Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 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.
 ...
PMID:Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 and CYP2E1. 130 44

Caffeine is sequentially metabolized by cytochrome P4501A2 (CYP1A2), N-acetyltransferase (NAT) and/or xanthine oxidase (XO). In the present study the activity of these three enzymes was estimated from ratios of the metabolites formed from dietary caffeine and excreted into the urine collected as spot samples. In the urine samples from 10 out of 377 subjects concentrations of caffeine metabolites were too low to allow reliable measurements of the ratios. In 335 healthy subjects the NAT activity showed a typically bimodal distribution with 47% fast acetylators and 53% slow acetylators, consistent with a Danish population. The ratios reflecting CYP1A2 and XO activities were log normal and normal distributed, respectively. In 103 non-smoking men and 90 non-smoking women the ratio of caffeine metabolites expressing CYP1A2 activity was 4.7 +/- 1.6 and 4.3 +/- 1.9 as compared to 7.8 +/- 2.5 and 7.3 +/- 3.0 in 31 male and 25 female subjects smoking 10 cigarettes/day or more respectively, verifying induction of CYP1A2 by tobacco (P less than 0.05), but minimal sex-related differences. In 12 non-smoking pregnant women and in 28 women using oral contraceptives the CYP1A2 ratio was 29 and 20% reduced respectively (P less than 0.05). In a multivariate analysis the only significant predictor of the XO ratio was the consumption of caffeine with an increase of 2% per cup of coffee or equivalent (P less than 0.05). In 23 healthy male subjects 30 days of vigorous exercise increased the CYP1A2 ratio by 70% and the XO ratio by 42% (P less than 0.05), but left the NAT ratio unchanged. In nine healthy volunteers daily ingestion of 500 g of broccoli for 10 days increased the CYP1A2 ratio by an average of 12% (P less than 0.05), compared to a control period with ingestion of an equivalent weight of non-cruciferous green vegetables. The ratios of metabolites from dietary caffeine in spot urine samples offer ethical, non-invasive and reliable estimates of CYP1A2, NAT and XO. These enzymes are highly relevant for the bioactivation of potentially toxic compounds and the formation of oxygen radicals. The method is applicable in large-scale epidemiological studies, allowing, for example, prospective testing of the relationship between these enzyme activities and the development of disease. Exercise may increase CYP1A2 activity to a magnitude corresponding to heavy smoking, as well as XO by mechanisms that remain to be clarified.
 ...
PMID:Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine. 139 40

The use of two caffeine metabolite ratios for acetylator phenotyping was validated by demonstrating concordance with two sulfamethazine tests in 178 unrelated healthy subjects. The caffeine metabolites used for this purpose were 5-acetylamino-6-amino-3-methyluracil (AAMU), 1-methylxanthine (1X), and 1-methylurate (1U). The ratio AAMU/(AAMU + 1X + 1U), referred to as molar ratio or N-acetyltransferase, was compared with the ratio AAMU/1X. The results indicated that, for screening purposes, the acetylator phenotype can be determined by analysis of a 6-hour urine sample after a cup of coffee or strong tea or a can of caffeine-containing soft drink. The ratio AAMU/1X is the ratio of choice for the study of subjects in whom variability of xanthine oxidase can be neglected; use of the ratio AAMU/(AAMU + 1X + 1U) appears appropriate for special purposes. Gender, ethnic origin, habitual or moderate consumption of coffee, tea, soft drinks, or ethanol, or cigarette smoking have little if any effect on the caffeine tests for acetylator phenotyping.
 ...
PMID:Caffeine as a metabolic probe: validation of its use for acetylator phenotyping. 206 Feb 54

Urinary metabolites excreted after oral caffeine were quantified in a healthy sample (n = 68) from the Toronto population by HPLC analyses. The profile of metabolites, assessed by examining particular metabolite ratios, was found to differ widely among subjects. Ratios denoting cytochrome P-450-dependent activities were shown to be interethnically variable between oriental and Caucasian groups, whereas those indicative of xanthine oxidase activity exhibited neither significant interindividual variation nor an ethnic difference. It was also shown that a ratio providing an index of polymorphic N-acetyltransferase activity holds promise as a simple marker for acetylator status in man.
 ...
PMID:Variability in caffeine metabolism. 668 5

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.
 ...
PMID:Low CYP1A2 activity in rural Shona children of Zimbabwe. 782 78

Patients with familial adenomatous polyposis (FAP) and age and sex matched controls were tested for cytochrome P4501A2 (CYP1A2), N-acetyltransferase, and xanthine oxidase activities using caffeine urinary metabolites as a discriminator. FAP patients showed significant underactivity of N-acetyltransferase (which inactivates some carcinogens) and significant overactivity of CYP1A2 (which activates some carcinogens). Xanthine oxidase activity, which can generate free radicals and cause cellular damage, was significantly increased in the FAP patients. All but one of the FAP patients had undergone colectomy. A separate group of six patients was therefore assessed before and at an average time of eight weeks after colectomy. No effect on enzyme activity was seen. The differences in enzyme activities detected in this study could produce an excess of active carcinogenic metabolites in the bile of FAP patients and contribute to the high risk for intestinal cancer in FAP.
 ...
PMID:Caffeine phenotyping of cytochrome P4501A2, N-acetyltransferase, and xanthine oxidase in patients with familial adenomatous polyposis. 856 46

