruit. The PcCS has 1083bp and the protein sequence has greater similarity and identity with the caffeine synthase from cocoa (BTS1) and tea (TCS1). A recombinant PcCS allowed functional characterization of the enzyme as a bifunctional CS, able to catalyse the methylation of 7-methylxanthine to theobromine (3,7-dimethylxanthine), and theobromine to caffeine (1,3,7-trimethylxanthine), respectively. Among several substrates tested, PcCS showed higher affinity for theobromine, differing from all other caffeine synthases described so far, which have higher affinity for paraxanthine. When compared to previous knowledge on the protein structure of coffee caffeine synthase, the unique substrate affinity of PcCS is probably explained by the amino acid residues found in the active site of the predicted protein.

  6. Mutant quantity and quality in mammalian cells (A{sub L}) exposed to cesium-137 gamma radiation: Effect of caffeine

    SciTech Connect

    McGuinness, S.M.; Shibuya, M.L.; Ueno, A.M.

    1995-06-01

    We examined the effect of caffeine (1,3,7-trimethylxanthine) on the quantity and quality of mutations in cultured mammalian A{sub L} human-hamster hybrid cells exposed to {sup 137}Cs {gamma} radiation. At a dose (1.5 mg/ml for 16 h) that reduced the plating efficiency (PE) by 20%, caffeine was not itself a significant mutagen, but it increased by approximately twofold the slope of the dose-response curve for induction of S1{sup {minus}} mutants by {sup 137}Cs {gamma} radiation. Molecular analysis of 235 S1{sup {minus}} mutants using a series of DNA probes mapped to the human chromosome 11 in the A{sub L} hybrid cells revealed that 73 to 85% of the mutations in unexposed cells and in cells treated with caffeine alone, {sup 137}Cs {gamma} rays alone or {sup 137}Cs {gamma} rays plus caffeine were large deletions involving millions of base pairs of DNA. Most of these deletions were contiguous with the region of the MIC1 gene at 11p13 that encodes the S1 cell surface antigen. In other mutants that had suffered multiple marker loss, the deletions were intermittent along chromosome 11. These {open_quotes}complex{close_quotes} mutations were rare for {sup 137}Cs {gamma} irradiation (1/63 = 1.5%) but relatively prevalent (23-50%) for other exposure conditions. Thus caffeine appears to alter both the quantity and quality of mutations induced by {sup 137}Cs {gamma} irradiation. 62 refs., 3 figs., 3 tabs.

  7. Quantification of theobromine and caffeine in saliva, plasma and urine via liquid chromatography-tandem mass spectrometry: a single analytical protocol applicable to cocoa intervention studies.

    PubMed

    Ptolemy, Adam S; Tzioumis, Emma; Thomke, Arjun; Rifai, Sami; Kellogg, Mark

    2010-02-01

    Targeted analyses of clinically relevant metabolites in human biofluids often require extensive sample preparation (e.g., desalting, protein removal and/or preconcentration) prior to quantitation. In this report, a single ultra-centrifugation based sample pretreatment combined with a designed liquid chromatography-tandem mass spectrometry (LC-MS/MS) protocol provides selective quantification of 3,7-dimethylxanthine (theobromine) and 1,3,7-trimethylxanthine (caffeine) in human saliva, plasma and urine samples. The optimized chromatography permitted elution of both analytes within 1.3 min of the applied gradient. Positive-mode electrospray ionization and a triple quadruple MS/MS instrument operated in multiple reaction mode were used for detection. (13)C(3) isotopically labeled caffeine was included as an internal standard to improve accuracy and precision. Implementing a 20-fold dilution of the isolated low MW biofluid fraction prior to injection effectively minimized the deleterious contributions of all three matrices to quantitation. The assay was linear over a 160-fold concentration range from 2.5 to 400 micromol L(-1) for both theobromine (average R(2) 0.9968) and caffeine (average R(2) 0.9997) respectively. Analyte peak area variations for 2.5 micromol L(-1) caffeine and theobromine in saliva, plasma and urine ranged from 5 and 10% (intra-day, N=10) to 9 and 13% (inter-day, N=25) respectively. The intra- and inter-day precision of theobromine and caffeine elution times were 3 and <1% for all biofluids and concentrations tested. Recoveries for caffeine and theobromine ranged from 114 to 118% and 99 to 105% at concentration levels of 10 and 300 micromol L(-1). This validated protocol also permitted the relative saliva, plasma and urine distribution of both theobromine and caffeine to be quantified following a cocoa intervention.

  8. Caffeine 7-N-demethylation and C-8-oxidation mediated by liver microsomal cytochrome P450 enzymes in common marmosets.

