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)

Myocardial phospholipase D (PLD) is primarily localized at the sarcolemmal level and selectively hydrolyzes phosphatidylcholine to form phosphatidic acid as part of the signal transduction mechanisms for regulating Ca2+ movements in the heart. Since the myocardial cell damage induced by oxidative stress is associated with abnormalities in Ca2+ homeostasis and thiol status, we examined the thiol group dependence and the effects of oxidant species on this enzyme. Sarcolemmal membranes isolated from rat heart were exposed to several types of thiol group modifiers. Alkylation with N-ethylmaleimide or methyl methanethiosulfonate, mercaptide formation with p-chloromercuriphenylsulfonic acid, and thiol-disulfide exchange with 5,5'-dithio-bis(2-nitrobenzoate) depressed sarcolemmal PLD activity; in all cases the depression was prevented by dithiothreitol. At different concentrations of N-ethylmaleimide the PLD depression correlated well (r = 0.98) with the decrease in total thiol group content of the membrane. The enzyme activity was not affected by xanthine-xanthine oxidase, a superoxide anion-generating system, but was depressed by hydrogen peroxide (H2O2) in a concentration-dependent manner. This inhibitory effect was prevented by catalase as well as by dithiothreitol, but not by D-mannitol. The effect of a hydroxyl radical-generating system (Fenton reaction) could not be assessed because of an interfering direct inhibition by Fe2+. Dithiothreitol was also able to restore PLD activity in H2O2-pretreated membranes and to prevent a severe deactivation of the enzyme by hypochlorous acid (HOCI). Protection by glutathione and inhibition by its oxidized form were also observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Depression of cardiac sarcolemmal phospholipase D activity by oxidant-induced thiol modification. 151 67

Treatment of rats with a single carcinogenic dose of CdCl2 (i.e., 30 mumol/kg) caused severe hemorrhagic damage in the testis within the first 12 h after the metal. Subsequently, atrophy with calcification developed in the next 2-3 mo. Atrophied tissues regenerated during the 1 yr after exposure. Twelve hours after exposure to the Cd treatment, lipid peroxidation levels, Fe content, and cellular production of H2O2 were remarkably elevated in testicular Leydig cells, the target cell population for Cd carcinogenesis. At the same time, glutathione peroxidase activity rose, glutathione reductase and catalase activities were reduced, and superoxide dismutase activity was unchanged. Xanthine oxidase activity in Leydig cells was also elevated at 6 and 9 h after the Cd treatment. Reduced glutathione in testes was decreased and oxidized glutathione was increased 12 h after exposure to the metal. These facts suggest that the carcinogenic doses of Cd induced oxidative stress while compromising cellular defense mechanisms against such stress. Therefore, active oxygen species such as H2O2 may have an important role in the initiation of carcinogenesis within the target cell population.
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PMID:Role of oxidative stress in single-dose, cadmium-induced testicular cancer. 152 11

We examined the effects of tumor necrosis factor-alpha (TNF alpha) stimulation of endothelial cells on the increase in endothelial permeability induced by H2O2. Bovine pulmonary microvascular endothelial cells (BPMVEC) were grown to confluence on a microporous filter and the 125I-albumin clearance rate across the monolayer was determined. Pretreatment with TNF alpha (100 U/ml) for 6 h had no direct effect on transendothelial 125I-albumin permeability. However, TNF alpha pretreatment enhanced the susceptibility of BPMVEC to H2O2; that is, H2O2 (10 microM) alone had no direct effect, whereas H2O2 increased 125I-albumin permeability more than threefold when added to monolayers pretreated for 6 h with TNF alpha. Determination of lactate dehydrogenase release indicated that increased permeability was not due to cytolysis. We measured the intracellular contents of GSH and catalase to determine their possible role in mediating the increased susceptibility to H2O2. TNF alpha treatment (100 U/ml for 6 h) decreased total GSH content and concomitantly increased the oxidized GSH content, but did not alter the cellular catalase activity. The role of GSH was examined by pretreating endothelial cells with 2 mM GSH for 3 h, which produced an 80% increase in intracellular GSH content. GSH repletion inhibited the increased sensitivity of the TNF alpha-treated endothelial cells to H2O2. We tested the effects of xanthine oxidase (XO) inhibition since XO activation may be a source of oxidants responsible for the decrease in cellular GSH content. Pretreatment with 0.5 mM oxypurinol attenuated the synergistic effect of TNF alpha and H2O2 on endothelial permeability. The results indicate that decreased oxidant buffering capacity secondary to TNF alpha-induced reduction in intracellular GSH content mediates the increased susceptibility of endothelial cells to H2O2. This mechanism may contribute to oxidant-dependent vascular endothelial injury in septicemia associated with TNF alpha release.
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PMID:Tumor necrosis factor-alpha-mediated decrease in glutathione increases the sensitivity of pulmonary vascular endothelial cells to H2O2. 154 73

