Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Six human cytochrome P450s expressed in HepG2 cells using vaccinia virus cDNA-directed expression, were used to study the biotransformation of caffeine and its metabolites. CYP1A2 alone was responsible for caffeine 3-demethylation and paraxanthine 7-demethylation; in addition, 1A2 catalysed virtually all reactions related to caffeine and its metabolites. The metabolic profile of caffeine biotransformation by CYP1A2 averaged 81.5% for paraxanthine, 10.8% for theobromine and 5.4% for theophylline formation. It remained quite uniform when caffeine concentrations were varied. The most striking finding was that CYP2E1 (the ethanol-inducible form) had major influences upon caffeine metabolism: in particular, it catalysed the formation of theophylline and theobromine from caffeine. Thus, the in vivo metabolite profiling of caffeine may reveal CYP2E1 activities in addition to the previously documented activities of CYP1A2, polymorphic N-acetyltransferase and xanthine oxidase.
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PMID:Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 and CYP2E1. 130 44

Caffeine was used as a metabolic probe to screen healthy subjects for their activities of two enzymes, deduced to be CYP1A2 (an inducible cytochrome P450) and xanthine oxidase. A longitudinal study revealed modest effects of caffeine dose, ethanol intake, and time-of-day on the CYP1A2 index, without any effect on the xanthine oxidase index. The coefficients of intraindividual variation not accounted for were 5.0% for the xanthine oxidase and 17.2% for the CYP1A2 index. In a population study, both indexes showed a log normal distribution, with CYP1A2 values of most subjects covering a 6.3-fold range but only a 1.7-fold range with xanthine oxidase. The CYP1A2 index was 33% decreased in women who used oral contraceptives and substantially increased in cigarette smokers. Neither the CYP1A2 nor the xanthine oxidase index differed between volunteers of Chinese and European extraction. Four of 178 subjects showed unexplained low xanthine oxidase values (i.e., values several standard deviations below the mean).
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PMID:Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities. 193 64

The oxidation of O6-benzylguanine, an inactivator of O6-alkylguanine-DNA alkyltransferase, was examined using human liver cytosol, microsomes, and several P450 isoforms. Incubation of O6-benzylguanine with human liver cytosol resulted in the formation of O6-benzyl-8-oxoguanine, which was inhibited by menadione, a potent inhibitor of aldehyde oxidase. Inhibition by allopurinol, a xanthine oxidase inhibitor, was less dramatic. Oxidation of O6-benzylguanine also occurred with pooled human liver microsomes and was inhibited by both furafylline and troleandomycin, selective inhibitors of CYP1A2 and CYP3A4, respectively. Human P450s CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2E1, and CYP3A4 expressed in Hep G2 hepatoma cells using vaccinia virus vectors were incubated with 10 or 200 microM O6-benzylguanine. At 10 microM, O6-benzylguanine was oxidized primarily by CYP1A2 and to a lesser extent by CYP3A4. However, an appreciable increase in CYP3A4 contribution was noted at 200 microM. CYP1A2 exhibited a more than 200-fold higher relative catalytic activity (Vmax/Km) compared with CYP3A4. Therefore, at therapeutically relevant concentrations of O6-benzylguanine, CYP1A2 could be primarily involved in its oxidation since it shows a much lower Km value (1.3 microM) than CYP3A4 (52.2 microM) and cytosol (81.5 microM). However, one would expect interindividual variation in the extent of oxidation of O6-benzylguanine depending on the levels of aldehyde oxidase, CYP1A2, and CYP3A4.
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PMID:Human liver oxidative metabolism of O6-benzylguanine. 750 88

Caffeine is increasingly used as a biochemical probe for liver function, in cancer epidemiology, and in pharmacogenetics, with its recognized ability to assess the activities of CYP1A2, xanthine oxidase, and N-acetyltransferase-2. The activity of these hepatic enzymes was tested in 45 Shona children from a rural area of Zimbabwe with use of caffeine as a probe. Many of these rural black children had lower indexes of CYP1A2 activity than otherwise on our extensive records; the average value (3.78 +/- 2.9) was significantly (p < 0.001) lower than that of healthy white urban children from Zimbabwe (8.86 +/- 3.36) or from Canada (7.92 +/- 1.88), or that of healthy Canadian adults (5.96 +/- 2.4). A higher CYP1A2 activity in children than in adults is usual. The low CYP1A2 activity of the children from rural Zimbabwe calls for medical studies and suggests a widespread and perhaps serious impairment of certain liver functions. Causes could be parasitic infections with Schistosoma mansoni, causing schistosomiasis, which are endemic, in addition to generally poor nutrition and frequent iodine deficiency. By contrast, the xanthine oxidase activity in rural Shona children was slightly higher than that reported for a healthy Canadian adult population. The N-acetyltransferase activities were comparable in both the rural and urban children and were also similar to those reported in a population study of healthy adult Canadians.
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PMID:Low CYP1A2 activity in rural Shona children of Zimbabwe. 782 78

