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)

It is now clear that oxygen-derived free radicals play an important part in several models of experimentally induced reperfusion injury. Although there are certainly multiple components to clinical ischemic and reperfusion injury, it appears likely that free-radical production may make a major contribution at certain stages in the progression of the injury. The primary source of superoxide in reperfused reoxygenated tissues appears to be the enzyme xanthine oxidase, released during ischemia by a calcium-triggered proteolytic attack on xanthine dehydrogenase. Reperfused tissues are protected in a variety of laboratory models by scavengers of superoxide radicals or hydroxyl radicals or by allopurinol or other inhibitors of xanthine oxidase. Dysfunction induced by free radicals may thus be a major component of ischemic diseases of the heart, bowel, liver, kidney, and brain.
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PMID:Oxygen-derived free radicals in postischemic tissue injury. 298 4

At a concentration much lower than that usually employed for measuring cytosolic ionized Ca2+ concentrations, arsenazo III underwent a one-electron reduction by rat liver cytosolic fraction or a hypoxanthine-xanthine oxidase system to produce an azo anion radical metabolite. NADH, NADPH, N1-methylnicotinamide, hypoxanthine, and xanthine, in that order, could serve as a source of reducing equivalents for the production of this free radical by the cytosolic fraction. The steady-state concentration of the azo anion radical and the arsenazo III-stimulated O2 consumption were enhanced by calcium and magnesium. Antipyrylazo III was ineffective in increasing O2 consumption by rat liver cytosolic fraction and gave a much weaker ESR signal of an azo anion radical with both the liver cytosolic fraction, in the presence of NADH, and the hypoxanthine-xanthine oxidase system.
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PMID:Reduction of the metallochromic indicators arsenazo III and antipyrylazo III to their free radical metabolites by cytoplasmic enzymes. 298 21

Recent studies have established a major role for oxygen-derived free radicals in post ischemic tissue injury to the intestine. During ischemia, there appears to be a calcium-triggered, protease-dependent conversion of the native xanthine dehydrogenase to a superoxide-producing xanthine oxidase. The catabolic degradation of ATP during ischemia provides an oxidizable substrate, hypoxanthine. On reperfusion, molecular oxygen is resupplied and a burst of superoxide production ensues, resulting in extensive tissue damage. The same mechanism appears to occur in myocardial ischemia. Xanthine dehydrogenase rapidly converts to the oxidase during nonperfusion in the rat heart. In the isolated perfused working rat heart model, 40 min of anoxia followed by reoxygenation results in substantial release of creatine kinase. The release of creatine kinase is blocked almost completely by pretreatment of the rats with allopurinol, a specific inhibitor of xanthine oxidase.
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PMID:Free radicals and myocardial ischemia. The role of xanthine oxidase. 298 6

In vitro, arachidonic acid depressed calcium transport by sarcoplasmic reticulum (SR) in the homogenate of canine masseter muscle. This effect was inhibited by superoxide dismutase (SOD), a scavenger of the superoxide anion radial ( . O-2), at pH 7.0, and by SOD plus d-mannitol, a scavenger of hydroxyl free radical ( . OH), at pH 5.5. Indomethacin and 2-aminomethyl-4-tert-butyl-6-propionyl phenol (ONO-3144), a compound known to accelerate the conversion of prostaglandin G2 (PGG2) to PGH2 and scavenge free radicals, inhibited the effect of arachidonic acid at both pH 7.0 and pH 5.5. PGG2, but not PGH2, duplicated the effect of arachidonic acid. The effect of PGG2 on SR function was similar to that of exogenous free radicals generated from the xanthine-xanthine oxidase system. Incubation at pH 5.5, in the absence of an exogenous free-radical generating system, depressed SR calcium transport in the homogenate and in isolated SR. This effect in the homogenate was inhibited by indomethacin or by ONO-3144. At 10-min incubation at pH 5.5, SOD partially and temporarily reversed the depressant effect of acidosis. The addition of SOD plus d-mannitol completely reversed the system. d-Mannitol alone was ineffective. Arachidonic acid was able to mimic these effects of acidosis, except that arachidonic acid further depressed isolated SR calcium transport. These results demonstrate that acidosis can depress SR calcium transport in the homogenate of masseter muscle by an oxygen-free radical mechanism by the generation of . O-2 and . OH. Our results also demonstrate that significant oxygen radical generation can occur through the cyclooxygenase pathway of arachidonic acid metabolism at an acidotic pH in the cellular environment outside of the SR of the muscle cell, and seems to be responsible for the generation of the . OH derived from . O-2.
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PMID:Inhibition by free radical scavengers and by cyclooxygenase inhibitors of the effect of acidosis on calcium transport by masseter muscle sarcoplasmic reticulum. 298 87