Peroxynitrite (ONOO-) is a potent oxidizing agent that initiates lipid peroxidation and sulfhydryl oxidation and may be responsible for a portion of the cytotoxicity attributed to superoxide anion (.O2-). We quantified the extent to which ONOO-, xanthine plus xanthine oxidase (XO) and hydrogen peroxide (H2O2), decreased sodium (Na+) uptake into membrane vesicles derived from colonic cells of dexamethasone-treated rats. Carrier-free 22Na+ uptake into vesicles was measured in the presence of an inside-negative membrane potential, produced by the addition of the potassium ionophore valinomycin (10 microM) after removal of all external potassium by cation exchange chromatography. Preincubation of vesicles with either 100 microM or 1 mM ONOO- for 30 s decreased the amiloride-blockable fraction of Na+ uptake by 27 +/- 7% and 65 +/- 2%, respectively (means +/- S.E.; n greater than or equal to 5; P less than 0.05 from control). However, the amiloride-insensitive part of Na+ uptake was not affected, indicating that there was no overt destruction of these vesicles by these ONOO- concentrations. Decomposed ONOO-, hydrogen peroxide (1 microM-10 mM), or xanthine (500 microM) plus XO (10-30 mU/ml), either in the absence or in the presence of 100 microM FeEDTA, did not decrease Na+ uptake. These data suggest that ONOO- is a potent injurious agent that can compromise Na+ uptake across epithelial cells, possibly by damaging Na+ channels.
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PMID:Peroxynitrite inhibits sodium uptake in rat colonic membrane vesicles. 155 Aug 56

Two superoxide dismutase-mimetic lipophilic copper complexes, Cu(II)2(indomethacin)4 [Cu(II)2(indo)4] and Cu(II)2(3,5-diisopropylsalicylate)4 [Cu(II)2(3,5-DIPS)4], were tested for their effects on the respiratory burst of intact human granulocytes and on xanthine oxidase, under conditions where superoxide and hydrogen peroxide were generated. The effect of the copper complexes on these enzyme systems (as opposed to their dismutase effect on superoxide) was determined by measuring oxygen uptake with an oxygen meter. It was found that, after a short delay, both systems were inhibited markedly by micromolar amounts of these complexes. This inhibition was prevented by treatment with EDTA or catalase if added prior to starting the reaction. Similar inhibitory effects were seen using copper sulfate. It appears that these lipophilic SOD-mimetic compounds can, in the presence of H2O2 and O2-, give rise to a species that can inhibit some component of the respiratory burst oxidase or protein kinase C in intact granulocytes and xanthine oxidase in solution. The observed decrease in O2- levels observed upon addition of these compounds is likely due to inhibition of the source and not to their SOD-mimetic properties.
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PMID:Inhibition by superoxide dismutase-mimetic copper complexes of phorbol ester-induced respiratory burst in human granulocytes. 155 79

