Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

In a case-control study of 73 women with and 141 women without spontaneous abortion, the authors determined the activity of the three principal caffeine-metabolizing enzymes--cytochrome P-4501A2 (CYP1A2), xanthine oxidase, and N-acetyltransferase 2--by measuring levels of caffeine metabolites in urine. After examining the effect of enzyme activity and different levels of caffeine intake, they concluded that there was no evidence that an interaction between enzyme activity and caffeine intake during pregnancy resulted in risk of spontaneous abortion. In a subsample comparing 24 cases with recurrent (two or more) spontaneous abortions and 21 controls with two or more livebirths and no previous spontaneous abortions, the unadjusted odds ratio for low CYP1A2 enzyme activity (below the median) was 0.92 (95% confidence interval (CI) 0.28-3.04) compared with higher CYP1A2 activity. The odds ratio for risk of recurrent spontaneous abortion and low xanthine oxidase activity (below the median) versus higher activity was 0.37 (95% CI 0.10-1.29). Phenotypically slow acetylators (N-acetyltransferase 2 index <0.37) had an odds ratio of 1.58 (95% CI 0.48-5.13) for recurrent loss compared with rapid acetylators. Thus, some association of the latter two caffeine-metabolizing enzymes with recurrent spontaneous abortion is suggested but may also be due to chance.
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PMID:Rate of caffeine metabolism and risk of spontaneous abortion. 952 38

Terbinafine is an allylamine antifungal agent used for the treatment of onychomycosis. It has previously been reported to interact with caffeine and is metabolized in part by the cytochrome P450 systems. This open-label, randomized, crossover study was conducted to examine the effect of terbinafine on the activity of cytochrome P450 1A2 (CYP1A2), N-acetyltransferase (NAT-2), and xanthine oxidase (XO). Twelve healthy nonsmoking adult volunteers were enrolled. Each received single doses of caffeine (100 mg), and urine was collected for a 16-hour period with and without multiple-dose oral administration of terbinafine (250 mg daily for 3 days). Study periods were separated by a 4-week washout period. Urinary caffeine metabolite ratios were used to assess CYP1A2, NAT-2 and XO activity. Comparison of mean metabolic ratios for treatment with and without terbinafine indicated that terbinafine did not appear to alter the activity of CYP1A2, NAT-2, or XO, all of which regulate the biotransformation of caffeine.
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PMID:Absence of effect of terbinafine on the activity of CYP1A2, NAT-2, and xanthine oxidase. 960 54

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

Urinary metabolic ratios of caffeine are used in humans to assess the enzymatic activities of cytochrome P450 isoenzyme 1A2 (CYP1A2), xanthine oxidase (XO) and for phenotyping individuals for the bimodal N-acetyltransferase 2 (NAT2), all of them involved in the activation or detoxification of various xenobiotic compounds. Most reported analytical procedures for the measurement of the urinary metabolites of caffeine include a liquid-liquid extraction of urine samples prior to their analysis by reversed-phase HPLC. At neutral to basic pH however, 5-acetylamino-6-formylamino-3-methyluracil (AFMU), a metabolite of caffeine, spontaneously decomposes to 5-acetylamino-6-amino-3-methyluracil (AAMU). Since AAMU is not extracted in most organic solvents, the extent of AFMU decomposition cannot be precisely assessed. Although the decomposition reaction can be minimized by immediate acidification of the urine, accurate results can only be obtained when both AAMU and AFMU are monitored, or alternatively, if AAMU is measured after complete transformation of AFMU into AAMU in basic conditions. We report a liquid chromatographic method for the simultaneous quantitative analysis of the five urinary metabolites of caffeine used for the CYP1A2, XO and NAT2 phenotyping studies: AAMU, AFMU, 1-methylxanthine, 1-methyluric acid and 1,7-dimethyluric acid. These metabolites are satisfactory separated from all other known caffeine metabolites as well as endogenous urinary constituents. Sample treatment does not require any liquid-liquid extraction procedure. Urine samples are diluted and centrifuged before being injected (10 microl) onto a YMC-Pack Polyamine II (250x4.6 mm) column. A step-wise gradient elution program is applied using acetonitrile-0.75% (v/v) formic acid: (91:9) at 0 min-->(75:25) at 25 min-->(65:35) at 35 min-->(65:35) at 45 min, followed by a re-equilibration step to the initial solvent composition. The flow-rate is 1.0 ml/min and the separations are monitored by UV absorbance at 260 and 280 nm. The procedure described here represents a substantial improvement over previous methods: a single analysis and a minimal urine sample treatment enables the simultaneous quantitation of five caffeine metabolites, notably AFMU and AAMU, used for the determination of CYP450 1A2, XO and NAT2 enzyme activity. Importantly enough, phenotyping individuals for the bimodal NAT2 is made possible without the uncertainty associated with the deformylation of AFMU, which is likely to happen at all steps prior to the analysis, during sample storage and even in the bladder of the subjects.
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PMID:Extractionless method for the simultaneous high-performance liquid chromatographic determination of urinary caffeine metabolites for N-acetyltransferase 2, cytochrome P450 1A2 and xanthine oxidase activity assessment. 1139 35

