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)

Washed human platelets prevent edema formation in isolated rabbit lungs infused with xanthine oxidase, an enzyme that injures endothelial membranes by generating extracellular oxidants. We hypothesized that platelets would similarly preserve membrane permeability in isolated lungs exposed to ischemia-reperfusion injury, a model that perturbs endothelial cells by the generation of intracellular oxidants. Isolated perfused rabbit lungs (IPL) were exposed to warm ischemia-reperfusion to cause lung edema. The infusion of washed human platelets (1.05 +/- 0.02 x 10(10) cells) prevented edema formation as measured by lung weight gain, wet-to-dry lung weight ratios, histological edema, and preservation of paraendothelial cell tight junctions. Inhibition of the platelet glutathione redox cycle with 1,3-bis(2-chloroethyl)-1-nitrosourea, dehydroepiandrosterone, or 1-chloro-2,4-dinitrobenzene interfered with platelet protective effects. In contrast, inhibition of platelet catalase with aminotriazole and H2O2 had no effect on platelet protection. Lung tissue malonyldialdehyde concentrations were similar in isolated lungs exposed to ischemia-reperfusion with or without the infusion of platelets. These results indicate that platelet attenuation of ischemia-reperfusion lung edema depends on platelet glutathione redox cycle antioxidants but not platelet catalase.
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PMID:Washed human platelets prevent ischemia-reperfusion edema in isolated rabbit lungs. 203 73

Because platelets contain active antioxidant systems, the capacity of platelets to attenuate oxidant lung injury was investigated. Purine and xanthine oxidase were infused into isolated perfused rabbit lungs (IPL) to generate H2O2, thereby causing increased membrane permeability edema. The coinfusion of washed human platelets (1.20 +/- 0.07 x 10(10) cells) attenuated the degree of edema formation as measured by lung weight gain and lung lavage albumin concentration. Electron microscopy of lung preparations demonstrated platelet adherence to capillary endothelial luminal surfaces of oxidant-injured lungs, but there was no evidence of vascular plugging with platelet macroaggregates. The platelet glutathione redox cycle or platelet catalase were inhibited before infusion of platelets into the IPL with purine and xanthine oxidase. Inhibition of the glutathione redox cycle with 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-chloro-2,4-dinitrobenzene, or buthionine sulfoximine prevented platelet attenuation of lung injury. Inactivation of platelet catalase with 3-amino-1,2,4-triazole, however, did not significantly reduce the platelet-induced lung protection. We conclude that the platelet glutathione redox cycle plays a major role in reducing enzymatically generated toxic O2 metabolites and attenuating lung injury.
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PMID:Human platelets attenuate oxidant injury in isolated rabbit lungs. 318 95

Preexposure to hypoxia increased survival and lung reduced glutathione-to-oxidized glutathione ratios (GSH/GSSG) and decreased pleural effusions in rats subsequently exposed to continuous hyperoxia. In addition, lungs from hypoxia-preexposed rats developed less acute edematous injury (decreased lung weight gains and lung lavage albumin concentrations) than lungs from normoxia-preexposed rats when isolated and perfused with hydrogen peroxide (H2O2) generated by xanthine oxidase (XO) or glucose oxidase (GO). In contrast, when perfused with elastase or exposed to a hydrostatic left atrial pressure challenge, lungs isolated from hypoxia-preexposed rats developed the same acute edematous injury as lungs from normoxia-preexposed rats. The mechanism by which hypoxia preexposure conferred protection against H2O2 appeared to depend on hexose monophosphate shunt (HMPS)-dependent increases in lung glutathione redox cycle activity. First, before perfusion with GO, lungs from hypoxia-preexposed rats had increased glutathione peroxidase and glucose 6-phosphate dehydrogenase (but not catalase or glutathione reductase) activities compared with lungs from normoxia-preexposed rats. Second, after perfusion with GO, lungs from hypoxia-preexposed rats had increased H2O2 reducing equivalents, as reflected by increased GSH/GSSG and NADPH/NADPH+, compared with lungs from normoxia-preexposed rats. Third, pretreatment of rats with an HMPS inhibitor, (6-aminonicotinamide) or a glutathione reductase inhibitor, [1,3-bis(2-chloroethyl)-1-nitrosourea] prevented hypoxia-conferred protection against H2O2-mediated acute edematous injury in isolated lungs. These findings suggest that increased detoxification of H2O2 by glutathione redox cycle and HMPS-dependent mechanisms contributes to tolerance to hyperoxia and resistance to H2O2 of lungs from hypoxia-preexposed rats.
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PMID:Hypoxia increases glutathione redox cycle and protects rat lungs against oxidants. 321 62

