UNIPROT:P47989 - FACTA Search

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Query: UNIPROT:P47989 (xanthine oxidase)
8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-[N-phenylcarboxamido]-2-thiobarbituric acid (merbarone) is a non-sedating derivative of thiobarbituric acid originally developed for anticancer use. In the initial clinical study, a profound reduction in serum uric acid was observed. In 20 patients who received five daily doses of merbarone ranging from 100 to 750 mg/m2, serum uric acid concentration was reduced from a mean pretreatment value of 5.7 +/- 1.6 mg/dL to a mean lowest value of 1.3 +/- 0.5 mg/dL. In most patients, the onset of the effect occurred with 24 hours and was maximal by 48 to 72 hours. Metabolic studies in two patients showed an increase in urinary uric acid excretion within 24 hours after initiation of drug treatment. A marked increase in fractional excretion of uric acid was sustained throughout the period of drug treatment. Urinary excretion of total oxypurines (xanthine and hypoxanthine) was increased twofold to threefold relative to baseline levels. Ultrafiltration studies showed that merbarone did not significantly displace binding of urate from albumin. When merbarone was incubated with xanthine oxidase in vitro, several reaction products were observed, including 2-oxo-2-desthio-merbarone and a compound with retention time similar to 4'-OH-merbarone. Both of these compounds have been described previously as metabolites of merbarone in human subjects. The parent drug and both metabolites were found to inhibit xanthine oxidase (Ki = 41, 36, and 240 mumols/L, respectively). However, this inhibitory effect was substantially less potent than allopurinol (Ki = 0.025 mumols/L). This study indicates that merbarone induces profound hypouricemia primarily by increasing uric acid excretion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Induction of profound hypouricemia by a non-sedating thiobarbiturate. 272 94

We examined the basis of reperfusion-induced pulmonary edema produced by pulmonary artery occlusion and subsequent reperfusion. After a 24-h period of occlusion of a rabbit pulmonary artery followed by a 2-h period of reperfusion, the lungs were removed from the animal and perfused with a 0.5 g% Ringer's-albumin solution. An increase in lung weight was observed within 60 min compared with control lungs (i.e., lungs subjected to pulmonary arterial occlusion but not reperfusion) (p less than 0.05). Shorter periods of occlusion (6 or 12 h) did not result in edema, which suggests that a period of ischemia was required for the reperfusion-induced pulmonary edema. The extravascular lung water content also increased in the contralateral lung (i.e., the lung not subjected to pulmonary arterial occlusion and reperfusion). The capillary filtration coefficient increased in reperfused lungs compared with controls (p less than 0.05), indicating an increase in lung vascular permeability following reperfusion. Infusion of allopurinol (a xanthine oxidase inhibitor) and superoxide dismutase during the reperfusion period prevented the increases in lung weight and vascular permeability; infusion of catalase was ineffective. We conclude that pulmonary reperfusion following pulmonary artery occlusion increases pulmonary vascular permeability, which is mediated by the generation of oxidants.
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PMID:Pulmonary edema after pulmonary artery occlusion and reperfusion. 281 6

Xanthine oxidase (XO)-generated toxic O2 metabolites appear to contribute to reperfusion injury, but the possibility that XO is involved in hyperoxic or neutrophil elastase-mediated injury has not been investigated. We found that lungs isolated from rats fed a tungsten-rich diet had negligible XO activities and after exposure to hyperoxia developed less acute edematous injury during perfusion with buffer or purified neutrophil elastase than XO-replete lungs from control rats which had been exposed to hyperoxia. In parallel, tungsten-treated XO-depleted cultured bovine pulmonary arterial endothelial cells made less superoxide anion and as monolayers leaked less 125I-labeled albumin after exposure to neutrophil elastase than XO-replete endothelial cell monolayers. Our findings suggest that XO-derived O2 metabolites contribute to acute edematous lung injury from hyperoxia directly and by enhancing susceptibility to neutrophil elastase.
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PMID:Xanthine oxidase mediates elastase-induced injury to isolated lungs and endothelium. 282 85

