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)

Compelling evidence has been accumulated which indicates that myocardial tissue damage occurring during reperfusion after an ischaemic period may partly be due to the formation of oxygen free radicals and subsequent peroxidative processes. It has been well established that the actual toxicity of free radicals is dependent on the presence of free iron in the heart tissue. Based upon the hypothesis of McCord et al., proposing xanthine oxidase mediated formation of superoxide (O2-.) during the conversion of ATP-breakdown product(s) (hypo)xanthine to urate, we studied whether xanthine oxidase was able to mobilize free iron from the intra- and extracellular iron-binding proteins, ferritin and transferrin. It appeared that there was an O2-.-dependent and O2-.-independent mechanism by which xanthine oxidase could mobilize iron from ferritin while no iron mobilization from transferrin was detectable. The capacity of xanthine oxidase to mobilize iron from ferritin by an O2-.-independent mechanism implies that already during the anoxic/ischaemic period, iron may become available in the tissue which, upon the re-entrance of O2, catalyzes the formation of the very reactive OH radicals. The interaction between endothelial cells and cardiocytes in free radical homeostasis is discussed with the emphasis on the tissue localization of xanthine oxidase. The latter is located in endothelial cells implying an interaction between xanthine oxidase-induced endothelial cells initiated lipid peroxidation and the actual overall myocardial tissue damage.
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PMID:Lipid peroxidation and myocardial ischaemic damage: cause or consequence? 331 Oct 8

We have investigated the effect of oxidants on ligand recognition and internalization by the macrophage mannose receptor. Rat bone marrow macrophages were treated with increasing concentrations of H2O2 for 30 min at 37 degrees C. Fifty percent inhibition of ligand uptake was observed at 250 microM, with only 10% of control uptake remaining following exposure to 1 mM H2O2 for 30 min. Electron micrographic analysis of macrophages following H2O2 treatment showed no morphological alterations compared to untreated cells. Ligand uptake was also inhibited by the following H2O2 generating systems: menadione, xanthine/xanthine oxidase, glucose/glucose oxidase, and phorbol 12-myristate 13-acetate-stimulated polymorphonuclear leukocytes. Inhibition could be blocked by catalase plus or minus superoxide dismutase. Treatment of macrophages at 4 degrees C with H2O2 had no effect on ligand binding, whereas treatment with H2O2 at 37 degrees C reduced binding to 15% of control levels and decreased the number of surface receptors to one-third of control cells. H2O2 treatment inhibited ligand degradation by macrophages, but did not prevent ligand movement from the surface to the interior of the cell. In addition, ligand delivery to lysosomes was blocked by oxidant treatment. These results suggest that treatment of macrophages with reagent H2O2 or H2O2-generating systems inhibits the normal ligand delivery and receptor recycling process involving the mannose receptor. Potential mechanisms might include receptor oxidation, alterations in ATP levels, or membrane lipid peroxidation.
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PMID:Oxidant-mediated inhibition of ligand uptake by the macrophage mannose receptor. 333 43

The evidence is convincing that oxidants and agents which induce a cellular pro-oxidant state can act as carcinogens, in particular as promoters and progressors. Importantly, infiltrated phagocytes represent a source of oxidants in inflamed tissues. We have studied the mechanism of the promotional action of active oxygen (AO) in mouse epidermal cells JB6 by comparing the non-promotable clone 30 to the promotable clone 41. In order to mimick AO released by phagocytes we used xanthine/xanthine oxidase as a source of extracellular superoxide and hydrogen peroxide. We found that AO stimulated the growth only of promotable clone 41 after an initial period of moderate inhibition while it was strongly cytostatic for non-promotable clone 30. Reasons for the higher cytostatic effect of AO on the non-promotable clone 30 were discovered when we measured DNA strand breakage and poly ADP-ribosylation of chromosomal proteins. At equal doses AO induced 4-5 times more DNA breaks in clone 30 in reactions which required iron--and probably also calcium--ions. The higher amount of DNA breakage in clone 30 was reflected in a higher extent of poly ADP-ribosylation. Excessive DNA breakage and poly ADP-ribosylation which causes the depletion of NAD and ATP may be responsible for the strong cytostatic effect of AO in clone 30. We conclude that differential resistance to the cytostatic/cytotoxic effect of AO in part determines the promotability of mouse epidermal cells JB6.
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PMID:Active oxygen induced DNA strand breakage and poly ADP-ribosylation in promotable and non-promotable JB6 mouse epidermal cells. 333 7

