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)

1. Ethanol metabolism in slices or homogenates of transplantable hepatocellular carcinoma HC-252 (HC-252) was 50 to 60% of the rate found in host liver slices or homogenates when they were expressed per gram of tissue wet weight and 70 to 80% of the liver when the rates were expressed per milligram of tissue protein. At 10 mM ethanol, the activities of alcohol dehydrogenase in tumor and liver supernatants were comparable. 2. Tumor microsomes did not oxidize ethanol in the presence of a NADPH-generating system, indicating the absence of the microsomal ethanol-oxidizing system and catalase-mediated peroxidation of ethanol. The HC-252 microsomes were contaminated with catalase, and acetaldehyde production occurred in the presence of a H2O2-generating system (xanthine oxidase). The virtual absence of ethanol oxidation and drug metabolism (aminopyrine demethylase and aniline hydroxylase) in HC-252 microsomes may be due to the low activities of NADPH-cytochrome c reductase, NADPH oxidase, and NADPH-dependent oxygen uptake. 3. Microsomal oxidation of ethanol was present in Morris hepatoma 5123C, a well-differentiated tumor of intermediate growth rate, while activity was negligible in microsomes from Morris hepatoma 7288CTC, a less differentiated tumor. Microsomal NADPH oxidase was present in the well differentiated tumor 5123C but was lacking in the less differentiated tumor 7288CTC. Several microsomal, mitochondrial, and cytosolic properties of HC-252 are similar to those of Morris hepatoma 7288CTC but differ from those of the more differentiated 5123C tumor and normal liver. 4. The content of mitochondrial protein in HC-252 was only 25% that of liver, and oxygen consumption per gram of tumor was only 28% that of the liver. When corrected for the mitochondrial protein content, oxygen uptake in tumor HC-252 and liver homogenates was comparable. Isolated tumor and liver mitochondria displayed comparable State 4 and 3 rates of oxygen consumption with succinate and glutamate as substrates. The activities of the reconstituted malate-aspartate and alpha-glycerophosphate shuttles were only slightly lower in isolated HC-252 mitochondria compared to liver mitochondria, when shuttles were reconstituted with purified enzymes. 5. Antimycin inhibited alcohol metabolism,and pyruvate stimulated alcohol metabolism, much less in tumor slices than in liver slices, suggesting the presence of an augmented mitochondria-independent, cytosolic mechanism for oxidizing reducing equivalents in the tumor. These factors suggest that oxidation of NADH is the limiting factor in ethanol metabolism. Whereas, in the liver mitochondrial reoxidation is predominant, in HC-252, cytosolic reoxidation of NADH also plays a major role.
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PMID:Ethanol metabolism by a transplantable hepatocellular carcinoma. Role of microsomes and mitochondria. 13 37

1. Cellulose acetate zymograms of alcohol dehydrogenase (ADH), aldehyde dehydrogenase, sorbitol dehydrogenase, aldehyde oxidase, "phenazine" oxidase and xanthine oxidase extracted from tissues of inbred mice were examined. 2. ADH isozymes were differentially distributed in mouse tissues: A2--liver, kidney, adrenals and intestine; B2--all tissues examined; C2--stomach, adrenals, epididymis, ovary, uterus, lung. 3. Two NAD+-specific aldehyde dehydrogenase isozymes were observed in liver and kidney and differentially distributed in other tissues. Alcohol dehydrogenase, aldehyde oxidase, "phenazine" oxidase and xanthine oxidase were also stained when aldehyde dehydrogenase was being examined. 4. Two aldehyde oxidase isozymes exhibited highest activities in liver. 5. "Phenazine oxidase" was widely distributed in mouse tissues whereas xanthine oxidase exhibited highest activity in intestine and liver extracts. 6. Genetic variants for ADH-C2 established its identity with a second form of sorbitol dehydrogenase observed in stomach and other tissues. The major sorbitol dehydrogenase was found in high activity in liver, kidney, pancreas and male reproductive tissues.
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PMID:Electrophoretic analyses of alcohol dehydrogenase, aldehyde dehydrogenase, aldehyde oxidase, sorbitol dehydrogenase and xanthine oxidase from mouse tissues. 31 79

