Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

It was obtained from our laboratories that the expression of hepatic microsomal cytochrome P450 (CYP) 1A2 increased approximately 3.5 times in mutant Nagase analbuminemic rats (NARs, an animal model for human familial analbuminemia), and theophylline was reported to be metabolized to 1,3-dimethyluric acid (1,3-DMU) and 1-methylxanthine (which was further metabolized to 1-methyluric acid, 1-MU, via xanthine oxidase) via CYP1A2 in rats. Hence, the pharmacokinetic parameters of theophylline, 1,3-DMU and 1-MU were compared after intravenous administration of aminophylline, 5 mg/kg as theophylline, to control Sprague-Dawley rats and NARs. In NARs, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of theophylline was significantly smaller (1,040 versus 1,750 microg min/ml) than that in control rats and this could be due to significantly faster renal clearance (CL(R), 1.39 versus 0.571 ml/min/kg, due to inhibition of renal reabsorption of unchanged theophylline) and nonrenal clearance (CL(NR), 3.36 versus 2.25 ml/min/kg, due to 3.5-fold increase in CYP1A2) than those in control rats. Based on in vitro hepatic microsomal studies, the intrinsic 1,3-DMU formation clearance was significantly faster in NARs than that in control rats (267 versus 180 x 10(-6) ml/min). After intravenous administration of 1,3-DMU, the renal secretion of 1,3-DMU was inhibited in NARs. Inhibition of renal secretion or reabsorption of various compounds in NARs was also discussed.
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PMID:Pharmacokinetics of intravenous theophylline in mutant Nagase analbuminemic rats. 1257 Sep 24

Previously, we have validated a 4-drug phenotyping cocktail, the "Cooperstown cocktail," using caffeine (cytochrome p450 [CYP] 1A2, N-acetyltransferase-2 [NAT2], and xanthine oxidase [XO]), dextromethorphan (CYP2D6), omeprazole (CYP2C19), and intravenous midazolam (hepatic CYP3A). Data suggest that warfarin can be used as a safe and accurate biomarker for CYP2C9, and if warfarin is administered with vitamin K, the pharmacodynamic effect is ablated. Twelve subjects received the Cooperstown cocktail, warfarin plus vitamin K, and both sets of biomarkers (Cooperstown 5+1 cocktail) in a randomized crossover fashion. On the basis of log-transformed data and a paired t test, no significant difference was seen for S-warfarin area under the serum concentration-time curve from time 0 to infinity (P =.09), omeprazole metabolic ratio (P =.374), caffeine metabolic ratio (P =.169 for CYP1A2 activity), midazolam plasma clearance (P =.573), or dextromethorphan metabolic ratio (P =.747) with the Cooperstown cocktail, warfarin plus vitamin K alone, or the Cooperstown 5+1 cocktail. During drug administration, the only side effect was mild and short-lived sedation after intravenous midazolam administration. Phenotypic measurements were in concordance with the subject's CYP2C9, CYP2C19, and CYP2D6 genotypes. The Cooperstown 5+1 cocktail may be used to simultaneously assess the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A, NAT2, and XO.
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PMID:Combined phenotypic assessment of cytochrome p450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase-2, and xanthine oxidase activities with the "Cooperstown 5+1 cocktail". 1458 84

The Chinese herbal medicine sho-saiko-to is a mixture of seven herbal components (Bupleurum root, Pinellia tuber, Scutellaria root, Jujube fruit, Ginseng root, Glycyrrhiza root and Ginger rhizome) that is widely administered to patients with chronic hepatitis in Japan. We assessed the effects of sho-saiko-to on the activity of cytochrome P450 (CYP) 1A2, CYP3A and xanthine oxidase (XO) in man. Twenty-six healthy subjects were studied to evaluate their baseline activity of CYP1A2 and XO by the respective urinary metabolic ratios of an 8-h urine sample after an oral 150-mg dose of caffeine and of CYP3A by a urinary excretion ratio of 6beta-hydroxycortisol (6beta-HC) to free cortisol (FC). Thereafter, the subjects received a twice-daily 2.5-g dose of sho-saiko-to for five days, and underwent the caffeine test on day 1 and day 5. The mean activity of CYP1A2 decreased by 16% on both day 1 and day 5 compared with the baseline (P=0.001). The mean activity of XO also significantly decreased by 25% on day 1 and 20% on day 5 (P<0.0001) compared with the baseline value. The activity of CYP3A tended to be lower on day 5 than the baseline (P=0.146). It is concluded that sho-saiko-to reduces CYP1A2 and XO activity in man.
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PMID:The in-vivo effects of sho-saiko-to, a traditional Chinese herbal medicine, on two cytochrome P450 enzymes (1A2 and 3A) and xanthine oxidase in man. 1471 67