    PubMed

    Uehara, Shotaro; Uno, Yasuhiro; Inoue, Takashi; Suzuki, Takako; Utoh, Masahiro; Sasaki, Erika; Yamazaki, Hiroshi

    2015-10-27

    1. 3-N-Demethylation of caffeine (1,3,7-trimethylxanthine) is mediated by human cytochrome P450 1A2, whereas 7-N-demethylation and C-8-hydroxylation are reportedly catalyzed by monkey P450 2C9 and rat P450 1A2, respectively. 2. Roles of marmoset P450 enzymes in caffeine oxidation were investigated using nine marmoset liver microsomes and 14 recombinantly expressed marmoset P450 enzymes. 3. Predominant caffeine 7-N-demethylation and C-8-hydroxylation activities in marmoset liver microsomes were moderately (r = 0.78, p < 0.05) and highly (r = 0.82, p < 0.01) correlated with midazolam 1'-hydroxylation activities, respectively, while the former was not strongly affected by ketoconazole or α-naphthoflavone. 4. Caffeine C-8-hydroxylation in liver microsomes was inhibited by ketoconazole and activated by α-naphthoflavone, suggesting main involvements of P450 3As. 5. Recombinant marmoset P450 3As had high Vmax/Km values for C-8-hydroxylation, comparable to Km values for marmoset liver microsomes. Marmoset P450 1As efficiently mediated caffeine 3-N-demethylation and C-8-hydroxylation with apparently lower Km values than those of liver microsomes. 6. These results collectively suggest highly active marmoset P450 3A enzymes toward caffeine 8-hydorxylaiton and involvement of multiple P450 isoforms including P450 1A in caffeine 7-N- and 3-N-demethylations in marmoset livers. Marmoset P450s have slightly different properties to human or monkey P450s regarding caffeine metabolic pathways.

  9. Cytochrome P450-dependent metabolism of caffeine in Drosophila melanogaster.

    PubMed

    Coelho, Alexandra; Fraichard, Stephane; Le Goff, Gaëlle; Faure, Philippe; Artur, Yves; Ferveur, Jean-François; Heydel, Jean-Marie

    2015-01-01

    Caffeine (1, 3, 7-trimethylxanthine), an alkaloid produced by plants, has antioxidant and insecticide properties that can affect metabolism and cognition. In vertebrates, the metabolites derived from caffeine have been identified, and their functions have been characterized. However, the metabolites of caffeine in insects remain unknown. Thus, using radiolabelled caffeine, we have identified some of the primary caffeine metabolites produced in the body of Drosophila melanogaster males, including theobromine, paraxanthine and theophylline. In contrast to mammals, theobromine was the predominant metabolite (paraxanthine in humans; theophylline in monkeys; 1, 3, 7-trimethyluric acid in rodents). A transcriptomic screen of Drosophila flies exposed to caffeine revealed the coordinated variation of a large set of genes that encode xenobiotic-metabolizing proteins, including several cytochromes P450s (CYPs) that were highly overexpressed. Flies treated with metyrapone--an inhibitor of CYP enzymes--showed dramatically decreased caffeine metabolism, indicating that CYPs are involved in this process. Using interference RNA genetic silencing, we measured the metabolic and transcriptomic effect of three candidate CYPs. Silencing of CYP6d5 completely abolished theobromine synthesis, whereas CYP6a8 and CYP12d1 silencing induced different consequences on metabolism and gene expression. Therefore, we characterized several metabolic products and some enzymes potentially involved in the degradation of caffeine. In conclusion, this pioneer approach to caffeine metabolism in insects opens novel perspectives for the investigation of the physiological effects of caffeine metabolites. It also indicates that caffeine could be used as a biomarker to evaluate CYP phenotypes in Drosophila and other insects.

  10. Cytochrome P450-Dependent Metabolism of Caffeine in Drosophila melanogaster

    PubMed Central

    Coelho, Alexandra; Fraichard, Stephane; Le Goff, Gaëlle; Faure, Philippe; Artur, Yves; Ferveur, Jean-François; Heydel, Jean-Marie