1. Enzyme systems responsible for formation of cyclopropane ring-cleavage metabolites (M1 and M2) of illudin S in rat liver were characterized. 2. The enzymes were localized in the cytosol fraction and utilized NADPH alone as electron donor; they were not affected by oxygen and had low pH optima. 3. Formation of metabolites M1 and M2 was inhibited completely by dicumarol (10(-4) M), an inhibitor of DT-diaphorase. 4. Menadione (10(-4) M) and quercetin (10(-4) M) both inhibited formation of M1 and M2 by 35% and 15%, respectively, but quinacrine, barbital, pyrazole and p-chloromercuribenzoic acid had no significant effect. 5. Results show that the enzyme systems may differ from DT-diaphorase, aldehyde oxidase, xanthine oxidase, ketone reductase, aldose reductase, aldehyde reductase and alcohol dehydrogenase, known cytosolic enzymes responsible for xenobiotic metabolism.
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PMID:Metabolism by rat liver cytosol of illudin S, a toxic substance of Lampteromyces japonicus. II. Characterization of illudin S-metabolizing enzyme. 137 39

Doxorubicin is an antineoplastic drug which undergoes oxidation-reduction cycling and produces toxicity to some cancer cell lines. Since oxidation-reduction cycling requires reducing equivalents and because ethanol metabolism via alcohol dehydrogenase (ADH) increases NADH, the effect of ethanol on doxorubicin toxicity was examined in cultured cells. Since some cells exhibit resistance to anthracyclines such as doxorubicin, two different Chinese hamster ovary cell lines were used, one sensitive (AUX B1) and one resistant (CHRC5) to doxorubicin. Studies were designed to determine if ethanol could decrease resistance to doxorubicin. Cells were treated for 24 h with doxorubicin in the presence or absence of ethanol, and the number of live cells was estimated spectrophotometrically. Ethanol (60-150 mM) potentiated the doxorubicin-induced decrease in cell number in both cell lines. In AUX B1 cells the concentration of doxorubicin required for half-maximal inhibition of cell survival was reduced 20-fold by ethanol, and a completely nontoxic concentration of doxorubicin decreased the number of surviving cells to 30% in the presence of ethanol. Addition of ethanol to the medium also increased doxorubicin-induced inhibition of cell survival in CHRC5 cells, but the effect was less dramatic than in AUX B1 cells. The effect of ethanol on cell number was concentration related; the half-maximal response was observed with about 1 mM ethanol. The hypothesis that ethanol potentiates doxorubicin toxicity by generation of NADH during metabolism by ADH was strengthened by the observations that both cell lines possess ADH activity (30-400 units/10(12) cells) and that ethanol (0.1-0.5 mM) increased NADH fluorescence 15-80% over basal values in cultured cells. Further, the effect of doxorubicin on cell number was also potentiated by another substrate for ADH, 2-ethylhexanol. Desferrioxamine, an iron chelator, increased survival in cells treated with doxorubicin plus ethanol by up to 60% (half-maximal effect, 1 mM), and (+)-catechin, a radical scavenger, abolished the decrease in cell number due to doxorubicin plus ethanol at concentrations greater than 0.1 mM. Allopurinol, an inhibitor of xanthine oxidase with radical scavenging properties, diminished the effect of doxorubicin plus ethanol on cell number by 60% (P less than 0.05). Taken together, these data are consistent with the hypothesis that ethanol potentiates toxicity due to doxorubicin by providing reducing equivalents for oxidation-reduction cycling which produce toxic reduced oxygen species.
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PMID:Ethanol potentiates doxorubicin-induced inhibition of cell survival in cultured Chinese hamster ovary cells. 200 22