Preincubation of rat brain synaptosomes with xanthine and xanthine oxidase (X/XO) in Ca2+-free Krebs buffer resulted in a 27% inhibition of synaptosomal gamma-aminobutyric acid (GABA) uptake. Addition of 1.5 mM CaCl2 increased the inhibition with X/XO to 46%, and inhibition was essentially complete when the calcium ionophore A23187 also was included. In other studies, preincubation of purified rat brain mitochondria with the combination of X/XO and 4 microM CaCl2 produced a significant (38%) decrease in state 3 respiration with glutamate/malate as substrate that was not seen with either X/XO or Ca2+ alone. Similar results were obtained using cultured mouse spinal cord neurons in which incubation with X/XO/ADP/FeCl2 and A23187 produced membrane damage as assessed by a 32% reduction of neuronal Na+, K+-ATPase activity. Neither X/XO/ADP/FeCl2 nor A23187 alone caused detectable inhibition. These results demonstrate the synergistic damaging effect of free radicals and Ca2+ on membrane function. In addition, they suggest that free radical-induced peroxidation of membrane lipid, occurring focally during complete or nearly complete ischemia in vivo, could result in intense cellular perturbation when coupled with increased intracellular Ca2+.
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PMID:Calcium enhances in vitro free radical-induced damage to brain synaptosomes, mitochondria, and cultured spinal cord neurons. 299 23

The superoxide radicals generated by the xanthine oxidase reaction reduced the myofibrillar Ca2+-ATPase activity. This negative effect was prevented by superoxide dismutase or by dithiothreitol, a protective thiol compound. Partial protection was achieved by catalase, while mannitol was ineffective. The myofibrillar Ca2+-ATPase exposed to O2-. radicals did not modify the affinity for Ca2+ while it showed a remarkable reduction of Vmax measured at the saturating level of Ca2+. The O2-. inhibited myofibrillar ATPase showed a higher value of Km for the cofactor associated to a reduced value of Vmax when studied in the presence of increasing concentration of ATP. Thus, circumstances that enhance the production of cardiac O2- radicals can be considered a negative metabolic event capable of depressing the myofibrillar Ca2+-ATPase activity.
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PMID:Inhibitory effect of superoxide radicals on cardiac myofibrillar ATPase activity. 299 80

Maintenance of an acidic intralysosomal compartment may be relevant to multiple aspects of neutrophil function. The effect of lysosomal alkalinization on the neutrophil respiratory burst was studied by measuring cytochrome c reduction in response to soluble stimuli in the presence of lysosomotropic weak bases. The weak bases chloroquine, ammonium chloride, methylamine, and clindamycin all raised the intralysosomal pH and inhibited neutrophil oxidative metabolism at concentrations ranging from 0.1 to 100 mmol/L. Inhibition was dose dependent for each base and correlated significantly with the degree of lysosomal alkalinization. Concentrations that did not alkalinize the lysosome did not inhibit the respiratory burst. Inhibition by weak bases was seen when oxidative metabolism was stimulated by phorbol myristate acetate, calcium ionophore A23187, formyl-methionyl-leucyl-phenylalanine, opsonized zymosan, or sodium fluoride. Increasing the stimulus concentration (from 5 ng/mL to 5 micrograms/mL phorbol myristate acetate and from 0.5 to 1 mumol/L A23187) diminished or abolished inhibition by weak bases. Washing the cells after incubation with bases and before stimulation substantially reversed the inhibition. None of the bases impaired detection of superoxide in a cell-free xanthine-xanthine oxidase assay. Other indexes of oxidative metabolism, including oxygen consumption and hydrogen peroxide release, were also inhibited by weak bases. Analysis of particulate NADPH oxidase activity from neutrophils stimulated in the presence of bases suggested that these cells assemble a subnormal amount of an enzyme complex with normal kinetic characteristics. Lysosomotropic weak bases alkalinized the neutrophil lysosome and produced inhibition of oxidative metabolism that was dose related, was not stimulus specific, and was largely reversed by washing the cells before stimulation. A possible explanation would be altered assembly of the enzyme complex involved in respiratory burst activation as a consequence of impaired granule/plasma membrane fusion in the presence of diminished transmembrane pH gradients.
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PMID:Inhibition of neutrophil oxidative metabolism by lysosomotropic weak bases. 300 23