O6-Benzylguanine is an effective inhibitor of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase, and enhances the effectiveness of 1,3-bis(2-chloroethyl)-1-nitrosourea in cells in culture and animal tumor models. To prepare O6-benzylguanine for clinical trials and to determine the availability and disposition of O6-benzyl-7,8-dihydro-8-oxoguanine (O6-benzyl-8-oxoguanine), its major metabolite, pharmacokinetic parameters of these compounds were investigated in male Sprague-Dawley rats. Noncompartmental pharmacokinetic parameters were determined following intravenous administration of O6-benzylguanine or O6-benzyl-8-oxoguanine in rats. Half-life, clearance, and volume of distribution were respectively, 1.6 hr, 160 ml/hr/kg, and 405 ml/kg for O6-benzylguanine, and 1.2 hr, 312 ml/hr/kg, and 507 ml/kg for O6-benzyl-8-oxoguanine. At least 37% of O6-benzylguanine was converted to O6-benzyl-8-oxoguanine after administration of O6-benzylguanine. Renal excretion accounted for 8 and 62% of the administered O6-benzylguanine and O6-benzyl-8-oxoguanine, respectively. Administration of phenobarbital to rats before O6-benzylguanine resulted in a 17- to 19-fold increase in the amount of oxidized product in the urine. Kinetic constants, KM and Vmax were estimated as 19.6 microM and 0.02 nmol/min/mg protein and 13.4 microM and 0.96 nmol/min/mg protein, for uninduced and induced rat liver microsomes, respectively. The use of inhibitors of cytosolic enzymes, xanthine oxidase, and aldehyde oxidase indicated that aldehyde oxidase is primarily involved in the cytosolic oxidation of O6-benzylguanine.
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PMID:Pharmacokinetics of O6-benzylguanine in rats and its metabolism by rat liver microsomes. 868 50

The role of H(2)O(2) and protein thiol oxidation in oxidative stress-induced epithelial paracellular permeability was investigated in Caco-2 cell monolayers. Treatment with a H(2)O(2) generating system (xanthine oxidase + xanthine) or H(2)O(2) (20 microM) increased the paracellular permeability. Xanthine oxidase-induced permeability was potentiated by superoxide dismutase and prevented by catalase. H(2)O(2)-induced permeability was prevented by ferrous sulfate and potentiated by deferoxamine and 1,10-phenanthroline. GSH, N-acetyl-L-cysteine, dithiothreitol, mercaptosuccinate, and diethylmaleate inhibited H(2)O(2)-induced permeability, but it was potentiated by 1,3-bis(2-chloroethyl)-1-nitrosourea. H(2)O(2) reduced cellular GSH and protein thiols and increased GSSG. H(2)O(2)-mediated reduction of GSH-to-GSSG ratio was prevented by ferrous sulfate, GSH, N-acetyl-L-cysteine, diethylmaleate, and mercaptosuccinate and potentiated by 1,10-phenanthroline and 1, 3-bis(2-chloroethyl)-1-nitrosourea. Incubation of soluble fraction of cells with GSSG reduced protein tyrosine phosphatase (PTPase) activity, which was prevented by coincubation with GSH. PTPase activity was also lower in H(2)O(2)-treated cells. This study indicates that H(2)O(2), but not O(2)(-). or.OH, increases paracellular permeability of Caco-2 cell monolayer by a mechanism that involves oxidation of GSH and inhibition of PTPases.
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PMID:Glutathione oxidation and PTPase inhibition by hydrogen peroxide in Caco-2 cell monolayer. 1091 42