Reactive oxygen metabolites generated from the enzyme xanthine oxidase (XO) play an important role in the pathogenesis of ischemia-induced tissue injury. The observation that intracellular proteins such as aspartate transaminase (AST) and alcohol dehydrogenase (ADH) are released from the ischemic liver during reperfusion led us to postulate that XO could be released into the systemic circulation. Livers from fasted rats were extirpated, perfused with oxygenated Krebs-Henseleit buffer, and subjected to 2 h ischemia followed by 2 h reperfusion. Reperfusion increased AST in the perfusate from 1 +/- 1 to 830 +/- 280 U/l, whereas ADH increased from 0.3 +/- 0.1 to 95 +/- 26 U/l. Concomitantly, xanthine dehydrogenase (XDH) + XO activity in the perfusate increased from 0 to 4.1 +/- 1.0 mU/ml. A 64% decrease in endogenous tissue XDH + XO activity paralleled release of XDH + XO. The XDH + XO activity predicted to appear in the circulation after hepatic ischemia was sufficient, when supplied with substrate, to produce severe vascular endothelial injury in vitro, even in the presence of serum or whole blood. These results suggest that massive quantities of XDH and XO are released into the circulation after hepatic ischemia and that the resulting reactive oxygen metabolites could produce widespread tissue injury.
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PMID:Circulating xanthine oxidase: potential mediator of ischemic injury. 233 69

Effects of four main inhibitors of rat liver tissue alcohol dehydrogenase (4-methyl pyrasol, dimethyl sulfoxide, amide isovaleric acid and dioxime benzoylacetic aldehyde) were studied. Constants and type of inhibition of these substances were evaluate. Effects of these inhibitors on alternative pathways of aliphatic alcohols oxidation were studied: on microsomal ethanol oxidizing system, catalase, xanthine oxidase and on aldehyde dehydrogenases.
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PMID:[Alcohol dehydrogenase inhibitors and their effect on major enzymatic systems involved in oxidation of aliphatic alcohols]. 238 35

Evidence in alcoholics as well as in experimental models support the role of hepatic lipid peroxidation in the pathogenesis of alcohol-induced liver injury, but the mechanism of this injury is not fully delineated. Previous studies of the metabolism of ethanol by alcohol dehydrogenase revealed iron mobilization from ferritin that was markedly stimulated by superoxide radical generation by xanthine oxidase. Peroxidation of hepatic lipid membranes (assessed as malondialdehyde production) was studied during in vitro alcohol metabolism by alcohol dehydrogenase. Peroxidation was initiated by acetaldehyde-xanthine oxidase, stimulated by ferritin, and inhibited by superoxide dismutase or chelation or iron with desferrioxamine. In conclusion, lipid peroxidation may be initiated during the metabolism of ethanol by alcohol dehydrogenase by an iron-dependent acetaldehyde-xanthine oxidase mechanism.
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PMID:Acetaldehyde-mediated hepatic lipid peroxidation: role of superoxide and ferritin. 303 92