Quantification of intracellular and extracellular levels and production rates of reactive oxygen species is crucial to understanding their contribution to tissue pathophysiology. We measured basal rates of oxidant production and the activity of xanthine oxidase, proposed to be a key source of O2- and H2O2, in endothelial cells. Then we examined the influence of tumor necrosis factor-alpha and lipopolysaccharide on endothelial cell oxidant metabolism, in response to the proposal that these inflammatory mediators initiate vascular injury in part by stimulating endothelial xanthine oxidase-mediated production of O2- and H2O2. We determined a basal intracellular H2O2 concentration of 32.8 +/- 10.7 pM in cultured bovine aortic endothelial cells by kinetic analysis of aminotriazole-mediated inactivation of endogenous catalase. Catalase activity was 5.72 +/- 1.61 U/mg cell protein and glutathione peroxidase activity was much lower, 8.13 +/- 3.79 mU/mg protein. Only 0.48 +/- 0.18% of total glucose metabolism occurred via the pentose phosphate pathway. The rate of extracellular H2O2 release was 75 +/- 12 pmol.min-1.mg cell protein-1. Intracellular xanthine dehydrogenase/oxidase activity determined by pterin oxidation was 2.32 +/- 0.75 microU/mg with 47.1 +/- 11.7% in the oxidase form. Intracellular purine levels of 1.19 +/- 1.04 nmol hypoxanthine/mg protein, 0.13 +/- 0.17 nmol xanthine/mg protein, and undetectable uric acid were consistent with a low activity of xanthine dehydrogenase/oxidase. Exposure of endothelial cells to 1000 U/ml tumor necrosis factor (TNF) or 1 microgram/ml lipopolysaccharide (LPS) for 1-12 h did not alter basal endothelial cell oxidant production or xanthine dehydrogenase/oxidase activity. These results do not support a casual role for H2O2 in the direct endothelial toxicity of TNF and LPS.
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PMID:Responses of vascular endothelial oxidant metabolism to lipopolysaccharide and tumor necrosis factor-alpha. 156 24

The conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO) and the reaction of XO-derived partially reduced oxygen species (PROS) have been suggested to be important in diverse mechanisms of tissue pathophysiology, including oxygen toxicity. Bovine aortic endothelial cells expressed variable amounts of XDH and XO activity in culture. Xanthine dehydrogenase plus xanthine oxidase specific activity increased in dividing cells, peaked after achieving confluency, and decreased in postconfluent cells. Exposure of BAEC to hyperoxia (95% O2; 5% CO2) for 0-48 h caused no change in cell protein or DNA when compared to normoxic controls. Cell XDH+XO activity decreased 98% after 48 h of 95% O2 exposure and decreased 68% after 48 h normoxia. During hyperoxia, the percentage of cell XDH+XO in the XO form increased to 100%, but was unchanged in air controls. Cell catalase activity was unaffected by hyperoxia and lactate dehydrogenase activity was minimally elevated. Hyperoxia resulted in enhanced cell detachment from monolayers, which increased 112% compared to controls. Release of DNA and preincorporated [8-14C]adenine was also used to assess hyperoxic cell injury and did not significantly change in exposed cells. Pretreatment of cells with allopurinol for 1 h inhibited XDH+XO activity 100%, which could be reversed after oxidation of cell lysates with potassium ferricyanide (K3Fe(CN)6). After 48 h of culture in air with allopurinol, cell XDH+XO activity was enhanced when assayed after reversal of inhibition with K3Fe(CN)6, and cell detachment was decreased. In contrast, allopurinol treatment of cells 1 h prior to and during 48 h of hyperoxic exposure did not reduce cell damage. After K3Fe(CN)6 oxidation, XDH+XO activity was undetectable in hyperoxic cell lysates. Thus, XO-derived PROS did not contribute to cell injury or inactivation of XDH+XO during hyperoxia. It is concluded that endogenous cell XO was not a significant source of reactive oxygen species during hyperoxia and contributes only minimally to net cell production of O2- and H2O2 during normoxia.
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PMID:The contribution of vascular endothelial xanthine dehydrogenase/oxidase to oxygen-mediated cell injury. 156 25

The effect of hypoxia on subsequent susceptibility of porcine pulmonary artery endothelial cells (PAEC) to hydrogen peroxide (H2O2) injury was studied. Preexposure of PAEC to hypoxia for 3 or more h significantly increased susceptibility to subsequent H2O2 challenge. Analysis of the activities of antioxidant enzymes and xanthine oxidase/dehydrogenase suggested that changes in these enzymes in hypoxic PAEC were not responsible for the increased susceptibility. However, hypoxia resulted in significant time-dependent decreases in total glutathione at 12 h or more. The rate of glutathione regeneration in diethylmaleate-treated PAEC and the rate of uptake of cystine and glycine were significantly lower during hypoxia. Hypoxia also caused depletion of ATP and NADPH levels in PAEC, but these did not occur until well after hypoxia-enhanced susceptibility to H2O2 injury was demonstrable. Alterations in glutathione levels and enhanced susceptibility were reversible when hypoxic PAEC were returned to normoxia. These results indicate that hypoxia increased the susceptibility to H2O2 injury by decreasing the ability of PAEC to maintain and regenerate cellular glutathione content in response to H2O2 challenge.
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PMID:Hypoxia increases the susceptibility of pulmonary artery endothelial cells to hydrogen peroxide injury. 157 99