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

A RP-HPLC method was developed for the assessment of caffeine and its metabolites in urine and was used for the evaluation of the CYP1A2, CYP2A6, xanthine oxidase (XO) and N-acetyl-transferase-2 (NAT-2) in vivo activities in 44 Greek volunteers (21 men, 23 women). Spot urine samples were analyzed 6 h after 200 mg caffeine consumption, following a 30 h methylxantine-free diet. The major urinary caffeine metabolites are 1-methyluric acid (1U), 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine (1X), 1,7-dimethyluric acid (17U) and 1,7-dimethylxanthine (17X). CYP1A2, CYP2A6, XO and NAT-2 activities were estimated from the metabolic ratios (AFMU + 1U + 1X)/17U, 17U/17X, 1U/(1X + 1U) and AFMU/(AFMU + 1U + 1X), respectively. Metabolites and internal standard were extracted with chloroform/isopropanol (85:15, v/v) and separated on a C18 column by an isocratic HPLC system using a two-step elution with manual switch from solvent A (0.1% acetic acid-methanol-acetonitrile, 92:4:5 v/v) to solvent B (0.1% acetic acid-methanol, 60:40, v/v), and detected at 280 nm. The method exhibited adequate metabolite separation (resolution factors >1.48), accuracy (94.1-106.3%) and intraday and interday precision <8.02 and <8.78%, respectively (n = 6). Smoking affected only CYP1A2, whereas gender had no effect in any enzyme activity. NAT-2 exhibited bimodal distribution, 63.6% of volunteers being slow acetylators. The developed RP-HPLC method was fully validated and successfully applied for the evaluation of CYP1A2, CYP2A6, XO and NAT-2 activities.
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PMID:In vivo evaluation of CYP1A2, CYP2A6, NAT-2 and xanthine oxidase activities in a Greek population sample by the RP-HPLC monitoring of caffeine metabolic ratios. 1722 22

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

Binding and activation of the aryl hydrocarbon receptor (AhR) is thought to be an essential step in the toxicity of the environmental pollutants dioxins and dioxin-like PCBs. However, also a number of natural compounds, referred to as NAhRAs (natural Ah-receptor agonists), which are present in, for example, fruits and vegetables, can bind and activate this receptor. To study their potential effects in humans, we first investigated the effect of the prototypical AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on gene expression in ex vivo exposed freshly isolated human lymphocytes, and compared the resulting gene expression profile with those caused by the well-known NAhRA indolo[3,2-b]carbazole (ICZ), originating from cruciferous vegetables, and by a hexane extract of NAhRA-containing grapefruit juice (GJE). Only ICZ induced a gene expression profile similar to TCDD in the lymphocytes, and both significantly up-regulated CYP1B1 and TIPARP (TCDD-inducible poly (ADP-ribose) polymerase) mRNA. Next, we performed a human intervention study with NAhRA-containing cruciferous vegetables and grapefruit juice. The expression of the prototypical AhR-responsive genes CYP1A1, CYP1B1 and NQO1 in whole blood cells and in freshly isolated lymphocytes was not significantly affected. Also enzyme activities of CYP1A2, CYP2A6, N-acetyltransferase 2 (NAT2) and xanthine oxidase (XO), as judged by caffeine metabolites in urine, were unaffected, except for a small down-regulation of NAT2 activity by grapefruit juice. Examination of blood plasma with DR CALUX showed a 12% increased AhR agonist activity 3 and 24 h after consumption of cruciferous vegetables, but did not show a significant effect of grapefruit juice consumption. We conclude that intake of NAhRAs from food may result in minor AhR-related effects measurable in human blood and urine.
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PMID:A human intervention study with foods containing natural Ah-receptor agonists does not significantly show AhR-mediated effects as measured in blood cells and urine. 1876 78

1. Quercetin, one of the most abundant natural flavonoids, has been reported to modulate the activity of several drug-metabolising enzymes. The aim of the present study was to investigate the effects of quercetin on cytochrome P450 (CYP) 1A2, CYP2A6, N-acetyltransferase (NAT2) and xanthine oxidase (XO) activity in healthy volunteers using caffeine as a probe drug. 2. Twelve unrelated, healthy volunteers were recruited to the study. There were two phases to the study; in the first phase, each subject was given a single oral dose of caffeine (one 100 mg capsule) with 150 mL water; in the second phase, each subject was give a 500 mg quercetin capsule once daily for 13 continuous days and was coadministered a 100 mg caffeine capsule on the 13th day. Urinary caffeine metabolite ratios were used as indicators of the activity of CYP1A2, CYP2A6, NAT2 and XO. The pharmacokinetics of caffeine and its metabolites were determined by HPLC. 3. In the quercetin-treated group, CYP1A2 activity was decreased by 10.4% (95% confidence interval (CI), 1.1-29.8%; P = 0.039), whereas increases were observed in CYP2A6 (by 25.3%; 95% CI, 6.2-34.5%; P = 0.002), NAT2 (by 88.7%; 95% CI, 7.1-160.2%; P = 0.010) and XO activity (by 15.0%; 95% CI, 1.6-21.6%; P = 0.007). Plasma C(max) and the AUC((0-24 h)) of 1,7-dimethylxanthine were decreased by 17.2% (95% CI, 6.4-28.0%; P = 0.024) and 16.2% (95% CI, 3.9-28.5%; P = 0.032), respectively. The urinary excretion of 1,7-dimethylxanthine and 1-methylxanthine was significantly decreased by 32.4% (95% CI, 2.5-62.1%; P = 0.036) and 156.1% (95% CI, 53.3-258.9%; P = 0.004), respectively. The urinary excretion of 1,7-dimethylurate and 1-methylurate was increased by 82.9% (95% CI, 56.0-165.4%; P = 0.030) and 97.8% (95% CI, 12.1-183.5%; P = 0.029), respectively. No changes were observed in the urinary excretion of caffeine and 5-acetylamino-6-formylamino-3-methyluracil between the two study phases. 4. The results of the present study indicate that quercetin inhibits CYP1A2 function, but enhances CYP2A6, NAT2 and XO activity. Simultaneously, some pharmacokinetic parameters relating to 1,7-dimethylxanthine were affected by quercetin. Thus, we conclude that quercetin affects CYP1A2, CYP2A6, NAT2 and XO activity in vivo.
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PMID:Simultaneous action of the flavonoid quercetin on cytochrome P450 (CYP) 1A2, CYP2A6, N-acetyltransferase and xanthine oxidase activity in healthy volunteers. 1921 33


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