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)

The oxidation of acetaldehyde (generated from the metabolism of ethanol) by oxidases such as xanthine oxidase generates free radicals which can mobilize ferritin iron, alter hepatic glutathione and produce lipid peroxidation. The stomach, a site of ethanol metabolism and rich in xanthine oxidase, was studied with respect to the effects of ethanol on intrinsic factor (IF) binding of vitamin B-12 as well as gastric glutathione (GSH). Incubations of gastric homogenates with acetaldehyde-xanthine oxidase inhibited the B-12 binding ability by IF. A large acute dose of ethanol in vivo (5 g/kg, conc. greater than 40% w/v) decreased gastric IF binding of B-12 and depressed gastric GSH; these effects were markedly attenuated by the feeding of sodium tungstate which inhibited xanthine oxidase. Changes in B-12 binding paralleled changes in gastric GSH. Scatchard plots of IF binding of B-12 for homogenates suggested decreased number of binding sites rather than altered affinity. In conclusion, the gastric metabolism of ethanol generates free radicals which alter IF binding of B-12, depress gastric GSH and may play a role in alcohol-induced gastric injury.
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PMID:Effect of ethanol-generated free radicals on gastric intrinsic factor and glutathione. 232 89

Hepatic lipid peroxidation has been implicated in the pathogenesis of alcohol-induced liver injury, but the mechanism(s) by which ethanol metabolism or resultant free radicals initiate lipid peroxidation is not fully defined. The role of the molybdenum-containing enzymes aldehyde oxidase and xanthine oxidase in the generation of such free radicals was investigated by measuring alkane production (lipoperoxidation products) in isolated rat hepatocytes during ethanol metabolism. Inhibition of aldehyde oxidase and xanthine oxidase (by feeding tungstate at 100 mg/day per kg) decreased alkane production (80-95%), whereas allopurinol (20 mg/kg by mouth), a marked inhibitor of xanthine oxidase, inhibited alkane production by only 35-50%. Addition of acetaldehyde (0-100 microM) (in the presence of 50 microM-4-methylpyrazole) increased alkane production in a dose-dependent manner (Km of aldehyde oxidase for acetaldehyde 1 mM); menadione, an inhibitor of aldehyde oxidase, virtually inhibited alkane production. Desferrioxamine (5-10 microM) completely abolished alkane production induced by both ethanol and acetaldehyde, indicating the importance of catalytic iron. Thus free radicals generated during the metabolism of acetaldehyde by aldehyde oxidase may be a fundamental mechanism in the initiation of alcohol-induced liver injury.
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PMID:The role of aldehyde oxidase in ethanol-induced hepatic lipid peroxidation in the rat. 236 95

Aldophosphamide, the penultimate cytotoxic metabolite of cyclophosphamide, can be detoxified by an oxidation reaction catalyzed by certain aldehyde dehydrogenases. The selective toxicity of cyclophosphamide is due, at least in part, to a greater expression of the relevant aldehyde dehydrogenase activity in normal cells relative to that expressed in certain tumor cells. Not known at the onset of this investigation was which of the several known mouse aldehyde dehydrogenases catalyze this reaction. Twelve enzymes that catalyze the NAD(P)-linked oxidation of aldophosphamide, acetaldehyde, benzaldehyde, and/or octanal were chromatographically resolved from mouse liver. Four of these appear to be novel; four others were determined to be betaine aldehyde dehydrogenase, succinic semialdehyde dehydrogenase, glutamic gamma-semialdehyde dehydrogenase, and xanthine oxidase (dehydrogenase). An additional aldehyde dehydrogenase, namely AHD-4, was semipurified from stomach. The stomach enzyme and nine of the hepatic enzymes catalyze the oxidation of aldophosphamide. Km values for these reactions range from 16 microM to 2.5 mM. The relevant aldehyde dehydrogenase of major importance varies with the tissue. In the liver, the major cytosolic aldehyde dehydrogenase, namely AHD-2, accounts for greater than 60% of total hepatic aldehyde dehydrogenase-catalyzed aldophosphamide (160 microM) detoxification. Succinic semialdehyde dehydrogenase (AHD-12) and three of the novel hepatic aldehyde dehydrogenases, namely AHD-8, AHD-10, and AHD-13, also contribute significantly to total hepatic aldehyde dehydrogenase-catalyzed aldophosphamide detoxification. In the stomach, AHD-4 and AHD-8 account for approximately 86% of total aldehyde dehydrogenase-catalyzed aldophosphamide (160 microM) detoxification. AHD-2 was not found in this tissue. Of all the aldehyde dehydrogenases examined, AHD-2 and AHD-8 were estimated to be the most efficient catalysts of aldophosphamide oxidation. Thus, these enzymes would seem most likely to be operative when tumor cells acquire aldehyde dehydrogenase-mediated cyclophosphamide resistance.
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PMID:Identification of the mouse aldehyde dehydrogenases important in aldophosphamide detoxification. 237 64

