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)

The success of thrombolytic/reperfusion therapy in limiting the extent of myocardial infarction may be limited by reperfusion injury. Damage from acute ischemia is not due solely to the interruption of blood flow; rather, ischemia initiates a cascade of reactions involving partially reduced oxygen, inflammatory mediators, mechanical capillary obstruction by granulocytes and other events that lead to irreversible injury. A surprising consequence is that reperfusion by delivering oxygen and granulocytes may counteract some of the benefits of restoring flow. Mechanisms of neutrophil and free radical injury include superoxide radical formation and lipid peroxidation, progressive leukocyte capillary plugging and capillary no-reflow, and edema. The interaction of various specific mechanisms of injury in the heart (i.e., xanthine oxidase, mitochondrial superoxide leak, neutrophil superoxide, degranulation and capillary plugging, and neutrophil-derived vasoconstrictors) deserves further study.
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PMID:Free radical and granulocyte-mediated injury during myocardial ischemia and reperfusion. 253 48

Superoxide radicals inactivate endoplasmic reticular (ER) Ca2+ pump in membranes isolated from smooth muscle of pig right coronary artery [Am. J. Physiol. 255 (Cell Physiol. 24): C297-C303, 1988]. We report on protective mechanisms against such inactivation. This tissue contained superoxide dismutase (SOD) and catalase. SOD was distributed primarily in cytosolic fraction, was cyanide sensitive, and was also present in mitochondrial fraction, and approximately 25% of this was cyanide insensitive. Catalase was distributed mainly in mitochondrial fraction and did not protect against inactivation of ER Ca2+ pump by superoxide radicals generated using xanthine plus xanthine oxidase. However, cytosolic fraction protected against this inactivation by two mechanisms: 1) DTT carried over from homogenization medium and 2) its intrinsic SOD content. Soluble fraction was concentrated, dialyzed to remove 1,4-dithiothreitol (DTT), lyophilized, and suspended in a small volume of DTT-free buffer. It still protected against superoxide inactivation of Ca2+ pump. On Sephacryl-300 gel chromatography, protecting activity comigrated with SOD. DTT protected against inactivation, but glutathione and cysteine protected only partially. Neither sulfhydryl agents nor SOD could reverse the inactivation process. Ca2+ pump activity was abolished by dithionitrobenzoate and p-chloromercuric benzoate. Superoxide may inactivate ER Ca2+ pump by irreversibly modifying key sulfhydryl group(s) on pump molecule and SOD in coronary artery smooth muscle may partially protect against this inactivation.
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PMID:Protection of Ca pump of coronary artery against inactivation by superoxide radical. 253 68

The reactions of superoxide radical with persistent nitroxide spin-adducts or with stable spin-labels were studied using ESR spectrometry. Superoxide radicals were produced enzymatically using xanthine - xanthine oxidase or chemically by dissolving potassium superoxide in DMSO. Hydroxyl and methyl spin-adducts of the spin-trap DMPO were performed by sonolysis and subsequently reacted with superoxide radical. Superoxide-induced depletion of DMPO--OH obeyed second order kinetics. Contrary to previously published mechanisms, the reaction requires neither transition metal ions nor thiols. The depleted spin-adducts could not be restored by reoxidation with ferricyanide or copper +H2O2; thus, the superoxide-mediated destruction does not result in a mere one-electron reduction product. Superoxide also depletes other DMPO spin-adducts including DMPO--CH3 and DMPO--H, but not PBN--CH3. In addition, some 5-membered ring stable nitroxides are depleted by superoxide in a pseudo-zero order reaction. In studying systems which generate O2- and OH, the superoxide-induced destruction of DMPO--OH may well lead to erroneous conclusions regarding the primary radicals produced. In particular this reaction might be operative under circumstances where elevated rates of superoxide production take place, such as during oxygen consumption "burst" in phagocytosis, degranulation, or paraquat intoxication.
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PMID:Superoxide reaction with nitroxide spin-adducts. 254 65

Xanthine oxidase has been hypothesized to be an important source of biological free radical generation. The enzyme generates the superoxide radical, .O2- and has been widely applied as a .O2- generating system; however, the enzyme may also generate other forms of reduced oxygen. We have applied electron paramagnetic resonance (EPR) spectroscopy using the spin trap 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO) to characterize the different radical species generated by xanthine oxidase along with the mechanisms of their generation. Upon reaction of xanthine with xanthine oxidase equilibrated with air, both DMPO-OOH and DMPO-OH radicals are observed. In the presence of ethanol or dimethyl sulfoxide, alpha-hydroxyethyl or methyl radicals are generated, respectively, indicating that significant DMPO-OH generation occurred directly from OH rather than simply from the breakdown of DMPO-OOH. Superoxide dismutase totally scavenged the DMPO-OOH signal but not the DMPO-OH signal suggesting that .O2- was not required for .OH generation. Catalase markedly decreased the DMPO-OH signal, while superoxide dismutase + catalase totally scavenged all radical generation. Thus, xanthine oxidase generates .OH via the reduction of O2 to H2O2, which in turn is reduced to .OH. In anaerobic preparations, the enzyme reduces H2O2 to .OH as evidenced by the appearance of a pure DMPO-OH signal. The presence of the flavin in the enzyme is required for both .O2- and .OH generation confirming that the flavin is the site of O2 reduction. The ratio of .O2- and .OH generation was affected by the relative concentrations of dissolved O2 and H2O2. Thus, xanthine oxidase can generate the highly reactive .OH radical as well as the less reactive .O2- radical. The direct production of .OH by xanthine oxidase in cells and tissues containing this enzyme could explain the presence of oxidative cellular damage which is not prevented by superoxide dismutase.
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PMID:Characterization of free radical generation by xanthine oxidase. Evidence for hydroxyl radical generation. 254 34

