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)

In this paper we demonstrate that in the absence of free metal ions, active oxygen species, generated by activated macrophages or xanthine/xanthine oxidase (XOD), carry out oxidative degradation of collagen fibrils type I in conjunction with proteases. The collagen degradation is completely prevented by ascorbate (AH2) but not by catalase. The free metal ion-independent collagen degradation is a two-step process: (i) oxidation of collagen and (ii) subsequent proteolytic cleavage of the oxidatively modified collagen. AH2 completely prevents collagen oxidation and thereby protects the collagen from subsequent proteolytic degradation. This is in contrast to free metal ion-catalyzed spontaneous fragmentation of collagen, which is accelerated by AH2 and inhibited by catalase (Kato, Y., Uchida, K., and Kawakishi, S. (1992) J. Biol. Chem. 267, 23646-23651). Studies using xanthine/XOD and model polypeptides, namely, poly-L-Pro, poly-L-hydroxyproline, poly-L-Lys, and poly(Pro-Gly-Pro) indicate that although O2-. is needed along with XOD, oxidation of model polypeptides appears to be a direct function of XOD iron, which is also stimulated by cytochrome P450.
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PMID:Free metal ion-independent oxidative damage of collagen. Protection by ascorbic acid. 798 27

The characterization of the enzymatic step(s) involved in the reduction of 3'-azido-3'-deoxythymidine (zidovudine)(ZDV) to 3'-amino-3'-deoxythymidine (AMT) was pursued. AMT formation by human liver microsomes was NADPH dependent, enhanced under anaerobic conditions, and increased by flavin adenine dinucleotide (FAD) and FMN. Carbon monoxide inhibited AMT formation by up to 80%. The effect of theophylline (CYP1A substrate), tolbutamide (CYP2C substrate), chlorzoxazone, thiobenzamide, p-nitrophenol, mercaptoethanol, isoniazid (CYP2E substrates), cortisol (CYP3A substrate), ketoconazole, itraconazole, fluconazole, cimetidine, micronazole (CYP inhibitors), methimazole (flavin-containing mono-oxygenase inhibitor), chloramphenicol (undergoes nitroreduction), allopurinol (xanthine oxidase inhibitor) and dicoumarol (DT-diaphorase inhibitor) on AMT formation were studied to see if the reduction reaction was mediated by a particular isozyme. The greatest inhibition was observed with ketoconazole (concentration producing 50% inhibition = 78.0 microM). At this concentration ketoconazole acted as a non-selective inhibitor of several CYP isozymes. Overall, these data suggested that ZDV reduction was probably mediated by both cytochrome P450 isozymes and NADPH-cytochrome P450 reductase. Formation of AMT, as measured by intrinsic clearance (Clint), was significantly increased in microsomes from rats pre-treated with phenobarbitone, dexamethasone and clofibrate (inducers of CYP2B, CYP3A and CYP4A, respectively). Pre-treatment of rats with beta-naphthoflavone and ethanol (CYP1A and CYP2E1 inducers, respectively) had no effect on AMT formation.
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PMID:The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. 805 24

Microsomes and reconstituted systems containing cytochrome P450 can oxidize glycerol to formaldehyde in a reaction catalyzed by an oxidant produced from the interaction of nonheme iron with H2O2. To evaluate the mechanism for this oxidation, the generation of glycerol radicals by various systems was compared to rates of formaldehyde production from glycerol. Photolysis of H2O2, oxidation of xanthine by xanthine oxidase in the presence of iron catalysts, or NADPH-dependent microsomal electron transfer in the presence of ferric-EDTA produced hydroxyl radicals. In the presence of glycerol these reaction systems produced DMPO-glycerol radical adducts which were detected by ESR spectroscopy. Despite the production of .OH and glycerol spin-trapped adducts by these reaction systems, very low amounts or nondetectable amounts of formaldehyde were produced from the glycerol. However, significant amounts of formaldehyde were observed when microsomes were incubated in the presence of ferric ammonium sulfate or ferric-ATP, although .OH production was lower with these iron catalysts than with ferric-EDTA. These results fail to support correlation between .OH production and oxidation of glycerol to formaldehyde. Under conditions in which glycerol was oxidized to formaldehyde, no glycerol radical species could be observed with DMPO as the spin-trapping agent. These results suggest the oxidant (not .OH) derived from the interaction of H2O2 with iron apparently cleaves glycerol to formaldehyde without the formation of a radical intermediate. Alternatively, the radical intermediate may be produced at a too low concentration to be detected or the radical intermediate may not be formed as a free species and therefore cannot be spin-trapped.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxidation of glycerol to formaldehyde by microsomes: are glycerol radicals produced in the reaction pathway? 806 25