Pyrazole, an effective inhibitor of alcohol dehydrogenase, was previously shown to be a scavenger of the hydroxyl radical. 4-Hydroxypyrazole is a major metabolite in the urine of animals administered pyrazole in vivo. Experiments were conducted to show that 4-hydroxypyrazole was a product of the interaction of pyrazole with hydroxyl radical generated from three different systems. The systems utilized were the iron-catalyzed oxidation of ascorbate, the coupled oxidation of hypoxanthine by xanthine oxidase, and NADPH-dependent microsomal electron transfer. Ferric-EDTA was added to all the systems to catalyze the production of hydroxyl radicals. A HPLC procedure employing either uv detection or electrochemical detection was utilized to assay for the production of 4-hydroxypyrazole. The three systems all supported the oxidation of pyrazole to 4-hydroxypyrazole by a reaction which was sensitive to inhibition by competitive hydroxyl radical scavengers such as ethanol, mannitol, or dimethyl sulfoxide and to catalase. The sensitivity to catalase implicates H2O2 as the precursor of the hydroxyl radical by all three systems. Superoxide dismutase inhibited production of 4-hydroxypyrazole only in the xanthine oxidase reaction system. In the absence of ferric-EDTA (and azide), microsomes catalyzed the oxidation of pyrazole to 4-hydroxypyrazole by a cytochrome P-450-dependent reaction which was independent of hydroxyl radicals. This latter pathway may be primarily responsible for the in vivo metabolism of pyrazole to 4-hydroxypyrazole. The production of 4-hydroxypyrazole from the interaction of pyrazole with hydroxyl radicals may be a sensitive, rapid technique for the detection of these radicals in certain tissues or under certain conditions, e.g., increasing oxidative stress.
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PMID:Production of 4-hydroxypyrazole from the interaction of the alcohol dehydrogenase inhibitor pyrazole with hydroxyl radical. 303 2

A single oral administration of ethanol (5 g/kg) to rats induced a marked increase in lipid peroxidation, in the liver and kidney within 9 hr, as assessed by malondialdehyde accumulation. The pretreatment with alcohol dehydrogenase (ADH) inhibitor, 4-methylpyrazole (1 mmol/kg) caused approximately 50% inhibition of the hepatic ADH activity and abolished this ethanol-induced lipid peroxidation. The disulfiram treatment (100 mg/kg) significantly inhibited 63% of the hepatic low Km aldehyde dehydrogenase (ALDH) but not the high Km ALDH. The cyanamide treatment (15 mg/kg) effectively decreased 83% of the low Km and 70% of the high Km ALDH in the liver. Although there was more than a 20-fold elevation of acetaldehyde levels by the inhibition of acetaldehyde metabolism with disulfiram or cyanamide, the ethanol-induced lipid peroxidation was significantly suppressed by pretreatment with these drugs. More than 90% inhibition of xanthine oxidase and dehydrogenase by the pretreatment with allopurinol (100 mg/kg), with no effect on the hepatic ADH and ALDH activities, did not alter the enhancement of lipid peroxidation following ethanol administration. We propose that the metabolism of acetaldehyde (probably via the low Km ALDH) and not acetaldehyde itself is responsible for the ethanol-induced lipid peroxidation in vivo and that the contribution of xanthine oxidase, as an initiator of lipid peroxidation through acetaldehyde oxidation is minute during acute intoxication.
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PMID:The metabolism of acetaldehyde and not acetaldehyde itself is responsible for in vivo ethanol-induced lipid peroxidation in rats. 317 76

Ethanol at initial concentrations between 0.75 and 6 g/l produced a dose-dependent release of the enzymes glutamic-pyruvic-transaminase and sorbitol dehydrogenase (GPT, SDH) from the isolated perfused rat liver. At the concentration of 6 g/l, it also decreased the oxygen consumption and elevated the calcium content of the isolated livers. These toxic effects of ethanol were significantly enhanced in livers, the glutathione content of which had been depleted by pretreatment with phorone. Ethanol-induced toxicity in glutathione-depleted isolated livers could be prevented both by inhibition of alcohol dehydrogenase with 4-methylpyrazole and of xanthine oxidase with allopurinol. In rats, in vivo, 1.6 g/kg ethanol injected intravenously produced a small increase in serum GPT and SDH concentrations 4 h after its administration. This increase in enzyme activities was several-fold higher and longer lasting in rats pretreated with phorone. Glutathione depletion per se did not induce hepatotoxicity in vitro or in vivo. Since glutathione is involved in several lines of defense against oxidative damage, our results of an enhanced susceptibility of glutathione-depleted livers to ethanol toxicity favour the hypothesis that ethanol exerts its hepatotoxic action via an activation of molecular oxygen.
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PMID:Enhancement by glutathione depletion of ethanol-induced acute hepatotoxicity in vitro and in vivo. 360 86


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