We investigated the effect of xanthine (X) plus xanthine oxidase (XO) on pulmonary microvascular endothelial permeability in isolated rabbit lungs perfused with Krebs buffer containing bovine serum albumin (5 g/100 ml). Addition of five mU/ml XO and 500 microM X to the perfusate caused a twofold increase in the pulmonary capillary filtration coefficient (Kf,c) 30 min later without increasing the pulmonary capillary pressure. This increase was prevented by allopurinol or catalase but not by superoxide dismutase or dimethyl sulfoxide. Because these data implicated hydrogen peroxide (H2O2) as the injurious agent, we measured its concentration in the perfusate after the addition of X and XO for a 60-min interval. In the absence of lung tissue and albumin, H2O2 increased with time, reaching a concentration of approximately 250 microM by 60 min. If albumin (5 g/100 ml) was added to the perfusate, or in the presence of lung tissue, the corresponding values were 100 microM and less than 10 microM, respectively. To understand the mechanisms of H2O2 scavenging by lung tissue, we added a 250 microM bolus of H2O2 to the lung perfusate. We found that H2O2 was removed rapidly, with a half-life of 0.31 +/- 0.04 (SE) min. This variable was not increased significantly by inhibition of lung catalase activity with sodium azide or inhibition of the lung glutathione redox cycle with 1-chloro-2,4-dinitrobenzene. However, inhibition of both enzymatic systems increased the half-life of H2O2 removal to 0.71 +/- 0.09 (SE) min (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of extracellular reactive oxygen species injury to the pulmonary microvasculature. 160 78

Dupuytren's contracture is a deforming, fibrotic condition of the palmar fascia which has confounded clinicians and scientists since the early descriptions by Guillaume Dupuytren in 1831. It predominantly affects elderly, male caucasians, has a hereditary predisposition and has strong associations with diabetes, alcohol consumption, cigarette smoking and HIV infection. The major morphological features are an increase in fibroblasts, particularly around narrowed fibroblasts; a finding consistent with localised ischaemia. During ischaemia, adenosine triphosphate (ATP) is converted to hypoxanthine and xanthine, and endothelial xanthine dehydrogenase to xanthine oxidase (alcohol also mediates this change, a finding of particular relevance given the association of Dupuytren's contracture with alcohol intake). Xanthine oxidase catalyses the oxidation of hypoxanthine to xanthine and uric acid with the release of superoxide free radicals (O2-), hydrogen peroxide (H2O2) and hydroxyl radicals (OH.). These free radicals are highly reactive, with half-lives in the order of milliseconds and are toxic in high concentrations. A potential for free radical generation in Dupuytren's contracture was elicited by finding a sixfold increase in hypoxanthine concentrations in Dupuytren's contracture compared with control palmar fascia. In vitro studies affirmed the toxic effects of oxygen free radicals to Dupuytren's contracture fibroblasts, but also showed that, at lower concentrations (concentrations similar to those likely to occur in Dupuytren's contracture), free radicals had a stimulatory effect on fibroblast proliferation. Cultured fibroblasts were found to release their own O2-. These endogenously released free radicals were also found to be important in fibroblast proliferation. The collagen changes of Dupuytren's contracture were examined. The results established that fibroblast origin was unimportant, but that inhibition of type I collagen production at high fibroblast density accounted for the increase in type III/I collagen ratios observed by previous investigators. These biochemical and morphological observations throw new light on Dupuytren's contracture. They suggest that age, genetic and environmental factors may contribute to micro vessel narrowing with consequent localised ischaemia and free radical generation. Endothelial xanthine oxidase derived free radicals may both damage the surrounding stroma and stimulate fibroblasts to proliferate. Proliferating fibroblasts lay down and contract collagen in lines of stress.Progressive fibroblast proliferation and deposition of collagen is likely to encourage further microvessel narrowing with a positive feedback effect consistent with the progressive nature of the condition.
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PMID:An insight into Dupuytren's contracture. 161 55


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