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

Oxygen free radicals may be generated during ethanol metabolization by cytochrome P450, or due to the formation of xanthine oxidase by ethanol effect on xanthine dehydrogenase. After transformation into acetaldehyde, the metabolism of this compound by xanthine oxidase or by aldehyde oxidase also generates oxygen radicals. We present the hypothesis of a vicious cycle during ethanol metabolization by aldehyde oxidase, which would amplify the process and be responsible for an increased degree of lipid peroxidation.
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PMID:[Alcohol and free oxygen radicals]. 839 65

Oxidation of the experimental anti-tumour agent N-[(2'-dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601316; acridine carboxamide) to the 9(10H)acridone, followed by ring hydroxylation and glucuronidation, appears to be the main pathway of detoxication of AC in the rat and mouse. The acridone formation has been further characterized in vitro using an enzyme-enriched fraction where activity per milligram protein is increased approximately 10-fold compared with the cytosolic fraction. Inhibition by amsacrine [4'-(9-acridinylamino)methanesulphon-m-anisidide; NSC 249992] and menadione (50% inhibition at 6.4 and 1.8 microM, respectively) but not allopurinol (to 30 microM) indicates that the activity is due to aldehyde oxidase, without the involvement of xanthine oxidase. Interestingly, acridone formation in both the cytosolic and enzyme-enriched fractions is highly sensitive to the classical cytochrome P450 inhibitor SKF-525A [proadifen hydrochloride; 2'-(diethylamino)ethyl 2,2-diphenylpentenoate] (50% inhibition at 9.2 and 1.9 microM, respectively). Further analysis indicates mixed non-competitive type inhibition by SKF-525A (K(is), 0.3 microM; K(ii), 4.9 microM). Little or no inhibition was seen with cimetidine, metyrapone or methimazole. No NADPH-dependent acridone formation was observed with the microsomal fraction. These data indicate that acridone formation previously observed in isolated rat hepatocytes and in vivo is most likely due to aldehyde oxidase rather than cytochrome P450.
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PMID:Inhibition by SKF-525A of the aldehyde oxidase-mediated metabolism of the experimental antitumour agent acridine carboxamide. 851 97

Pretreatment of porcine aortic endothelial cells with high D-glucose results in enhanced endothelium-derived relaxing factor (EDRF) formation (39%) due to increased endothelial Ca2+ release (57%) and Ca2+ entry (97%) to bradykinin. This study was designed to investigate the intracellular mechanisms by which high D-glucose affects endothelial Ca2+/EDRF response. The aldose-reductase inhibitors, sorbinil and zopolrestat, failed to diminish high D-glucose-mediated alterations in Ca2+/EDRF response, suggesting that aldose-reductase does not contribute to high D-glucose-initiated changes in Ca2+/EDRF signaling. Pretreatment of cells with the nonmetabolizing D-glucose analog, 3-O-methylglucopyranose (3-OMG), mimicked the effect of high D-glucose on Ca2+ release (41%) and Ca2+ entry (114%) to bradykinin, associated with elevated EDRF formation (26%). High D-glucose and 3-OMG increased superoxide anion (O2-) formation (133 and 293%, respectively), which was insensitive to inhibitors of cyclooxygenase (5,8,11,14-eicosatetraynoic acid [ETYA], indomethacin), lipoxygenase (ETYA, gossypol, nordihydroguaiaretic acid [NDGA]), cytochrome P450 (NDGA, econazole, miconazole), and nitric oxide (NO) synthase (L-omega N-nitroarginine), while it was diminished by desferal, a metal chelator. The gamma-glutamyl-cysteine-synthase inhibitor, buthioninesulfoximine (BSO), also increased formation of O2- by 365% and mimicked the effect of high D-glucose on Ca2+/EDRF signaling. The effects of high D-glucose, 3-OMG, and BSO were abolished by co-incubation with superoxide dismutase. Like high D-glucose, pretreatment with the O2(-)-generating system, xanthine oxidase/hypoxanthine, elevated bradykinin-stimulated Ca2+ release (+10%), Ca2+ entry (+75%), and EDRF (+73%). We suggest that prolonged exposure to pathologically high D-glucose concentration results in enhanced formation of O2-, possibly due to metal-mediated oxidation of D-glucose within the cells. This overshoot of O2- enhances agonist-stimulated Ca2+/EDRF signaling via a yet unknown mechanism.
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PMID:High D-glucose-induced changes in endothelial Ca2+/EDRF signaling are due to generation of superoxide anions. 882 76