Caffeine is a popular compound for phenotyping individuals for CYP4501A2, xanthine oxidase (XO) and N-acetyltransferase (NAT) utilising urinary metabolites. The analysis is complex since at least thirteen metabolites are excreted by man. Past methods have been less than satisfactory in that either not all the metabolites have been resolved and/or extractions selective for particular groups of metabolites are required prior to chromatography. We report a method for the rapid analysis of caffeine and metabolites in urine that negates the requirement for an extraction step, and also a method for plasma analysis.
 ...
PMID:Rapid method for the routine determination of caffeine and its metabolites by high-performance liquid chromatography. 801 20

Caffeine metabolism via the 3-demethylation pathway is sequentially catalyzed by cytochrome P4501A2 (CYP1A2), xanthine oxidase, and N-acetyltransferase. The activities of the three enzymes can be estimated from urinary metabolic ratios of four caffeine metabolites, 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methyluric acid (1MU), 1-methylxanthine (1MX), and 1,7-dimethyluric acid (17DMU), after the ingestion of caffeine. A method for quantitation of the four metabolites in human urine has been developed. The method is based on a one-step extraction with ethyl acetate/2-propanol followed by high-performance liquid chromatography with UV detection. The detection limit was 1 microM for AFMU, 1MU, and 1MX and 2 microM for 17DMU. The intraday and interday coefficients of variation were < 3% and < 7%, respectively, and the accuracy was within +/- 3%. The method was employed in a population study of 277 healthy volunteers, each of whom ingested 200 mg caffeine and provided a urine sample approximately 6 h later. The metabolite concentration ranges in the urines were 2.1-327 microM, 4.0-744 microM, 4.9-598 microM, and 6.4-260 microM for AFMU, 1MU, 1MX, and 17DMU, respectively. The CYP1A2 ratio (AFMU + 1MU + 1MX/17DMU) was significantly lower in women than in men, excluding smokers and oral contraceptive users. The CYP1A2 ratio was higher in smokers than in nonsmokers, confirming the induction of CYP1A2 by smoking. In women using oral contraceptives, the CYP1A2 ratio was, as expected, significantly lower than in women not using oral contraceptives. For the N-acetyltransferase ratio (AFMU/1MX) and the xanthine oxidase ratio (1MU/1MX), no differences were seen in terms of sex, smoking habits, or the use of oral contraceptives. All results are in agreement with previous reports on CYP1A2, N-acetyltransferase, and xanthine oxidase activities in humans. Thus, the method is both analytically and biologically reliable for the assessment of CYP1A2, N-acetyltransferase, and xanthine oxidase in humans.
 ...
PMID:Determination of urinary metabolites of caffeine for the assessment of cytochrome P4501A2, xanthine oxidase, and N-acetyltransferase activity in humans. 873 64

1. Caffeine (CA) is metabolized extensively and at least 17 metabolites arising from primary and secondary biotransformation pathways are found in urine following CA ingestion. The enzymes responsible for the formation of most of the metabolites derived from CA have been identified. 2. Given the near ubiquitous consumption of CA, this compound potentially constitutes a useful substrate probe for assessment of certain xenobiotic metabolizing enzyme activities in vivo. Indeed, various ratios of CA metabolites excreted in urine (urinary metabolic ratios; MRs) are now utilized widely for the population screening of enzyme activities. 3. Excretion of the acetylated secondary metabolite 5-actylamino-6-formylamino-3-methyluracil (AFMU) is dependent on the activity of the polymorphic N-acetyltransferase (NAT2), and certain MRs incorporating AFMU may be used for NAT2 phenotyping. 4. The conversion of 1-methylxanthine (1-MX), another secondary metabolite of CA, to 1-methyluric acid (1-MU) is catalyzed by xanthine oxidase (XO), and the urinary 1-MU to 1MX ratio reflects XO activity. 5. N3-demethylation to form paraxanthine (PX), a reaction mediated by cytochrome P4501A2 (CYP1A2), is the dominant primary metabolic pathway of CA. CA N3-demethylation activity may be used as a measure of human hepatic CYP1A2 in vitro. 6. Plasma CA clearance is considered to reflect CYP1A2 activity in vivo. Although a number of MRs are based on the excretion of PX metabolites (PX derived from CA is employed for the assessment of CYP1A2 activity in vivo), factors other than enzyme activity may affect these ratios.
 ...
PMID:The use of caffeine as a metabolic probe for human drug metabolizing enzymes. 891 37

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.
 ...
PMID:Absence of effect of terbinafine on the activity of CYP1A2, NAT-2, and xanthine oxidase. 960 54


1 2 3 Next >>