The effect of scavengers of oxygen radicals on canine cardiac sarcoplasmic reticulum (SR) Ca2+ uptake velocity was investigated at pH 6.4, the intracellular pH of the ischemic myocardium. With the generation of oxygen radicals from a xanthine-xanthine oxidase reaction, there was a significant depression of SR Ca2+ uptake velocity. Xanthine alone or xanthine plus denatured xanthine oxidase had no effect on this system. Superoxide dismutase (SOD), a scavenger of .O2-, or denatured SOD had no effect on the depression of Ca2+ uptake velocity induced by the xanthine-xanthine oxidase reaction. However, catalase, which can impair hydroxyl radical (.OH) formation by destroying the precursor H2O2, significantly inhibited the effect of the xanthine-xanthine oxidase reaction. This effect of catalase was enhanced by SOD, but not by denatured SOD. Dimethyl sulfoxide (Me2SO), a known .OH scavenger, completely inhibited the effect of the xanthine-xanthine oxidase reaction. The observed effect of oxygen radicals and radical scavengers was not seen in the calmodulin-depleted SR vesicles. Addition of exogenous calmodulin, however, reproduced the effect of oxygen radicals and the scavengers. The effect of oxygen radicals was enhanced by the calmodulin antagonists (compounds 48/80 and W-7) at concentrations which showed no effect alone on Ca2+ uptake velocity. Taken together, these findings strongly suggest that .OH, but not .O2-, is involved in a mechanism that may cause SR dysfunction, and that the effect of oxygen radicals is calmodulin dependent.
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PMID:Calmodulin participation in oxygen radical-induced cardiac sarcoplasmic reticulum calcium uptake reduction. 303 9

The effects of allopurinol pretreatment (1 mg/ml in the drinking water for 7 days at an estimated daily dose of 75 mg/kg) on biochemical and chemical changes occurring following left circumflex coronary artery ligation (40 min) and reperfusion (60 min) were examined in pentobarbital-anesthetized rabbits. During the ischemic phase, allopurinol pretreatment provided significant preservation of cellular ATP levels and of mitochondrial ATP generation as compared with untreated animals (P less than 0.05). During the reperfusion phase, allopurinol pretreatment significantly prevented the decrease in left ventricular pressure, sodium and calcium accumulation and decreases in sarcolemmal Na+,K+-stimulated and sarcoplasmic reticulum K+,Ca2+-stimulated ATPase activities as compared with untreated animals (P less than 0.05). In contrast, the decrease in mitochondrial (azide-sensitive) ATPase during ischemia and the partial recovery during reperfusion were unaffected by allopurinol pretreatment. Our results indicate that the myocardial protective effects of allopurinol may differ mechanistically in the ischemic and reperfusion phases of injury. The fact that rabbit hearts do not contain detectable xanthine oxidase activity would seem to preclude an obligatory role of this enzyme both in the generation of myocardial ischemic/reperfusion injury and in the protective actions of allopurinol.
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PMID:Effects of allopurinol on myocardial ischemic injury induced by coronary artery ligation and reperfusion. 303 15

The polyamines putrescine, spermidine and spermine, at concentrations of 10 microM, stimulated superoxide generation by human polymorphonuclear leukocytes induced by fMet-Leu-Phe in the presence of Ca2+. This positive effect was not evident in the absence of Ca2+ or when the polymorphonuclear leukocytes were stimulated by phorbol myristate acetate. Spermidine in the range of 10-100 microM showed a dose-dependent stimulatory effect on the superoxide generation induced by fMet-Leu-Phe, whilst at doses above 25 mM it produced an inhibitory effect. At this concentration, spermidine did not reduce the phorbol myristate acetate-neutrophil-induced O2-. generation, while an inhibitory effect by the polyamine was evident at concentrations above 50 mM. In addition, 100 microM spermidine increased the amount of superoxide generated and enhanced the ability of the chemotactic peptide to stimulate superoxide generation. The polyamines in the range of 10 microM-25 mM did not modify the activity of purified NADPH oxidase, nor the rate of reduction of cytochrome c as supported by the xanthine/xanthine oxidase reaction. These results indicate that physiological concentrations of polyamines can stimulate superoxide formation by polymorphonuclear leukocyte cells produced by the chemotactic peptide fMet-Leu-Phe, probably by increasing the availability of external calcium.
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PMID:Polyamines stimulate superoxide production in human neutrophils activated by N-fMet-Leu-Phe but not by phorbol myristate acetate. 304 Jan 18


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