We studied the oxidative and N-acetylator caffeine metabolic profile in 107 healthy Spanish volunteers. Smokers had significantly higher N-1- and N-3-demethylations activities than nonsmokers (p = 0.03 and p = 0.02, respectively), and the three caffeine demethylations indexes were strongly correlated with each other (r > 0.7; p < 0.001). Our in vivo studies suggest that CYP1A2 is involved, at least in part, in the primary N-demethylations of caffeine. A non-normal and possibly bimodal distribution was detected in the xanthine oxidase activity (p = 0.04), with about 4% of subjects deficient of this metabolic activity. The population exhibited a trimodal distribution of acetylator phenotype determined by use of the 5-acetylamino-6-amino-3-methyluracil/1-methylxanthine ratio (normality test; p = 0.004). Seventy subjects (65.4%) were phenotyped as slow acetylators. The mutated gene frequency was 0.81, which is similar to other white populations.
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PMID:Caffeine metabolism in a healthy Spanish population: N-acetylator phenotype and oxidation pathways. 814 95

Polymorphisms have been detected in a variety of xenobiotic-metabolizing enzymes at both the phenotypic and genotypic level. In the case of four enzymes, the cytochrome P450 CYP2D6, glutathione S-transferase mu, N-acetyltransferase 2 and serum cholinesterase, the majority of mutations which give rise to a defective phenotype have now been identified. Another group of enzymes show definite polymorphism at the phenotypic level but the exact genetic mechanisms responsible are not yet clear. These enzymes include the cytochromes P450 CYP1A1, CYP1A2 and a CYP2C form which metabolizes mephenytoin, a flavin-linked monooxygenase (fish-odour syndrome), paraoxonase, UDP-glucuronosyltransferase (Gilbert's syndrome) and thiopurine S-methyltransferase. In the case of a further group of enzymes, there is some evidence for polymorphism at either the phenotypic or genotypic level but this has not been unambiguously demonstrated. Examples of this class include the cytochrome P450 enzymes CYP2A6, CYP2E1, CYP2C9 and CYP3A4, xanthine oxidase, an S-oxidase which metabolizes carbocysteine, epoxide hydrolase, two forms of sulphotransferase and several methyltransferases. The nature of all these polymorphisms and possible polymorphisms is discussed in detail, with particular reference to the effects of this variation on drug metabolism and susceptibility to chemically-induced diseases.
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PMID:Metabolic polymorphisms. 836 90

Induction or inhibition of biotransformation enzymes, enzymes that activate or detoxify numerous xenobiotics, is one mechanism by which vegetables may alter cancer risk. Using a randomized crossover design, we examined the effect of various vegetable diets on cytochrome P450 (CYP) 1A2, N-acetyltransferase 2 (NAT2) and xanthine oxidase activity in humans. Men and women, non-smokers, on no medication and 20-40 years of age ate four 6-day controlled diets: basal (vegetable-free) and basal with three botanically defined vegetable groups. Enzyme activities were determined by measuring urinary caffeine metabolite ratios after a 200 mg caffeine dose on the last day of each feeding period. Mean CYP1A2 activity for 19 men and 17 women (least squares means adjusted for sex, GSTM1 genotype, urine volume and feeding period) with basal, brassica, allium and apiaceous vegetable diets differed significantly (P </=ISOdia</= 0. 0005) by diet, irrespective of the caffeine metabolite molar ratio used to describe CYP1A2 activity; brassica vegetables increased (P <0.04) and apiaceous vegetables decreased (P </=ISOdia</= 0.02) activity compared with the basal and allium diets. There was no effect of diet on NAT2 and xanthine oxidase activities and none of the subjects differed by GSTM1 genotype. These results demonstrate that while one vegetable subgroup induces human CYP1A2 activity, another subgroup inhibits it. This points to a complex association between consumption of a typical diet of various vegetables and biotransformation enzyme activities in humans, an association that may be difficult to interpret in observational studies.
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PMID:Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans: changes in caffeine metabolite ratios in response to controlled vegetable diets. 1083 4