The mechanism by which hypoxia leads to irreversible cellular damage is poorly understood. A decrease in purine nucleotides is common to all ischaemic tissues, yielding hypoxanthine as the substrate of the xanthine oxidase reaction. Excessive production of radicals via xanthine oxidase induces peroxidation of unsaturated fatty acids, accompanied with the formation of aldehydes. The nucleotides and aldehydes were determined by high-performance liquid chromatography (HPLC) of red blood cell extracts. Nucleotides and their derivatives were determined by HPLC on an ODS column and elution with 10 mM phosphate buffer containing 2 mM tert.-butylammonium phosphate. The aldehyde production in glucose deprived red blood cells was stimulated by addition of xanthine oxidase and by inhibition of different haemotype enzymes with sodium azide. Aldehydes were analysed by derivatization to dinitrophenylhydrazones, followed by thin-layer chromatographic and HPLC separation with aqueous methanol on an ODS column. The HPLC methods presented are appropriate for the determination of nucleotides, nucleosides and nucleobases, in addition to alkenals and hydroxyalkenals in extracts of oxidatively stressed red blood cells.
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PMID:Interrelation between nucleotide degradation and aldehyde formation in red blood cells. Influence of xanthine oxidase on metabolism: an application of nucleotide and aldehyde analyses by high-performance liquid chromatography. 238 Feb 99

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

Although folate deficiency and increased requirements for folate are observed in most alcoholics, the possibility that acetaldehyde generated from ethanol metabolism may increase folate catabolism has not been previously demonstrated. Folate cleavage was studied in vitro during the metabolism of acetaldehyde by xanthine oxidase, measured as the production of p-aminobenzoylglutamate from folate using h.p.l.c. Acetaldehyde/xanthine oxidase generated superoxide, which cleaved folates (5-methyltetrahydrofolate greater than folinic acid greater than folate) and was inhibited by superoxide dismutase. Cleavage was increased by addition of ferritin and inhibited by desferrioxamine (a tight chelator of iron), suggesting the importance of catalytic iron. Superoxide generated from the metabolism of ethanol to acetaldehyde in the presence of xanthine oxidase in vivo may contribute to the severity of folate deficiency in the alcoholic.
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PMID:Cleavage of folates during ethanol metabolism. Role of acetaldehyde/xanthine oxidase-generated superoxide. 253 25

The ability of acetaldehyde to generate free radicals is often ascribed to its oxidation by xanthine oxidase, with the subsequent production of reactive oxygen intermediates. Chemiluminescence associated with the oxidation of acetaldehyde by xanthine oxidase was inhibited by superoxide dismutase, catalase, or several hydroxyl radical scavenging agents, and was stimulated by the addition of EDTA or ferric-EDTA. This suggests that the light emission is primarily due to the production of hydroxyl radicals via an iron-catalyzed Haber-Weiss type of reaction. Chemiluminescence with hypoxanthine as substrate for xanthine oxidase was much lower than that found with acetaldehyde, yet rates of hydroxyl radical production were greater with hypoxanthine. Acetaldehyde increased light emission in the presence of hypoxanthine by a greater than additive effect. These results suggest a complex role for acetaldehyde in catalyzing xanthine oxidase-dependent chemiluminescence. It appears that besides being a substrate for xanthine oxidase, acetaldehyde also reacts with the generated hydroxyl radical to produce acetaldehyde radicals, which yield chemiluminescence upon their decay. Further studies will be required to evaluate whether the production of such species contributes to or plays a role in the generation of reactive oxygen intermediates and toxicity associated with acetaldehyde metabolism.
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PMID:Chemiluminescence from acetaldehyde oxidation by xanthine oxidase involves generation of and interactions with hydroxyl radicals. 253 93

