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)

With a variety of forms of ischemic and toxic tissue injury, cellular accumulation of Ca2+ and generation of oxygen free radicals may have adverse effects upon cellular and, in particular, mitochondrial membranes. Damage to mitochondria, resulting in impaired ATP synthesis and diminished activity of cellular energy-dependent processes, could contribute to cell death. In order to model, in vitro, conditions present post-ischemia or during toxin exposure, the interactions between Ca2+ and oxygen free radicals on isolated renal mitochondria were characterized. The oxygen free radicals were generated by hypoxanthine and xanthine oxidase to simulate in vitro one of the sources of oxygen free radicals in the early post-ischemic period in vivo. With site I substrates, pyruvate and malate, Ca2+ pretreatment, followed by exposure to oxygen free radicals, resulted in an inhibition of electron transport chain function and complete uncoupling of oxidative phosphorylation. These effects were partially mitigated by dibucaine, a phospholipase A2 inhibitor. With the site II substrate, succinate, the electron transport chain defect was not manifest and respiration remained partially coupled. The electron transport chain defect produced by Ca2+ and oxygen free radicals was localized to NADH CoQ reductase. Calcium and oxygen free radicals reduced mitochondrial ATPase activity by 55% and adenine nucleotide translocase activity by 65%. By contrast oxygen free radicals alone reduced ATPase activity by 32% and had no deleterious effects on translocase activity. Dibucaine partially prevented the Ca2+-dependent reduction in ATPase activity and totally prevented the Ca2+-dependent translocase damage observed in the presence of oxygen free radicals. These findings indicate that calcium potentiates oxygen free radical injury to mitochondria. The Ca2+-induced potentiation of oxygen free radical injury likely is due in part to activation of phospholipase A2. This detrimental interaction associated with Ca2+ uptake by mitochondria and exposure of the mitochondria to oxygen free radicals may explain the enhanced cellular injury observed during post-ischemic reperfusion.
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PMID:Mechanism of calcium potentiation of oxygen free radical injury to renal mitochondria. A model for post-ischemic and toxic mitochondrial damage. 287 85

Concentrations of 1-, 3-, and 7-methylxanthine and their uric acid metabolites were measured in plasma and brain affusate 20 min after ip injection of the monomethylxanthines into rats. 3-Methylxanthine was not metabolized to 3-methyluric acid. Similar concentrations of 7-methylxanthine and 7-methyluric acid were detected in both plasma and brain affusate. The oxidation of 1-methylxanthine to 1-methyluric acid occurred so rapidly that the parent compound could not be detected in plasma, and only low concentrations could be detected in brain. Similar patterns in rates of metabolism (1-methyl- greater than 7-methyl- much greater than 3-methylxanthine) were observed in both intact animals and perfused rat liver. The metabolism of 1-methylxanthine to 1-methyluric acid in perfused livers could be explained on the basis of the dehydrogenase form of xanthine oxidase. This conclusion is supported by the observations that the stoichiometry between oxygen utilization and methylurate formation was not consistent with catalysis by the oxidase form of the enzyme and that NADH formed from the metabolism of ethanol strongly inhibited 1-methylxanthine oxidation. In perfused liver, anaerobic conditions decreased rates of 1-methylxanthine metabolism by only 24%. These data demonstrate the presence of oxidizing substrates other than oxygen and NAD+ which are capable of maintaining xanthine oxidase activity during hypoxia. Moreover, rates of 1-methylxanthine metabolism during anoxia could be restored to normal, aerobic values by the infusion of pyruvate, which increased hepatic levels of NAD+. These data demonstrate that changes in the hepatic oxidation-reduction state may dramatically affect rates of xanthine oxidase-dependent metabolism in intact cells.
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PMID:In vivo and in vitro 1-methylxanthine metabolism in the rat. Evidence that the dehydrogenase form of xanthine oxidase predominates in intact perfused liver. 288 2

3 alpha-Hydroxysteroid dehydrogenase (EC 1.1.1.50) from Pseudomonas testosterone was inactivated by superoxide radicals generated by the aerobic xanthine oxidase reaction. Superoxide dismutase, NAD+, bovine serum albumin and histidine and cysteine as free amino acids partially protected the enzyme from inactivation. NADH-binding properties were determined by fluorescence spectroscopy, and no variation was found between native enzyme and the unmodified fraction of the partly inactivated one. The fluorescence emission maximum for the completely inactivated enzyme was shifted 10 nm to a longer wavelength when compared with the native one, and it seems possible that the modification of histidine and cysteine residues by superoxide radicals causes the conformational change of the enzyme and the consequent loss of catalytic activity.
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PMID:Inactivation of 3 alpha-hydroxysteroid dehydrogenase by superoxide radicals. Modification of histidine and cysteine residues causes the conformational change. 300 70