    2015-01-01

    Caffeine (1, 3, 7-trimethylxanthine), an alkaloid produced by plants, has antioxidant and insecticide properties that can affect metabolism and cognition. In vertebrates, the metabolites derived from caffeine have been identified, and their functions have been characterized. However, the metabolites of caffeine in insects remain unknown. Thus, using radiolabelled caffeine, we have identified some of the primary caffeine metabolites produced in the body of Drosophila melanogaster males, including theobromine, paraxanthine and theophylline. In contrast to mammals, theobromine was the predominant metabolite (paraxanthine in humans; theophylline in monkeys; 1, 3, 7-trimethyluric acid in rodents). A transcriptomic screen of Drosophila flies exposed to caffeine revealed the coordinated variation of a large set of genes that encode xenobiotic-metabolizing proteins, including several cytochromes P450s (CYPs) that were highly overexpressed. Flies treated with metyrapone—an inhibitor of CYP enzymes—showed dramatically decreased caffeine metabolism, indicating that CYPs are involved in this process. Using interference RNA genetic silencing, we measured the metabolic and transcriptomic effect of three candidate CYPs. Silencing of CYP6d5 completely abolished theobromine synthesis, whereas CYP6a8 and CYP12d1 silencing induced different consequences on metabolism and gene expression. Therefore, we characterized several metabolic products and some enzymes potentially involved in the degradation of caffeine. In conclusion, this pioneer approach to caffeine metabolism in insects opens novel perspectives for the investigation of the physiological effects of caffeine metabolites. It also indicates that caffeine could be used as a biomarker to evaluate CYP phenotypes in Drosophila and other insects. PMID:25671424

  11. Molecular Cloning and Functional Characterization of Three Distinct N-Methyltransferases Involved in the Caffeine Biosynthetic Pathway in Coffee Plants1

    PubMed Central

    Uefuji, Hirotaka; Ogita, Shinjiro; Yamaguchi, Yube; Koizumi, Nozomu; Sano, Hiroshi

    2003-01-01

    Caffeine is synthesized from xanthosine through N-methylation and ribose removal steps. In the present study, three types of cDNAs encoding N-methyltransferases were isolated from immature fruits of coffee (Coffea arabica) plants, and designated as CaXMT1, CaMXMT2, and CaDXMT1, respectively. The bacterially expressed encoded proteins were characterized for their catalytic properties. CaXMT1 catalyzed formation of 7-methylxanthosine from xanthosine with a Km value of 78 μm, CaMXMT2 catalyzed formation of 3,7-dimethylxanthine (theobromine) from 7-methylxanthine with a Km of 251 μm, and CaDXMT1 catalyzed formation of 1,3,7-trimethylxanthine (caffeine) from 3,7-dimethylxanthine with a Km of 1,222 μm. The crude extract of Escherichia coli was found to catalyze removal of the ribose moiety from 7-methylxanthosine, leading to the production of 7-methylxanthine. As a consequence, when all three recombinant proteins and E. coli extract were combined, xanthosine was successfully converted into caffeine in vitro. Transcripts for CaDXMT1 were predominantly found to accumulate in immature fruits, whereas those for CaXMT1 and CaMXMT2 were more broadly detected in sites encompassing the leaves, floral buds, and immature fruits. These results suggest that the presently identified three N-methyltransferases participate in caffeine biosynthesis in coffee plants and substantiate the proposed caffeine biosynthetic pathway: xanthosine → 7-methylxanthosine → 7-methylxanthine → theobromine → caffeine. PMID:12746542

  12. Caffeine synthase and related methyltransferases in plants.

    PubMed

    Misako, Kato; Kouichi, Mizuno

    2004-05-01

    Caffeine (1,3,7-trimethylxanthine) is a purine alkaloid present in high concentrations in tea and coffee and it is also found in a number of beverages such as coca cola. It is necessary to elucidate the caffeine biosynthetic pathway and to clone the genes related to the production of caffeine not only to determine the metabolism of the purine alkaloid but also to control the content of caffeine in tea and coffee. The available data support the operation of a xanthosine-->7-methylxanthosine-->7-methylxanthine-->theobromine-->caffeine pathway as the major route to caffeine. Since the caffeine biosynthetic pathway contains three S-adenosyl-L-methionine (SAM) dependent methylation steps, N-methyltransferases play important roles. This review focuses on the enzymes and genes involved in the methylation of purine ring. Caffeine synthase, the SAM-dependent methyltransferase involved in the last two steps of caffeine biosynthesis, was originally purified from young tea leaves (Camellia sinensis). The isolated cDNA, termed TCS1, consists of 1,483 base pairs and encodes a protein of 369 amino acids. Subsequently, the homologous genes that encode caffeine biosynthetic enzymes from coffee (Coffea arabica) were isolated. The recombinant proteins are classified into the three types on the basis of their substrate specificity i.e. 7-methylxanthosine synthase, theobromine synthase and caffeine synthase. The predicted amino acid sequences of caffeine biosynthetic enzymes derived from C. arabica exhibit more than 80% homology with those of the clones and but show only 40% homology with TCS1 derived from C. sinensis. In addition, they share 40% homology with the amino acid sequences of salicylic carboxyl methyltransferase, benzoic acid carboxyl methyltransferase and jasmonic acid carboxyl methyltransferase which belong to a family of motif B' methyltransferases which are novel plant methyltransferases with motif B' instead of motif B as the conserved region.