Stimulated neutrophils discharge large quantities of superoxide (O2.-), which dismutates to form H2O2. In combination with Cl-, H2O2 is converted into the potent oxidant hypochlorous acid (HOCl) by the haem enzyme myeloperoxidase. We have used an H2O2 electrode to monitor H2O2 uptake by myeloperoxidase, and have shown that in the presence of Cl- this accurately represents production of HOCl. Monochlorodimedon, which is routinely used to assay production of HOCl, inhibited H2O2 uptake by 95%. This result confirms that monochlorodimedon inhibits myeloperoxidase, and that the monochlorodimedon assay grossly underestimates the activity of myeloperoxidase. With 10 microM-H2O2 and 100 mM-Cl-, myeloperoxidase had a neutral pH optimum. Increasing the H2O2 concentration to 100 microM lowered the pH optimum to pH 6.5. Above the pH optimum there was a burst of H2O2 uptake that rapidly declined due to accumulation of Compound II. High concentrations of H2O2 inhibited myeloperoxidase and promoted the formation of Compound II. These effects of H2O2 were decreased at higher concentrations of Cl-. We propose that H2O2 competes with Cl- for Compound I and reduces it to Compound II, thereby inhibiting myeloperoxidase. Above pH 6.5, O2.- generated by xanthine oxidase and acetaldehyde prevented H2O2 from inhibiting myeloperoxidase, increasing the initial rate of H2O2 uptake. O2.- allowed myeloperoxidase to function optimally with 100 microM-H2O2 at pH 7.0. This occurred because, as previously demonstrated, O2.- prevents Compound II from accumulating by reducing it to ferric myeloperoxidase. In contrast, at pH 6.0, where Compound II did not accumulate, O2.- retarded the uptake of H2O2. We propose that by generating O2.- neutrophils prevent H2O2 and other one-electron donors from inhibiting myeloperoxidase, and ensure that this enzyme functions optimally at neutral pH.
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PMID:Influence of superoxide on myeloperoxidase kinetics measured with a hydrogen peroxide electrode. 255 13

Increasing evidence points to a major role for free radicals in the pathogenesis of alcohol-induced liver injury. In vitro, free radicals may be generated during ethanol metabolism by the further metabolism of acetaldehyde by molybdenum-dependent oxidases such as xanthine oxidase. Ferritin iron mobilized by such free radicals may serve as catalytic iron. Increased stores of ferritin iron and induction of microsomal P-450 reductase activity are mechanisms by which chronic alcohol feeding may potentiate the acute effects of alcohol.
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PMID:Lipid peroxidation, iron mobilization and radical generation induced by alcohol. 255 83

Purified human C5 was converted non-enzymically to an activated form as defined by its ability to participate in reactive lysis. This conversion occurred following exposure to systems that generate oxygen radicals, namely addition of H2O2 in the presence of ascorbic acid and iron or the addition of xanthine oxidase, acetaldehyde and iron. The conversion of C5 to a functionally active species was iron-dependent and inhibited by hydroxyl radical scavengers such as DMSO. The findings suggest that OH. is the active oxygen species that converts C5. The conversion product of C5, termed C5(H2O2), is C5b-like due to its ability to bind C6 and cause reactive lysis. C5(H2O2) is much more stable than C5b obtained by complement convertases. Although C5(H2O2) has lost the binding site of native C5 for C3b it can be cleaved by complement-derived convertases; the cleavage is, however, less efficient than in the case of native C5. The resulting cleavage product, which is C5a-like, is chemotactic although C5(H2O2) is not chemotactic. C5(H2O2) serves as a better substrate for plasma kallikrein than native C5, resulting in the generation of a C5a-like chemotactic product. These data indicate that oxygen radicals can bring about a conformational change in C5, causing it to behave as a functionally activated molecule of the complement system. This may have implications for the role of complement and its activation in the inflammatory response.
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PMID:Non-enzymic activation of the fifth component of human complement, by oxygen radicals. Some properties of the activation product, C5b-like C5. 256 Nov 80


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