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)

Reoxygenation injury that occurs when blood circulation is restored to previously ischemic tissues is currently discussed as a pathophysiological entity distinct from the primary anoxic injury that develops during ischemia per se. To test the hypothesis that reoxygenation injury in hepatocytes is caused by a postischemic burst of reactive oxygen species (ROS), including superoxide radicals, O2-., and hydrogen peroxide, H2O2, we performed a cytochemical study exploiting the peroxidase activity within peroxisomes as a sensitive ultrastructural detector of intracellular H2O2 generation. The osmiophilic polymer formed when tissue peroxidase is incubated with 3,3'-diaminobenzidine (DAB) and H2O2 was used as a marker for endogenous H2O2 in rat liver slices in short-term organ culture subjected to a cycle of 60-min ischemic anoxia and 30-min reoxygenation in the presence of DAB without exogenous H2O2. Peroxisomal reaction product was quantitatively evaluated in transmission electron micrographs of systematically sampled hepatocytes. Mean densities of positive peroxisomes per 1,000 micron2 (+/- SE) in liver slices subjected to various treatments were as follows: continuous anoxia (negative control) 0 +/- 0; normoxia + exogenous H2O2 (positive control) 45 +/- 12; normoxia only 26 +/- 2; ischemia-reoxygenation 13 +/- 6; ischemia-reoxygenation + xanthine oxidase inhibitor, oxypurinol 5 +/- 3; ischemia-reoxygenation + peroxidase inhibitor, aminotriazole 7 +/- 3. Endogenous H2O2 can be detected in hepatocytes by electron microscopic cytochemistry and may in part derive from xanthine oxidase, but it is not substantially increased in the postischemic state. We conclude that hepatocytes do not exhibit a postischemic burst of reactive oxygen species that could cause reoxygenation injury.
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PMID:Cytochemical studies of hydrogen peroxide generation in postischemic hepatocytes. 199 89

Verapamil administered before treatment, but not after treatment, had a beneficial effect on a 90-minute warm ischemia-reperfusion rat liver injury model. The possible activation of proteases converting the xanthine dehydrogenase to xanthine oxidase, the significant mitochondrial calcium loading during the ischemic period, and the potentiation of calcium and oxygen-derived free radicals to promote injury to mitochondria are mechanisms supported by this study, based on both histologic observations and on the pattern of enzyme leak after the acute ischemic event.
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PMID:The role of calcium ions and calcium channel entry blockers in experimental ischemia-reperfusion-induced liver injury. 199 40

Xanthine oxidase (XO) has been proposed as an important source of free radicals during ischemia. This enzyme normally exists as a dehydrogenase (XD), but it is converted to XO in some ischemic tissues. Recently, treatment of animals with the XD and XO inhibitor allopurinol or with free radical scavengers before cerebral ischemia has been shown to reduce brain injury. Therefore, we studied conversion of XD to XO in three ischemic and nonischemic brain regions during focal cerebral ischemia resulting from permanent occlusion of the middle cerebral artery (MCAO) in anesthetized rats. In nonischemic brain, 16-22% of the enzyme was in the XO form. After 24 h of ischemia this value was not significantly different (10-15%). Neither the total activity of XO nor that of XD changed, indicating that there was no irreversible conversion of XD to XO. To further explore the possible role of XO, we examined the effect of various doses of allopurinol (5, 20, or 100 mg/kg given 1 h before MCAO or 100 mg/kg given 48, 24, and 1 h before MCAO) on uric acid accumulation, brain edema formation, and cerebral blood flow (CBF) 24 h after MCAO. All but the lowest dose of allopurinol greatly reduced the appearance of uric acid in the ischemic brain; however, only the highest dose of allopurinol had any beneficial effect on brain edema. This reduction in brain edema occurred without a significant improvement in CBF. Thus XO is probably not an important source of free radicals in this model of focal cerebral ischemia.
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PMID:Xanthine oxidase is not a major source of free radicals in focal cerebral ischemia. 199 99