Propranolol is the beta-blocker most widely used in the management of cardiovascular disorders. It has been proposed that propranolol may act as a "chain-breaking" antioxidant. We have directly examined the ability of propranolol to inhibit superoxide-dependent, iron-promoted cardiac membrane phospholipid peroxidation, with xanthine oxidase (XOD) as a physiologically-recognized, enzymatic superoxide generator. Our results demonstrate that propranolol not only protects cardiac-membrane lipid from peroxidative damage, but also acts as a simple, reversible XOD inhibitor, noncompetitive with xanthine substrate. Propranolol, at effective antiperoxidant and XOD-inhibitory concentrations, cannot scavenge superoxide radical. The antiperoxidative profile of propranolol resembles that of the known XOD inhibitor allopurinol, although allopurinol, a tight-binding substrate-analog competitive with xanthine, inhibits XOD in a manner mechanistically very different from that of propranolol. Furthermore, the antiperoxidative profiles of both propranolol and allopurinol do not resemble those of chain-breaking antioxidants such as alpha-tocopherol. These data, along with the tendency of propranolol to concentrate in myocardial membranes and cytosol, suggest that the observed antioxidant action of propranolol, as a consequence of XOD inhibition, could play a pharmacologic role in propranolol's cardioprotective effects.
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PMID:Propranolol as xanthine oxidase inhibitor: implications for antioxidant activity. 254 74

The calcium ionophore A23187 causes endothelium-dependent contractions in canine basilar arteries. Removal of the endothelium, or treatment with indomethacin or superoxide dismutase (SOD), prevented the endothelium-dependent excitatory effect of the calcium ionophore. Catalase and deferoxamine were without effect. Superoxide anion generated by xanthine plus xanthine oxidase in the presence of catalase caused contractions of the vascular smooth muscle, which were abolished by SOD or heat inactivation of xanthine oxidase. The A23187-induced production of prostaglandins F2 alpha and E2 and thromboxane B2 was abolished by the removal of endothelium and by treatment with indomethacin but was not affected by the presence of SOD plus catalase. These observations are consistent with the hypothesis that superoxide anion, rather than prostaglandins generated by hydroperoxidase activity of cyclooxygenase, is an endothelium-derived contracting factor in canine cerebral arteries.
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PMID:Superoxide anion is an endothelium-derived contracting factor. 254 50

Damage to the bases in DNA produced by the hypoxanthine/xanthine oxidase system in the presence of iron ions was studied. The base products in DNA were measured using gas chromatography-mass spectrometry with selected ion monitoring after acidic hydrolysis of DNA and trimethylsilylation. Products identified were cytosine glycol, thymine glycol, 5,6-dihydroxycytosine, 4,6-diamino-5-formamidopyrimidine, 8-hydroxyadenine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, and 8-hydroxyguanine. These are typical hydroxyl radical-induced products of the bases in DNA. 2,6-Diamino-4-hydroxy-5-formamidopyrimidine was the major product, followed by 8-hydroxyguanine, in DNA treated with hypoxanthine/xanthine oxidase/Fe3+-EDTA. The use of Fe3+ did not cause as much damage to the bases in DNA as did the use of Fe3+-EDTA. In both systems, the formation of the products was inhibited by superoxide dismutase, catalase, dimethyl sulfoxide, mannitol, and desferrioxamine, but inhibitions were much stronger in the systems containing EDTA. Hence formation of hydroxyl radicals by a superoxide radical-assisted Fenton reaction is proposed to account for the results obtained. 2,6-Diamino-4-hydroxy-5-formamidopyrimidine, 5,6-dihydroxycytosine, 4,6-diamino-5-formamidopyrimidine, and 8-hydroxyguanine were proposed as the products in DNA to measure if one aims to measure DNA products as indices of oxidative DNA damage involving hydroxyl radicals in vivo.
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PMID:Iron ion-dependent modification of bases in DNA by the superoxide radical-generating system hypoxanthine/xanthine oxidase. 254 43