An HPLC method has been developed for the separation and the determination of caffeine and its metabolites in urine samples using a one extraction-analysis run and UV detection. The compounds were extracted by liquid-liquid extraction using chloroform-isopropylalcohol (85:15, v/v). Chromatographic separation was accomplished on an ODS analytical column with a mobile phase containing 0.05% acetic acid/methylalcohol (92.5:7.5, v/v). Compounds were monitored at 280 nm. The method was validated for the determination of AFMU, 1X, 1U, 17X and 17U caffeine metabolites required to assess the metabolic activity of the enzymes subject to in vivo caffeine testing. The validated assay was applied to urine samples from ten healthy volunteers. The method was proved to be suitable to assess simultaneously the enzymatic activity of cytochrome P450 CYP1A2 and CYP2A6, as well as N-acetyltransferase and xanthine oxidase.
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PMID:Liquid chromatographic method for the simultaneous determination of caffeine and fourteen caffeine metabolites in urine. 1107 88

Caffeine was used as a metabolic probe to measure, in 120 healthy volunteers, the activities of three enzymes, deduced to be N-acetyltransferase(NAT2), CYP1A2 and xanthine oxidase (XO). The caffeine metabolites of 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine(1X), 1-methyluric acid(1U), 1, 7-dimethylxanthine(17X), and 1, 7-dimethyluric acid(17U) in urine were determined with HPLC after 4-5 hours of caffeine drink. The ratios of AFMU/1X or AFMU/(AFMU + 1X + 1U), (AFMU + 1X + 1U)/17X or (AFMU + 1X + 1U)/17U, and 1U/1X or 1U/(1X + 1U) were used as the index of NAT2, CYP1A2, and XO activities respectively. Frequency distribution analysis of the metabolic ratios of NAT2 indicated two distinct group with 20 slow acetylators and 100 rapid acetylators. Similar CYP1A2 activity was found in Chinese compared with European volunteers. Frequency analysis of CYP1A2 indicated the log normal distribution in 120 Chinese. The CYP1A2 index was much higher in smokers than that in nonsmokers. But no obvious difference was observed between young and old volunteers. The XO index also showed log normal distribution and has the similar value compared with European volunteers. The concentration variations of 1X and 1U in young volunteers were much lower than that in old volunteers.
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PMID:[Determination of caffeine metabolite for the evaluation of N-acetyltransferase, CYP1A2 and xanthine oxidase activities]. 1159 99

In rats with acute renal failure induced by uranyl nitrate, the hepatic microsomal cytochrome P450 (CYP) 2E1 and CYP3A23 increased 2-4- and 4-times, respectively, CYP2C11 decreased to 80% of control, but the levels of CYP1A2 and CYP2B1/2 were not changed. It has been reported that theophylline was metabolized to 1,3-dimethyluric acid by CYP1A2 and CYP2E1 and 1-methylxanthine via CYP1A2, which was metabolized further to 1-methyluric acid via xanthine oxidase in rats. Hence, it was expected that the formation of 1,3-dimethyluric acid would show an increase in rats with renal failure as a result of induction of CYP2E1. The pharmacokinetics of theophylline were compared in control rats and rats with renal failure after intravenous administration of aminophylline, 5 mg kg(-1) as theophylline. In rats with renal failure, the plasma concentrations of theophylline were considerably lower and the resultant total area under the plasma concentration-time curve from time zero to time infinity (AUC(0- infinity )) of theophylline was significantly smaller (2,200 vs 1,550 microg min mL(-1)) compared with control rats. In rats with renal failure, the plasma concentrations of 1,3-dimethyluric acid were considerably higher and the resultant AUC(0-6 h) of 1,3-dimethyluric acid was significantly greater (44.4 vs 456 microg min mL(-1)) compared with control rats. Moreover, the AUC(0-6 h, 1,3-dimethyluric acid)/AUC(0- infinity, theophylline) ratio increased from 2.02% in control rats to 29.4% in rats with renal failure. The in-vitro intrinsic 1,3-dimethyluric acid formation clearance was significantly faster in rats with renal failure (734 vs 529 10(-6) mL min(-1)) compared with control rats using hepatic microsomal fraction. The results led us to conclude that in rats with uranyl nitrate-induced renal failure after the administration of aminophylline, 5 mg kg(-1) as theophylline, there was an increase in the formation of 1,3-dimethyluric acid as a result of an increase in CYP2E1 expression.
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PMID:Effects of acute renal failure induced by uranyl nitrate on the pharmacokinetics of intravenous theophylline in rats: the role of CYP2E1 induction in 1,3-dimethyluric acid formation. 1254


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