Trolox, a hydrophilic analog of vitamin E, was reported to scavenge peroxyl radicals from artificial systems better than its parent compound. Here we examined the possible cytoprotective effect of Trolox in cultured hepatocytes and in the rat liver. In cultured rat hepatocytes, 0.5 to 16 mmol/L Trolox (with optimum between 1 to 2 mmol/L) was observed to prolong the survival of cells exposed to oxyradicals generated with xanthine oxidase-hypoxanthine. The protection by 1 mmol/L Trolox surpassed that provided by either ascorbate, mannitol, superoxide dismutase and/or catalase--each at a level giving its maximal protection in the same system. In both a global and partial model of hepatic ischemia-reperfusion in rats, infusion of Trolox (7.5 to 10 mumol/kg body weight) just before reflow reduced by greater than 80% the liver necrosis sustained in untreated (no Trolox) control rats. Such organ salvage was apparently accompanied by approximately 50% reduction in the amount of hepatic conjugated dienes, which were quantified by a highly specific radiochemical assay. Since conjugated dienes are presumed to be good "markers" of oxyradical damage, our data may have provided a semiquantitative link between free radical-induced necrosis and its chemical imprint in vivo. The data also indicated a relatively rapid and potent antioxidant-like action by Trolox on rat hepatocytes and on the postischemic reperfused rat liver.
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PMID:Trolox protects rat hepatocytes against oxyradical damage and the ischemic rat liver from reperfusion injury. 199 27

Using a highly specific assay that minimizes enzyme inactivation in vitro, we found that rabbit myocardial tissue contained low levels of xanthine oxidase (XO) and xanthine dehydrogenase (XD) activity that were effectively inhibited by pretreatment of hearts with allopurinol. In parallel, allopurinol treatment also improved ventricular developed pressure, peak systolic pressure, and coronary flow in isolated hearts subjected to 30 min of normothermic global ischemia and 30 min of reperfusion. Although function was protected by allopurinol treatment, creatine kinase (CK) release was not altered by allopurinol. Inhibition of myocardial XO with allopurinol did not increase myocardial ATP or phosphocreatine. In addition, allopurinol did not scavenge superoxide anion or hydrogen peroxide in vitro. The results support the possibility that relatively low amounts of XO activity, similar to levels reported in human myocardium, may contribute to cardiac ischemia-reperfusion injury.
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PMID:Existence and participation of xanthine oxidase in reperfusion injury of ischemic rabbit myocardium. 200 Sep 75

Oxygen-derived free radicals have been implicated in a variety of diseases and pathologic processes, including ischemia reperfusion injury (IRI). Based on experimental work with rat skin-flap models, the enzyme xanthine oxidase (XO) has been proposed as a major source of free radicals responsible for tissue injury and flap necrosis. The presence of this enzyme is variable within different tissues of a specific species and between species. Xanthine oxidase levels in pig and human skin have not previously been reported. The activity of xanthine oxidase in the skin of rats (N = 16), pigs (N = 7), and humans (N = 8) was measured after varying intervals of ischemia and in the rat also following reperfusion. Control pig and human skin were found to contain minimal enzyme activity, almost 40 times less than that of the rat. In the rat, xanthine oxidase activity was stable throughout a prolonged period of ischemia, and a significant decrease in activity was found after 12 hours of reperfusion (p less than 0.05). In humans, xanthine oxidase activity was unaffected by ischemia time, and in the pig, it did not increase until 24 hours of ischemia (p less than 0.05). The potential sources of free radicals and the mechanism of action of xanthine oxidase and its inhibitor allopurinol in improving flap survival in different species are reviewed.
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PMID:Pathophysiology of ischemic skin flaps: differences in xanthine oxidase levels among rats, pigs, and humans. 200 72

Oxygen free radicals have been implicated as mediators of cellular injury in ischemia-reperfusion. Since intracellular Ca(2+)-overload has been considered to play a crucial role in ischemia-reperfusion injury, this study was undertaken to examine the effects of oxygen free radicals on Ca(2+)-stimulated Mg(2+)-dependent ATPase activities and ATP-dependent Ca2+ accumulation in rat cardiac sarcolemmal membranes in vitro. Isolated rat heart sarcolemmal membranes were incubated with xanthine (X) + xanthine oxidase (XO) and assayed for Ca(2+)-pump activities. X + XO inhibited the Ca(2+)-pump activities in a time-dependent manner; a significant inhibition of Ca(2+)-stimulated ATPase activity was seen after one min of incubation. Superoxide dismutase showed a protective effect on depression in Ca(2+)-pump activities due to X + XO. To understand the involvement of sulfhydryl groups changes in causing depression of Ca(2+)-pump activities, the effects of oxygen free radicals on heart sarcolemmal sulfhydryl groups were also investigated. Heart sarcolemmal sulfhydryl groups were decreased by X + XO in a time-dependent manner. Superoxide dismutase showed a protective effect on sulfhydryl group depression caused by X + XO. N-ethylmaleimide, a sulfhydryl reagent, showed inhibitory effect on Ca(2+)-pump activities both in a time-, and a dose-dependent manner; dithiothreitol and cysteine prevented changes in Ca(2+)-pump activities caused by N-ethylmaleimide. The inhibitory effect of X + XO on Ca(2+)-pump activities were also prevented by the addition of dithiothreitol or cysteine. A significant correlation between changes in sarcolemmal Ca(2+)-stimulated ATPase activity and sarcolemmal sulfhydryl groups was seen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of heart sarcolemmal Ca(2+)-pump activity by oxygen free radicals. 202 66