  13. Polymorphism and disorder in natural active ingredients. Low and high-temperature phases of anhydrous caffeine: Spectroscopic ((1)H-(14)N NMR-NQR/(14)N NQR) and solid-state computational modelling (DFT/QTAIM/RDS) study.

    PubMed

    Seliger, Janez; Žagar, Veselko; Apih, Tomaž; Gregorovič, Alan; Latosińska, Magdalena; Olejniczak, Grzegorz Andrzej; Latosińska, Jolanta Natalia

    2016-03-31

    The polymorphism of anhydrous caffeine (1,3,7-trimethylxanthine; 1,3,7-trimethyl-1H-purine-2,6-(3H,7H)-dione) has been studied by (1)H-(14)N NMR-NQR (Nuclear Magnetic Resonance-Nuclear Quadrupole Resonance) double resonance and pure (14)N NQR (Nuclear Quadrupole Resonance) followed by computational modelling (Density Functional Theory, supplemented Quantum Theory of Atoms in Molecules with Reduced Density Gradient) in solid state. For two stable (phase II, form β) and metastable (phase I, form α) polymorphs the complete NQR spectra consisting of 12 lines were recorded. The assignment of signals detected in experiment to particular nitrogen sites was verified with the help of DFT. The shifts of the NQR frequencies, quadrupole coupling constants and asymmetry parameters at each nitrogen site due to polymorphic transition were evaluated. The strongest shifts were observed at N(3) site, while the smallest at N(9) site. The commercial pharmaceutical sample was found to contain approximately 20-25% of phase I and 75-80% of phase II. The orientational disorder in phase II with a local molecular arrangement mimics that in phase I. Substantial differences in the intermolecular interaction phases I and II of caffeine were analysed using computational (DFT/QTAIM/RDS) approach. The analysis of local environment of each nitrogen nucleus permitted drawing some conclusions on the topology of interactions in both polymorphs. For the most stable orientations in phase I and phase II the maps of the principal component qz of EFG tensor and its asymmetry parameter at each point of the molecular system were calculated and visualized. The relevant maps calculated for both phases I and II indicates small variation in electrostatic potential upon phase change. Small differences between packings in phases slightly disturb the neighbourhood of the N(1) and N(7) nitrogens, thus are meaningless from the biological point of view. The composition of two phases in pharmaceutical material

  14. Topology of the interactions pattern in pharmaceutically relevant polymorphs of methylxanthines (caffeine, theobromine, and theophiline): combined experimental (¹H-¹⁴N nuclear quadrupole double resonance) and computational (DFT and Hirshfeld-based) study.

    PubMed

    Latosińska, Jolanta Natalia; Latosińska, Magdalena; Olejniczak, Grzegorz A; Seliger, Janez; Žagar, Veselko

    2014-09-22

    Three anhydrous methylxanthines: caffeine (1,3,7-trimethylxanthine; 1,3,7-trimethyl-1H-purine-2,6-(3H,7H)-dione) and its two metabolites theophylline (1,3-dimethylxanthine; 1,3-dimethyl-7H-purine-2,6-dione) and theobromine (3,7-dimethyl-xanthine; 3,7-dimethyl-7H-purine-2,6-dione), which reveal multifaceted therapeutic potential, have been studied experimentally in solid state by (1)H-(14)N NMR-NQR (nuclear magnetic resonance-nuclear quadrupole resonance) double resonance (NQDR). For each compound the complete NQR spectrum consisting of 12 lines was recorded. The multiplicity of NQR lines indicates the presence of a stable β form of anhydrous caffeine at 233 K and stable form II of anhydrous theobromine at 213 K. The assignment of signals detected in NQR experiment to particular nitrogen atoms was made on the basis of quantum chemistry calculations performed for monomer, cluster, and solid at the DFT/GGA/BLYP/DPD level. The shifts due to crystal packing interactions were evaluated, and the multiplets detected by NQR were assigned to N(9) in theobromine and N(1) and N(9) in caffeine. The ordering theobromine > theophylline > caffeine site and theophylline < theobromine < caffeine according to increasing electric field gradient (EFG) at the N(1) and N(7) sites, respectively, reflects the changes in biological activity profile of compounds from the methylxanthines series (different pharmacological effects). This difference is elucidated on the basis of the ability to form intra- and intermolecular interactions (hydrogen bonds and π···π stacking interactions). The introduction of methyl groups to xanthine restricts the ability of nitrogen atoms to participate in strong hydrogen bonds; as a result, the dominating effect shifts from hydrogen bond (theobromine) to π···π stacking (caffeine). Substantial differences in the intermolecular interactions in stable forms of methylxanthines differing in methylation (site or number) were analyzed within the Hirshfeld