The mechanism for ethanol-induced oxidative stress has been disputed because of the controversies on modulation of radical generating and scavenging activities by ethanol. In the present work, we attempted to clarify the acute effect of ethanol on the radical generating system as well as the radical scavenging system. For that purpose, chow-fed rats were given ethanol (5 g/kg) or isocaloric glucose solution by intragastric intubation and placed at 32 degrees C for 6 hr. Acute ethanol administration enhanced the expression of cytochrome P450 II E1(CYP II E1) in the liver and attenuated the activities of hepatic glutathione peroxidase (GPx) and reductase (GR). It also caused a significant increase in the level of hepatic thiobarbituric acid reactive substances (TBARS), an indicator of lipid peroxidation. On the other hand, acute ethanol feeding had no effect on the activities of catalase, xanthine oxidase (XO), glutathione transferase (GST) and glucose-6-phosphate dehydrogenase (G6PDH). From this result, it is suggested that acute ethanol administration causes the oxidative tissue damage by CYP II E1-associated radical generation and the decreased radical scavenging function due to the reduced activities of hepatic glutathione recycling system such as GPx and GR.
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PMID:Glutathione recycling is attenuated by acute ethanol feeding in rat liver. 928 31

Oxidative stress is well recognized to be a key step in the pathogenesis of ethanol-associated liver injury. Ethanol administration induces an increase in lipid peroxidation either by enhancing the production of oxygen reactive species and/or by decreasing the level of endogenous antioxidants. Numerous experimental studies have emphasized the role of the ethanol-inducible cytochrome P450 in the microsomes and the molybdo-flavoenzyme xanthine oxidase in the cytosol. This review shows the putative role of ethanol-induced disturbances in iron metabolism in relation to iron as a pro-oxidant factor. Ethanol administration also affects the mitochondrial free radical generation. Many previous studies suggest a role for active oxygens in ethanol-induced mitochondrial dysfunction in hepatocytes. Recent studies in our laboratory in the Department of Internal Medicine, Keio University, using a confocal laser scanning microscopic system strongly suggest that active oxidants generated during ethanol metabolism produce mitochondrial membrane permeability transition in isolated and cultured hepatocytes. In addition, acetaldehyde, ethanol consumption-associated endotoxaemia and subsequent release of inflammatory mediators may cause hepatocyte injury via both oxyradical-dependent and -independent mechanisms. These cytotoxic processes may lead to lethal hepatocyte injury. Investigations further implicate the endogenous glutathione-glutathione peroxidase system and catalase as important antioxidants and cytoprotective machinery in the hepatocytes exposed to ethanol.
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PMID:Pathogenesis of alcoholic liver disease with particular emphasis on oxidative stress. 940 47

In addition to cytochrome P450, oxidation of drugs and other xenobiotics can also be mediated by non-P450 enzymes, the most significant of which are flavin monooxygenase, monoamine oxidase, alcohol dehydrogenase, aldehyde dehydrogenase, aldehyde oxidase and xanthine oxidase. This article highlights the importance of these non-P450 enzymes in drug metabolism. A brief introduction to each of the non-P450 oxidizing enzymes is given in this review and the oxidative reactions have been illustrated with clinical examples. Drug oxidation catalyzed by enzymes such as flavin monooxygenase and monoamine oxidase may often produce the same metablolites as those generated by P450 adn thus drug interactions may be difficult to predict without a clear knowledge of the underlying enzymology. In contrast, oxidation via aldehyde oxidase and xanthine oxidase gives different metabolites to those resulting from P450 hydroxylation. Although oxidation catalyzed by non-P450 enzymes can lead to drug inactivation, oxidation may be essential for the generation of active metabolite(s). The activation of a number of prodrugs by non-P450 enzymes is thus described. It is concluded that there is still much to learn about factors affecting the non-P450 enzymes in the clinical situation.
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PMID:The role of non-P450 enzymes in drug oxidation. 944 66


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