Recent data suggest that uric acid is generated locally in the vessel wall by the action of xanthine oxidase. This enzyme, activated during ischemia/reperfusion by proteolytic conversion of xanthine dehydrogenase, catalyzes the oxidation of xanthine, thereby generating free radicals and uric acid. Because of the potential role of ischemia/reperfusion in vascular disease, we studied the effects of uric acid on rat aortic vascular smooth muscle cell (VSMC) growth. Uric acid stimulated VSMC DNA synthesis, as measured by [3H]thymidine incorporation, in a concentration-dependent manner with half-maximal activity at 150 microM. Maximal induction of DNA synthesis by uric acid (250 microM) was approximately 70% of 10% calf serum and equal to 10 ng/ml platelet-derived growth factor (PDGF) AB or 20 ng/ml fibroblast growth factor. Neither uric acid precursors (xanthine and hypoxanthine) nor antioxidants (ascorbic acid, glutathione, and alpha-tocopherol) were mitogenic for VSMC. Uric acid was mitogenic for VSMC but not for fibroblasts or renal epithelial cells. The time course for uric acid stimulation of VSMC growth was slower than serum, suggesting induction of an autocrine growth mechanism. Exposure of quiescent VSMC to uric acid stimulated accumulation of PDGF A-chain mRNA (greater than 5-fold at 8 h) and secretion of PDGF-like material in conditioned medium (greater than 10-fold at 24 h). Uric acid-induced [3H]thymidine incorporation was markedly inhibited by incubation with anti-PDGF A-chain polyclonal antibodies. Thus uric acid stimulates VSMC growth via an autocrine mechanism involving PDGF A-chain. These findings suggest that generation of uric acid during ischemia/reperfusion contributes to atherogenesis and intimal proliferation following arterial injury.
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PMID:Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression. 202 72

The reperfusion of previously ischemic tissue may lead to the formation of highly reactive free radicals that promote tissue injury. Xanthine oxidase has been implicated as one source of these free radicals. We examined the role of xanthine oxidase in brain injury using a cerebrospinal fluid compression model of global cerebral ischemia with 15 minutes of ischemia and 4 hours of reperfusion. Seven dogs were pretreated with the xanthine oxidase inhibitor allopurinol (50 mg/kg for 5 days). Neurophysiological recovery was monitored with cortical somatosensory evoked potentials. As an attempt to correlate brain recovery with the mechanism of protection, free brain malondialdehyde was measured at the end of reperfusion by high-performance liquid chromatography. Brain water content was measured by wet-dry weights. Compared with seven untreated control dogs, allopurinol pretreatment significantly improved recovery of somatosensory evoked potentials after 4 hours of reperfusion. However, the amount of free malondialdehyde in the allopurinol-treated dogs was 32% greater than that in the controls. Brain water content was similar in the two groups. These results suggest that xanthine oxidase contributes to brain injury after ischemia and reperfusion. However, tissue damage caused by xanthine oxidase may be mediated through mechanisms other than free radical production.
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PMID:Allopurinol pretreatment improves evoked response recovery following global cerebral ischemia in dogs. 202 98

Free radicals may arise from a number of sources as a result of a variety of cellular mechanisms; they are generated under both normal and pathological circumstances. The xanthine oxidase pathway, the arachidonic acid pathway, invading leucocytes, catecholamine oxidation, and mitochondrial activity can all lead to the production of a variety of reactive oxygen intermediates including superoxide, hydrogen peroxide, and the hydroxyl radical. Whatever their source, free radicals can be extremely toxic to the cell and they are capable of causing major membrane injury by initiating lipid peroxidation or by altering the activity of membrane-bound enzyme systems which control ionic movement. The cell possesses highly efficient protective mechanisms, including antioxidants such as vitamins C and E and the enzymes superoxide dismutase and catalase, all of which are designed to prevent the occurrence of free radical-induced injury under normal conditions. However, during ischaemia and reperfusion, these protective mechanisms may be overwhelmed and severe free radical-mediated injury may occur. Ischaemia may prime the myocardium for free radical-induced injury. The great majority of the evidence that manipulation of free radicals may protect against such injury is, however, circumstantial.
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PMID:Free radicals and the heart. 202 51


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