A systematic study of the influence of biological lipid peroxidation conditions on lipid hydroperoxide decomposition to thiobarbituric acid-reactive malondialdehyde is presented. A superoxide-dependent, iron-catalyzed peroxidation system was employed with xanthine oxidase plus hypoxanthine plus ferric iron-adenosine diphosphate complex as free radical generator. Purified cardiac membrane phospholipid (as liposomes) was the peroxidative target, and 15-hydroperoxy-eicosatetraenoic acid was used as a standard lipid hydroperoxide. Exposure of myocardial phospholipid to free radical generator at physiological pH (7.4) and temperature (37 degrees C) was found to support not only phospholipid peroxidation, but also rapid lipid hydroperoxide breakdown and consequent malondialdehyde formation during peroxidation. Under lipid peroxidation conditions, oxidative injury to the phospholipid polyunsaturated fatty acids required superoxide radical and ferric iron-adenosine diphosphate complex, whereas 37 degrees C temperature and trace iron were sufficient for lipid hydroperoxide decomposition to malondialdehyde. Harsh thiobarbituric acid-test conditions following peroxidation were not mandatory for either lipid hydroperoxide breakdown or thiobarbituric acid-reactive malondialdehyde formation. However, hydroperoxide decomposition that had begun in the peroxidation reaction could be completed during a subsequent thiobarbituric acid test in which no lipid autoxidation took place. Iron was more critical than heat in promoting the observed hydroperoxide decomposition to malondialdehyde during the lipid peroxidation reaction at 37 degrees C and pH 7.4. These data demonstrate that the radical generator, at physiological pH and temperature, serves a dual role as both initiator of membrane phospholipid peroxidation and promotor of lipid peroxide breakdown and thiobarbituric acid-reactive malondialdehyde formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thiobarbituric acid-reactive malondialdehyde formation during superoxide-dependent, iron-catalyzed lipid peroxidation: influence of peroxidation conditions. 254 30

Oxygenase-catalyzed and non-enzymatic polyunsaturated fatty acid peroxidations have potential pathogenic roles in ischemic-reperfusion damage to the myocardium. Certain oxygenase inhibitors protect heart muscle from irreversible ischemic injury, and some antiperoxidants can inhibit oxygenase enzymes. We investigated the antiperoxidative abilities of eight anti-ischemic, cardioprotective oxygenase inhibitors to prevent myocardial-membrane phospholipid peroxidation through superoxide-driven, iron-promoted reactions with xanthine oxidase as the source of superoxide. Flurbiprofen, ibuprofen, and REV-5901-5 did not affect peroxidation at concentrations up to 1000 microM. BW755C, AA-861, nafazatrom, dipyridamole, and propyl gallate did protect and cardiac lipids against oxidative injury in a concentration-dependent manner with respective and antiperoxidant IC50 values (concentrations at which peroxidation was inhibited by 50%) of 0.22, 1.25, 3.0, 3.6 and 50 microM. Catechin and phenidone, known oxygenase inhibitors not yet evaluated as anti-ischemic agents, were also found to be antiperoxidants at low micromolar concentrations. Four cyclooxygenase inhibitors ineffective against myocardial infarction (aspirin, indomethacin, naproxen, and sulfinpyrazone) evidenced no antiperoxidant properties at concentrations up to 500 microM. The oxygenase inhibitor-antiperoxidants identified could neither quench superoxide radical nor inhibit xanthine oxidase. However, they were able to interrupt the propagation of an on-going peroxidation reaction. Their antiperoxidant profiles resembled those of known antioxidants, such as alpha-tocopherol, which inhibit peroxidation by intercepting lipid free-radical intermediates. These data raise the possibility that at least some oxygenase inhibitors could exert cardioprotective effects by directly influencing the sensitivity of myocardial-membrane phospholipid to peroxidative injury. Consequently, recognition of the antiperoxidant properties of these agents may aid dissection of their physiological and pharmacological actions.
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PMID:Influence of cardioprotective cyclooxygenase and lipoxygenase inhibitors on peroxidative injury to myocardial-membrane phospholipid. 255 48

During the last few years, the scientific field has focused its attention on the pathogenic role of free radicals in the process of ischemia-revascularization. It is a well-known fact that xanthine oxidase is an important source of tissular free radicals. Bearing this in mind, we designed an experimental protocol to analyse the effect of allopurinol (a xanthine oxidase inhibitor) in the survival of rats after the occlusion of the superior mesenteric artery during a period of 90 minutes and its action on the superoxide radical liberation. The concentration of oxipurinol and allopurinol in the ischemic area (intestine), liver and blood were measured. We concluded that the administration of allopurinol increased the survival rate, which is correlated to higher concentrations of allopurinol and oxipurinol in the inner part of the intestinal cells. A correlation between the survival rate and superoxide radicals was not found.
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PMID:[Effect of xanthine oxidase inhibitors on the prognosis of acute intestinal ischemia]. 256 72


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