The ability of different homologues of Coenzyme Q to quench O2- was tested in vitro with three experimental systems known to generate O2-. Two of them were biological generators, namely the xanthine-xanthine oxidase system and the cyanide-insensitive NADPH oxidase of polymorphonuclear leucocytes. The third was a chemical generator of O2-, the NADH-phenazine methosulphate-nitroblue tetrazolium mixture. Short-side-chain ubiquinones were found to be the most potent scavengers of O2-, being effective at concentrations as low as 10(-7) M. This finding might be ascribed to the relatively greater water-solubility of the lower homologues of CoQ. We postulate that CoQ10 may well exert such an O2- -scavenging mechanisms in vivo where it is inserted in its natural phospholipid environment.
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PMID:In vitro effect of different ubiquinones on the scavenging of biologically generated O2-. 301 40

The antitumor antibiotic mitomycin C is shown to form a covalent complex with calf thymus DNA under anaerobic conditions in the presence of either NADPH cytochrome c reductase/NADPH, xanthine oxidase/NADH, or the chemical reducing system H2/PtO2. Digestion of the complex with DNase I/snake venom diesterase/alkaline phosphatase yields a single mitomycin deoxyguanosine adduct as the major DNA alkylation product, identified as N2-(2'' beta,7''-diaminomitosen-1'' alpha-yl) 2'-deoxyguanosine (Structure 2). Two minor adducts, 2-5% each of the total adduct pool, are isolated and identified as the 1'' beta stereoisomer of 2 (Structure 3), and 10''-decarbamoyl-2 (Structure 7). The same results were obtained with M13 DNA and poly(dG-dC).poly(dG-dC); however, in the latter case, a minor adduct apparently possessing two deoxyguanosine and one mitomycin unit is isolated. Digestion of the covalent mitomycin-calf thymus DNA complex with nuclease P1 yields four dinucleotide adducts, all of which consist of 2 linked at its 3' end to each of the four possible 5' nucleotides (A, T, G, and C). Upon treatment of each dinucleotide adduct with snake venom diesterase/alkaline phosphatase, 2 is released along with the corresponding free nucleoside. In apparent conflict with the present results, previous reports from another laboratory have indicated that modification of calf thymus DNA by mitomycin C under conditions identical to those described here result in the isolation of three mitomycin C mononucleotide adducts possessing linkages of the drug to N2 and O6 of guanine and N6 of adenine. Evidence is shown suggesting that the latter adducts are actually three of the above four dinucleotide derivatives of 2 obtained independently by us and, thus, all of them in fact possess an identical N2-mitosenylguanine adduct moiety. Model-building studies indicate an excellent fit of the guanine N2-linked drug molecule inside the minor groove of B-DNA with no appreciable distortion of the DNA structure.
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PMID:Reaction of DNA with chemically or enzymatically activated mitomycin C: isolation and structure of the major covalent adduct. 301 44

Heme-nonapeptide inhibits NADH and NADPH dependent lipid peroxidation of brain microsomes in the presence or absence of ADP-Fe complex. The transient accumulation of lipid peroxides during NADH or NADPH dependent, ADP-Fe stimulated lipid peroxidation, is inhibited by heme-nonapeptide. Oxygen consumption of brain microsomes in the presence of NADH or NADPH is stimulated by heme-nonapeptide. Reduction of cytochrome-c and nitro-tetrazolium-blue by O2- generated by xanthine oxidase is inhibited by heme-nonapeptide.
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PMID:Effect of a heme-peptide derived from cytochrome-c on lipid peroxidation. I. Effects on brain microsomes. 302 27

The activity of superoxide dismutase (SOD) from bovine erythrocytes was measured by the inhibition of nitrotetrazolium blue reduction rate in superoxide anion radical generation systems--xanthine/xanthine oxidase of NADH/phenazine methasulfate. The enzyme activity increases in the presence of compounds acting as electron donors in radical-involving reactions and decreased in the presence of compounds possessing the properties of electron acceptors. Activation of SOD by electron donors and its inhibition by electron acceptors was dependent on the concentration of the above compounds. In the absence of SOD electron donors and acceptors did not change the rate of tetrazolium blue reduction by superoxide anion radicals. The role of the new type of SOD regulation for the enzyme functioning in the cell is discussed.
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PMID:[Changes in superoxide dismutase activity in the presence of electron donors and acceptors]. 303 58