Caffeine is metabolised in humans primarily by cytochromes P450 1A2 and 2A6, xanthine dehydrogenase/oxidase, and N-acetyltransferase 2. The activities of these enzymes show a large variation due to genetic polymorphisms and/or induction by xenobiotics. Ratios of different caffeine metabolites in urine or other body fluids are frequently used to characterise the individual/actual activity of these enzymes. The common analytical method involves extensive sample preparation, followed by HPLC-UV. The presence of numerous other UV-absorbing chemicals in body fluids affects the sensitivity and selectivity of this method. We have developed an HPLC-electrospray-MS-MS method for the determination of 11 caffeine metabolites and two internal standards after a simple, extractionless preparation. Blank urine, obtained after 5 days on a methylxanthine-free diet, contained small amounts of some caffeine metabolites, but no other components producing any confounding signals. Eleven metabolites and internal standards were recovered at 90 to 110% after addition to the blank urine (0.1 to 2.5 micro M in the final sample involving a 20-fold dilution of urine) in the 0.1-2.5 micro M concentration range. Other metabolites, 5-acetylamino-6-amino-3-methyluracil (AAMU) and 5-acetylamino-6-formylamino-3-methyluracil (AFMU), were detected with similar recovery and precision, but required higher concentrations (3 to 30 micro M). AFMU was completely converted into AAMU by a short alkalisation of urine. The method was explored in six healthy individuals after consuming coffee (4 mg caffeine per kg body mass). These experiments demonstrated the simplicity, high sensitivity and selectivity of the method under conditions used for phenotyping.
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PMID:Extractionless method for the determination of urinary caffeine metabolites using high-performance liquid chromatography coupled with tandem mass spectrometry. 1274 14

The activities of hepatic cytochrome P450 (CYP) 1A2, N-acetyltransferase 2 (NAT-2), xanthine oxidase (XO), and CYP2D6 were evaluated in 12 young children (aged 3-8 years) with mild cystic fibrosis (CF) and 12 age-matched healthy control subjects by use of standard caffeine and dextromethorphan phenotyping methods. Subjects were given 4 oz of Coca-Cola (approximately 35 mg caffeine) (The Coca-Cola Company, Atlanta, Ga) and a single 0.5-mg/kg dose of dextromethorphan. Urine was collected for 8 hours after biomarker administration, and enzyme activity was assessed by use of previously validated caffeine and dextromethorphan molar ratios. CYP2D6 genotyping was also performed in 10 of 12 subjects with CF and 11 of 12 control subjects. There were no significant differences in the urinary molar ratios for any of the enzyme systems evaluated. These data suggest that CF does not alter the activities of CYP1A2, NAT-2, XO, and CYP2D6. Altered biotransformation of drugs in this patient population is likely enzyme- and isoform-specific and thus is apparent for only selected compounds that are substrates for enzymes other than CYP1A2, NAT-2, XO, and CYP2D6.
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PMID:Activities of cytochrome P450 1A2, N-acetyltransferase 2, xanthine oxidase, and cytochrome P450 2D6 are unaltered in children with cystic fibrosis. 1500 67