When exposed to oxidative stress, by oxygen radicals or H2O2, E. coli exhibited decreased growth, decreased protein synthesis, and dose-dependent increases in protein degradation. The quinone menadione induced proteolysis when cells were incubated in air, but was not effective when cells were incubated without oxygen. Anaerobically grown cells also exhibited significantly lower proteolytic capacity than did cells that were grown aerobically. Xanthine plus xanthine oxidase (which generate O2- and H2O2) caused a stimulation of proteolysis which was inhibitable by catalase, but not by superoxide dismutase: Indicating that H2O2 was responsible for the increased protein degradation. Indeed, H2O2 alone was effective in inducing increased intracellular proteolysis. Two-dimensional polyacrylamide gel electrophoresis of [3H]leucine labeled E. coli revealed greater than 50% decreases in the concentrations of 10-15 cell proteins following H2O2 or menadione exposure, while several other proteins were less severely affected. To test for the presence of soluble proteases, we prepared cell-free extracts of E. coli and incubated them with radio-labeled protein substrates. E. coli extracts degraded casein and globin polypeptides at rapid rates but showed little activity with native proteins such as superoxide dismutase, hemoglobin, bovine serum albumin, or catalase. When these same proteins were denatured by exposure to oxygen radicals or H2O2, however, they became excellent substrates for degradation in E. coli extracts. Studies with albumin revealed correlations greater than 0.95 between the degree of oxidative denaturation and proteolytic susceptibility. Pretreatment of E. coli with menadione or H2O2 did not increase the proteolytic capacity of cell extracts; indicating that neither protease activation, nor protease induction were required.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Degradation of oxidatively denatured proteins in Escherichia coli. 290 82

Many stimuli induce neutrophils to undergo an oxidative burst and generate toxic oxygen metabolites. The major products are O2- and H2O2, the latter being presumed to arise by spontaneous dismutation of the former. If H2O2 were indeed derived exclusively from released O2- according to the equation 2O2- + 2H+----H2O2 + O2, one would expect that relationship to be reflected in the ratio of the two metabolites detectable in the extracellular mileu of stimulated neutrophils. A second corollary is that H2O2 should not form when cytochrome c is present to scavenge O2- before it can dismutate. Although H2O2 cannot be measured directly in the presence of cytochrome c because it is consumed in reoxidizing reduced cytochrome c, its presence can be detected indirectly by the ability of catalase to improve the apparent yield of reduced cytochrome c. We found that the relative amounts of extracellular H2O2 and O2- that could be measured in the environment of stimulated neutrophils varied with the stimulus and that catalase protected reduced cytochrome c from H2O2 oxidation when some stimuli were used but not with others. For example, the ratio of O2- to H2O2 produced by neutrophils exposed to PMA was about 2:1, the expected result if H2O2 were derived from O2-. However when cytochalasin B was added to the cells before the stimulus, the yield of H2O2 was reduced but not the yield of O2-. When cells were allowed to settle and spread on tissue culture plastic they produced equimolar amounts of O2- and H2O2. Coating the plastic with IgG doubled cytochrome c reduction without effecting H2O2. In contrast, coating with albumin reduced H2O2 without effecting cytochrome c reduction. Soluble IgG aggregates induced production of mostly O2- whereas immune complexes resulted in release of both metabolites. FMLP and A23187 were similar to the soluble IgG aggregates in their effects and induced release of proportionately more O2- than H2O2. The addition of catalase to the cytochrome c solution improved the yield of reduced cytochrome c when PMA or IgG was used to stimulate the cells but not when FMLP was used. These and other data suggest that H2O2 release is not a linear function of the amount of O2- generated and that either a variable fraction of O2- spontaneously dismutates to H2O2 or the neutrophil NADPH oxidase, in a manner analogous to xanthine oxidase, is capable, under some circumstances, of producing H2O2 as well as O2-.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neutrophils may directly synthesize both H2O2 and O2- since surface stimuli induce their release in stimulus-specific ratios. 300 Sep 43