Acridine dyes, fluorescein and lucifer yellow CH are fluorescent photosensitizers used experimentally to selectively stain and photodynamically destroy eukaryotic cells and subcellular structures. We have determined that the mechanism of light- and oxygen-dependent inactivation of E. coli by these dyes involves oxygen radicals and hydrogen peroxide. All of the dyes oxidized NAD(P)H+ under illumination. Superoxide (O2), detected as the superoxide dismutase (SOD)-inhibitable reduction of ferricytochrome c, was a major product of the dye sensitized photooxidation. Cationic acridine dyes penetrated the membranes of E. coli and were photoreduced intracellularly. Reduced dyes diffused back into the medium and mediated the reduction of extracellular ferricytochrome c. The anionic dyes fluorescein and lucifer yellow CH were unable to mediate extracellular cytochrome c reduction, indicating that these dyes were impermeable to the E. coli membrane. Acridine dyes, when illuminated, inhibited the growth of E. coli in a rich medium, and induced the synthesis of SOD. Fluorescein and lucifer yellow CH did not inhibit growth or induce SOD synthesis because they were unable to enter the cells. Superoxide (O2) and hydrogen peroxide (H2O2), generated by the enzyme xanthine oxidase were toxic to E. coli B. Inactivation by xanthine oxidase was partially inhibited by exogenous SOD and completely inhibited by exogenous catalase or SOD plus catalase. Similarly, exogenous SOD plus catalase protected against inactivation by acridines and fluorescein-NADH or lucifer yellow CH-NADH mixtures. Prior induction of superoxide dismutase and catalase in E. coli B significantly protected cells against a subsequent challenge by illuminated acridine dyes. SOD and catalases preinduction combined with additions of exogenous SOD and catalase completely protected E. coli B against photodynamic inactivation by acridine yellow. The hydroxyl radical scavengers, dimethyl sulfoxide, sodium benzoate and thiourea, protected E. coli B against photodynamic inactivation by acridine orange. The results implicate O2, H2O2, and the hydroxyl radical (OH) as underlying molecular agents of the phototoxicity mediated by acridine orange, acridine yellow, fluorescein and lucifer yellow CH.
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PMID:Oxygen radicals mediate cell inactivation by acridine dyes, fluorescein, and lucifer yellow CH. 303 47

The relative amounts of monofunctional and bifunctional alkylation products of DNA with mitomycin C (MC) depend on whether one or both masked alkylating functions of MC are activated reductively; adduct 8 is the result of one function and adducts 7 and 9, formed as a pair, are the result of both functions being activated [Tomasz, M., Lipman, R., Chowdary, C., Pawlak, J., Verdine, G. L., & Nakanishi, K. (1987) Science (Washington, D.C.) 235, 1204-1208]. To determine the mechanism governing this differential reactivity of MC with DNA, MC-Micrococcus luteus DNA complexes formed under varying conditions in vitro were digested to nucleosides and adducts. Adduct distribution, analyzed by high-performance liquid chromatography, served as the measure of monofunctional and bifunctional activation. H2/PtO2 and xanthine oxidase/reduced nicotinamide adenine dinucleotide (NADH) activated MC mostly monofunctionally, and Na2S2O4 activated the drug bifunctionally under comparable conditions. Excess MC selectively suppressed, but excess PtO2 selectively promoted, bifunctional activation by H2/PtO2; excess xanthine oxidase and/or NADH also had promoting effects. O2 tested in the Na2S2O4 system was inhibitory. 10-Decarbamoyl-MC acted strictly monofunctionally under all conditions. Monoadducts bound to DNA were converted to bis adducts upon rereduction. A mechanism with the following features was derived: (i) Activation of MC at C-1 and C-10 is sequential (C-1 first). (ii) A one-time reduction is sufficient for both. (iii) Activation of the second function may be selectively inhibited by kinetic factors or O2. (iv) 7 and 9 are coproducts of bifunctional activation; their ratio depends on the DNA base sequence. (v) Activation of the second function involves an iminium intermediate. Direct applications to the action of MC in vivo are discussed.
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PMID:Mechanism of monofunctional and bifunctional alkylation of DNA by mitomycin C. 313 45

Lipid peroxidation has been invoked as a mechanism of alcoholic liver injury but its role has been controversial and the mechanism by which it occurs is unclear. Catalytic iron is known to play an important role in cellular injury and is produced during mobilization of ferritin iron. In vivo administration of a large acute dose of ethanol (5 g/kg) which produces hepatic lipid peroxidation in chow-fed rats resulted in mobilization of non-heme iron. The generation of NADH from alcohol metabolism via ADH or superoxide from acetaldehyde-xanthine oxidase mobilized iron from horse spleen ferritin in vitro. Chronic feeding of alcohol as 36% of energy for 6 weeks does not itself produce peroxidation in the rat but potentiates acute effects of ethanol. It produced microsomal induction which enhanced iron-stimulated lipid peroxidation and increased hepatic non-heme iron. Carbon monoxide increased rather than decreased accumulation of microsomal peroxidation products in vitro suggesting that cytochrome P-450 reductase mediates peroxidation but cytochrome P-450 may metabolize products. Incubation at lowered oxygen tensions equivalent to those observed in the perivenular zone (pO2 = 24 mmHg) enhanced in vitro iron mobilization but decreased peroxidation. Lipid peroxidation and its stimulation by iron mobilization and microsomal induction may be an important contributory mechanism of alcohol-induced liver injury.
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PMID:Lipid peroxidation as a mechanism of alcoholic liver injury: role of iron mobilization and microsomal induction. 313 9


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