Isolated perfused livers from fasted, but not from fed rats showed hepatotoxic responses when subjected to 30 min of hypoxia followed by 60 min of reoxygenation. Toxicity was evident by a release of glutamate-pyruvate-transaminase, lactate dehydrogenase and glutathione into the perfusate, by a depletion of hepatic glutathione and by an accumulation of calcium in the liver. This indicates, that the liver is resistant to hypoxic injury as long as glycogen is present to maintain anaerobic ATP-synthesis. This is substantiated by the fact that addition of fructose--but not glucose--to the medium resulted in a protection of the liver against hypoxic injury concomitant with its degradation to lactate + pyruvate. Superoxide dismutase, catalase, desferrioxamine and allopurinol prevented hypoxic liver injury suggesting a substantial role of reactive oxygen species formed via the xanthine oxidase reaction in mediating hypoxic liver injury.
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PMID:The involvement of reactive oxygen species in hypoxic injury to rat liver. 336 21

Myocardial ischemia initiates a series of cellular reactions which unless checked will culminate in cell death and tissue necrosis. Although reperfusion provides a means of preventing cell death it is not without hazard. In cases of mild ischemia, where tissue injury is in its reversible phase, reperfusion may precipitate potentially lethal ventricular arrhythmias and in cases of severe injury it may actually accelerate the process of cell death leading to hemorrhage and other forms of severe injury. The identity of mediators of cellular injury, and particularly the critical transition from reversible to irreversible injury, remains controversial. Whereas for a number of years ATP depletion, calcium overload and catecholamines have been considered as key factors in tissue injury, attention has recently been directed towards oxygen-derived free radicals (e.g. superoxide and the hydroxyl radical). In this article we discuss sources of free radicals in the mammalian heart (xanthine oxidase, mitochondria, leucocytes, and catecholamines) and present arguments based on quantitative and temporal considerations that the xanthine oxidase-mediated degradation of hypoxanthine is the most important source of free radicals and as such is the most appropriate target for therapeutic intervention. To support our arguments we present data from two species, the dog and the rat, in which we have shown how allopurinol, the specific inhibitor of xanthine oxidase, can afford a reduction of infarct size in the dog and can dramatically reduce the incidence of potentially lethal reperfusion-induced arrhythmias in the rat. Arising from these and other studies is the proposition that anti-free radical interventions (particularly those directed towards xanthine oxidase inhibition) may provide an important new therapeutic principle in the management of ischemia and reperfusion.
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PMID:Xanthine oxidase: a critical mediator of myocardial injury during ischemia and reperfusion? 352 23

The hepatocarcinogen acetamide, in single doses of 100 and 400 mg/kg b.wt., was shown to act as an initiator in a dose-dependent fashion in rat liver using the Solt-Farber method. Acetamide and its putative metabolite N-hydroxy-acetamide did not cause liver necrosis in single dose experiments. Acetamide showed no evidence for genotoxicity in tests for mutations in Salmonella typhimurium, for DNA damage in rat hepatoma cells or for DNA repair in isolated rat hepatocytes. In contrast, N-hydroxy-acetamide displayed genotoxic activity in all 3 test systems. Neither acetamide nor N-hydroxy-acetamide induced transformation of primary Syrian hamster embryo cells or gave evidence of inhibition of metabolic cooperation in V79 cells. Radiolabelled acetamide and N-hydroxy-acetamide were not bound covalently to proteins in the presence of various metabolic activation systems (microsomes plus NADPH or xanthine/xanthine oxidase, cytosol or cytosol plus acetyl CoA or proline plus ATP). N-Hydroxy-acetamide was cytotoxic to monolayers of isolated hepatocytes at concentrations above 2.5 mM. This cytotoxicity was increased after diethyl maleate treatment, but N-hydroxy-acetamide did not deplete cellular glutathione. A HPLC system was developed for the separation and quantification of acetamide, N-hydroxy-acetamide and acetic acid. No significant excretion of N-hydroxy-acetamide or acetic acid in the urine could be demonstrated after treatment of rats with 100 or 1,000 mg/kg b.wt. of acetamide. The underlying mechanism for the observed initiating effect of acetamide is obscure.
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PMID:Studies on the mechanism of acetamide hepatocarcinogenicity. 355 Jul 69