The oxygen paradox refers to the abrupt release of cytoplasmic enzymes and severe cellular disruption that occurs following reoxygenation of anoxic perfused hearts. In this study, the ability of a series of oxygen-derived free radical inhibitors and scavenging agents to protect isolated perfused rat hearts from the oxygen-induced enzyme release following 30 or 60 mins of anoxic perfusion (oxygen paradox) and cumene hydroperoxide-induced injury was evaluated. Malondialdehyde (MDA) release, an indicator of lipid peroxidation, and creatine kinase (CK) release, an indicator of cellular injury, were monitored. We evaluated five agents previously reported to scavenge or inhibit the formation of oxygen free radicals. The putative hydroxyl radical scavengers dimethylthiourea (DMTU) and mannitol; catalase, an agent protective against peroxide injury; allopurinol, an inhibitor of xanthine oxidase; and albumin, a non-specific protein control, were evaluated. Coronary flow rates and myocardial temperature were continuously monitored to ensure uniform perfusion conditions. The MDA assay was carefully monitored by constructing standard curves on each experimental day. Addition of 20 microM cumene hydroperoxide to oxygenated perfused hearts caused peroxidative cell injury as evidenced by significant MDA and CK release in the coronary effluent. DMTU and catalase provided near complete protection from cumene hydroperoxide-induced cell injury but did not reduce CK release from hearts subjected to either the mild (30-min) or the severe (60-min) oxygen paradox (reoxygenation-induced injury). Allopurinol caused a significant reduction in MDA release but not CK release from oxygen paradox-injured hearts. Allopurinol and albumin had no significant effect on MDA release from cumene-hydroperoxide-injured hearts. Catalase (300 U/ml) caused a mild but not statistically significant reduction in MDA release from cumene hydroperoxide injury but did not provide protection from the oxygen paradox at either injury level. Mannitol (120 mM), in contrast to DMTU, was ineffective in reducing cumene-induced injury but showed a significant protective effect against oxygen paradox-induced damage. It is concluded that the ability of mannitol to reduce reoxygenation-induced CK release in the oxygen paradox may be due to its osmotic activity and consequent ability to prevent cellular swelling rather than its activity as an oxygen-free radical scavenger.
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PMID:Effects of the free radical scavenger DMTU and mannitol on the oxygen paradox in perfused rat hearts. 311 97

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

When incubated with mitochondria in an air atmosphere, menadione and doxorubicin (which redox cycle with the respiratory chain to produce oxygen radicals), as well as xanthine oxidase plus xanthine (which generate superoxide and H2O2), stimulated the degradation of newly-synthesized [( 3H]leucine-labelled) mitochondrial polypeptides. No stimulation was observed in an N2 atmosphere, ATP was not required, and xanthine oxidase was not effective without xanthine. Various forms of oxidative stress induced varying degrees of protein cross-linking, protein fragmentation and proteolysis, as judged by gel electrophoresis and amino acid analysis. To learn more about the proteolytic enzymes involved in degradation, we undertook studies with purified protein substrates which had been exposed to oxidative stress (OH or H2O2) in vitro. Despite mitochondrial contamination with acid proteases of lysosomal (and other) origin, pH profiles revealed distinct proteolytic activities at both pH 4 and pH 8. The pH 8 activity preferentially degraded the oxidatively-denatured forms of haemoglobin, albumin and superoxide dismutase; was unaffected by digitonin; and exhibited a several-fold increase in activity upon mitochondrial disruption (highest activity being found in the matrix). In contrast, the pH 4 activity was dramatically decreased by digitonin treatment (to reduce lysosomal contamination); was unaffected by mitochondrial disruption; and showed no preference for oxidatively-denatured proteins. The pH 8 activity was not stimulated by ATP, but was inhibited by EDTA, haemin and phenylmethylsulphonyl fluoride. In contrast, the contaminating pH 4 activity was only inhibited by pepstatin and leupeptin. Thus, our experiments reveal a distinct mitochondrial (matrix) proteolytic pathway which can preferentially degrade oxidatively-denatured proteins.
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PMID:Mitochondria contain a proteolytic system which can recognize and degrade oxidatively-denatured proteins. 319 85

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

Milk proteins in acid whey were separated into five fractions according to molecular size by gel filtration chromatography. The second peak, P2, contained proteins between approximately 250,000 and 100,000 daltons. Proteins in P2 were concentrated. After separation into albumins and globulins, each protein group was isolated by DEAE chromatography and hydrophobic interaction chromatography, Isolated albumin fractions were a yellow-colored protein of 89,000 daltons, an unidentified protein of 73,000 daltons, a beta-lactoglobulin of 18,300 daltons, and a red-colored protein of 87,000 daltons. Two types of globulin fractions were isolated: 1) a globulin fraction that coagulated in saturated sodium sulfate but did not coagulate when dialyzed against deionized water included a brown-colored protein of 150,000 daltons, and 2) a bovine serum albumin of 67,000 daltons with unidentified 170,000 and 30,000 daltons bands. A true globulin fraction contained a 77,000 dalton unidentified protein with several faint bands. The red-colored protein was identified as lactoferrin and the brown-colored protein as xanthine oxidase (EC 1.2.3.2.). A yellow-colored protein was concluded to be the denatured protein of contaminated lactoperoxidase (EC 1.11.1.7).
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PMID:Isolation of some minor milk proteins, distributed in acid whey from approximately 100,000 to 250,000 daltons of particle size. 337 95

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