In Japan, patients with chronic airway disease are administered bakumondo-to (TJ-29), a mixture of six herbal components. We have assessed the effects of TJ-29 on the activities of cytochrome P450 (CYP) 1A2, xanthine oxidase and N-acetyltransferase 2 in 26 healthy subjects under a double-blind, randomized, placebo-controlled cross-over study design. The baseline activities of the three enzymes were assessed by the respective urinary metabolic ratios of an 8-h urine sample after an oral 150-mg dose of caffeine. Thereafter, the subjects received a thrice-daily 3.0-g dose of TJ-29 or placebo for seven days, and underwent the same caffeine test on the post-dose days 1 and 7. No statistically significant difference was observed in the activity of the three enzymes between those at baseline, and on day 1 after dosing with TJ-29 or placebo. The mean activity of CYP1A2, xanthine oxidase and N-acetyltransferase 2 tended to be lower on day 7 after dosing with TJ-29 compared with those at baseline and on day 7 after dosing with placebo. However, these changes were not statistically significant in CYP1A2 (P = 0.120), xanthine oxidase (P = 0.123) or N-acetyltransferase 2 (P = 0.056). In conclusion, TJ-29 did not appear to substantially affect the activity of CYP1A2, xanthine oxidase or N-acetyltransferase 2 in man.
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PMID:The in-vivo effect of bakumondo-to (TJ-29), a traditional Japanese medicine used for treatment of chronic airway disease, on cytochrome P450 1A2, xanthine oxidase and N-acetyltransferase 2 activity in man. 1532 86

The effects of a common oral contraceptive preparation on the activity of 7 drug-metabolizing enzymes were investigated using the validated Cooperstown 5+1 Cocktail. In a randomized crossover fashion, 10 premenopausal women received caffeine, dextromethorphan, omeprazole, intravenous midazolam, and warfarin + vitamin K with and without a triphasic oral contraceptive (ethinyl estradiol 35 microg) and varying doses of daily norgestimate (0.18, 0.215, and 0.25 mg). Bioequivalence testing showed nonequivalence in drug versus no-drug treatment on the activity of drug-metabolizing enzymes (as reflected by metabolite ratios following probe drug administration); the activity of CYP1A2, CYP2C19, and NAT-2 decreased following the oral contraceptive, whereas the activity of CYP2C9 and CYP2D6 increased. No effects on xanthine oxidase or hepatic CYP3A were seen. Application of a non-parametric statistical testing approach revealed a significant difference only for CYP1A2 and CYP2C19. This triphasic oral contraceptive may have a clinically significant effect on the activity of some drug-metabolizing enzymes.
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PMID:Effect of a triphasic oral contraceptive on drug-metabolizing enzyme activity as measured by the validated Cooperstown 5+1 cocktail. 1629 17

Cyclophosphamide (CPA) and adriamycin (ADR) are widely used drugs for cancer chemotherapy. It has been reported that CPA and ADR singly or in combination could alter activities of a variety of drug-metabolizing enzymes in animals via multiple mechanisms. However, the effects of CPA/ADR on drug metabolism are largely unknown in human beings. Losartan metabolism has been suggested as a marker for determination of CYP2C9 activity. Caffeine is a commonly used probe to assess the metabolic activities of CYP1A2, CYP2A6, N-acetyltransferase 2 (NAT2) and xanthine oxidase (XO). The present study was designed to analyze the effects of CPA/ADR on these drug-metabolizing enzymes by using losartan and caffeine as probe drugs. A single oral dose of 25 mg losartan and a cup of instant coffee was given to 15 breast cancer patients on three occasions (before, and 2-4 h and 3 weeks after the adjuvant CPA/ADR chemotherapy [600 mg CPA/m2/day, 60 mg ADR/m2/day]). Losartan, caffeine and their metabolites were analyzed by using high-pressure liquid chromatography. When compared with baseline, CYP1A2 activity was increased by 20% and CYP2C9 activity was decreased by 315% 3 weeks after the administration of CPA/ADR chemotherapy (p = 0.05). The chemotherapy did not change the activities of CYP2A6, NAT2 or XO. CPA/ADR treatment caused a differential effect on drug-metabolizing enzyme activities, and this may contribute to predicting the efficacy and toxicity of chemotherapeutics, as well as understanding the drug-drug interactions.
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PMID:Differential alteration of drug-metabolizing enzyme activities after cyclophosphamide/adriamycin administration in breast cancer patients. 1734 41


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