We have suggested that red blood cell proteolytic systems can degrade oxidatively damaged proteins, and that both damage and degradation are independent of lipid peroxidation (Davies, K. J. A., and Goldberg, A. L. (1987) J. Biol. Chem. 262, 8220-8226. These ideas have now been tested in cell-free extracts of rabbit erythrocytes and reticulocytes. Exposure to oxygen radicals or H2O2 increases the degradation of endogenous proteins in cell-free extracts, as in intact cells. Various radical-generating systems (acetaldehyde or xanthine + xanthine oxidase, ascorbic acid + iron, H2O2 + iron) and H2O2 alone enhanced the rates of proteolysis severalfold. Since these extracts were free of membrane lipids, protein damage and degradation must be independent of lipid peroxidation. An antioxidant buffer consisting of HEPES, glycerol, and dithiothreitol inhibited the increased proteolysis by 60-100%. Mannitol caused a 50-80% reduction in proteolysis suggesting that the hydroxyl radical (.OH), or a species with similar reactivity, may be the initiator of protein damage. When casein or bovine serum albumin were exposed to .OH (generated by H2O2 + Fe2+, or COCo radiation) these proteins were degraded up to 50 times faster than untreated proteins during subsequent incubations with red cell extracts. Mannitol inhibited this increase in proteolysis only if present during .OH exposure; mannitol did not affect the degradative system. Although ATP increased the degradation of untreated proteins 4- to 6-fold in reticulocyte extracts, it had little or no effect on the degradation of proteins exposed to .OH. ATP also did not stimulate hydrolysis of .OH-treated proteins in erythrocyte extracts. Leupeptin did not affect the degradative processes in either extract; thus lysosomal or Ca2+-activated thiol proteases were not involved. We propose that red cells contain a soluble, ATP-independent proteolytic pathway which may protect against the accumulation of proteins damaged by .OH or other active oxygen species.
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PMID:Proteins damaged by oxygen radicals are rapidly degraded in extracts of red blood cells. 359 73

Equilibrium dialysis studies on competitive binding of 59FeCl3 to xanthine oxidase and citrate or ATP have been carried out. Iron binding to the enzyme was observed in the presence of 0.1 mM of either chelator, suggesting that xanthine oxidase is likely to have iron bound in many in vitro experimental systems and raising the possibility that it may be able to compete for intracellular chelatable iron. One high-affinity-binding site per monomer was found, with an affinity constant of 5 X 10(12) M-1. The significance of this iron as a Fenton reaction catalyst is discussed.
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PMID:High-affinity iron binding by xanthine oxidase. 359 68

Using isolated hemoglobin-free perfused rat livers we investigated the hepatotoxic effects of hypoxia, ethanol or the combination of both. Hypoxia only (90 min) led to a weak toxicity as evidenced by the efflux of the enzymes glutamate-pyruvate-transaminase (GPT) and sorbitol dehydrogenase (SDH). This toxic effect was slightly higher in livers treated with ethanol (3 g/l) under normoxic conditions. Ethanol added under hypoxic conditions, however, showed a strong hepatotoxic effect. Under hypoxic conditions, lactate + pyruvate production was increased fivefold over control, indicating that glycolysis was more effectively undergone as main source of energy. Addition of ethanol suppressed this effect, indicating that ethanol inhibited glycolysis. These results indicate that ethanol potentiates hypoxic liver damage by inhibiting the main metabolic pathway yielding ATP under low oxygen tension resulting in a severe energy deficit. Allopurinol (100 mg/l) inhibited the toxic effects seen with ethanol + hypoxia. Also, the inhibitory action of ethanol on glycolysis was antagonized. Our results are consistent with the following model: hypoxia converts NAD-dependent xanthine dehydrogenase (XD) into the oxygen-dependent xanthine oxidase (XO). Due to hypoxia and ethanol, purine metabolites and acetaldehyde accumulate and are metabolized via XO. This process leads to the production of oxygen radicals which most probably mediate both the inhibition of glycolysis and the direct toxic effects towards liver cells.
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PMID:Enhancement of hypoxic liver damage by ethanol. Involvement of xanthine oxidase and the role of glycolysis. 363 22

Little is known about postnatal changes in myocardial purine metabolism. We therefore studied how ATP catabolism was affected by hypothermia and ischaemia in neonatal and adult hearts. Hypothermia during ischaemia protected isolated adult and newborn hearts against ATP decline. Reperfusion after normothermic ischaemia resulted in higher ATP levels in newborn hearts with less release of ATP-catabolites. During normoxia adult hearts released mainly urate (80% of total purine release), while newborns released mainly hypoxanthine (64%). During early reperfusion adult and newborn hearts released mainly inosine (50-60%). The very low xanthine oxidase activity in the neonatal heart could be an important factor in the observed ATP preservation during reperfusion.
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PMID:Developmental differences in myocardial ATP metabolism. 366 14


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