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)

The effect of the xanthine oxidase inhibitor, allopurinol, on myocardial ultrastructure after left circumflex coronary artery occlusion (40 min) with or without reperfusion (60 min) was examined in rabbits. Pretreatment of rabbits for 7 days with allopurinol (0.1% in the drinking water) resulted in a lower incidence of ventricular fibrillation in both ischemic and reperfusion phases. However, the number of Q waves, ST-segment elevation and premature ventricular contractions were similar in both groups of animals. Examination of hearts from allopurinol-treated animals revealed a distinct decrease in ultrastructural alterations following ischemia and reperfusion. Among the subcellular organelles studied, allopurinol had a preferential protective effect on the mitochondria both during the ischemic and reperfusion phases. In the allopurinol-treated animals, most mitochondria were intact and the cristae network preserved. Our study suggests that the preservation of mitochondrial structural and functional integrity by allopurinol may be an important determinant of its protective actions in myocardial ischemic/reperfusion injury.
Virchows Arch B Cell Pathol Incl Mol Pathol 1986
PMID:Effects of allopurinol pretreatment on myocardial ultrastructure and arrhythmias following coronary artery occlusion and reperfusion. 288 57

After anaerobic reductive activation by either NADPH cytochrome P-450 reductase (EC 1.6.2.4) or xanthine oxidase (EC 1.2.3.2), mitomycin C readily alkylated DNA. When the mitomycin C-alkylated DNA is digested by DNase, snake venom phosphodiasterase, and alkaline phosphatase, only partial release of the monofunctionally linked mitomycin C nucleotide adduct occurs. Cross-linked adducts are not released into dinucleotides but resist nuclease digestion and remain in oligonucleotides and insoluble precipitates. Kinetic analyses show that the nuclease-resistant fraction which is indicative of DNA cross-linking by mitomycin C takes place quite readily. This nuclease-resistant fraction is particularly significant when the amount of total bound mitomycin C is less than 15 mumol/mmol of DNA. The cross-linked mitomycin C product accounts for more than half of the total alkylation under all pH conditions tested. Our data suggest that particular DNA sites are available for DNA cross-linking by mitomycin C, and these sites are probably the preferred and immediate alkylating targets. Furthermore, DNA cross-links by mitomycin C are not the secondary product of monofunctional adducts. Activity of both flavoenzymes is pH dependent, hence, mitomycin C activation and the rate of DNA alkylation are pH dependent. At elevated mitomycin C alkylation of DNA, the highest amount of cross-linking occurs at neutral pH. High pressure liquid chromatographic separation of the nuclease-digested DNA detected one major and two less prominent mitomycin C adducts. These were verified to be mononucleotide mitosene types by UV spectra showing maximum absorbance at 312 and 250 nm. The major adduct was purified and identified as O6-(2'-deoxyguanosyl)-2,7-diaminomitosene by NMR, indicating that the O6 position of guanine is a preferred site in DNA for at least monofunctional linkage formation.
Mol Pharmacol 1986 Jun
PMID:DNA alkylation by enzyme-activated mitomycin C. 308 8

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.
J Mol Cell Cardiol 1987 Jun
PMID:Effects of the free radical scavenger DMTU and mannitol on the oxygen paradox in perfused rat hearts. 311 97

In an isolated, normothermic rat heart model (Langendorff, 37 degrees C), dimethylthiourea (DMTU) infusion only during reperfusion reduced both injury and measurable hydrogen peroxide (H2O2) concentrations after global ischemia. Cardiac function was assessed by measurement of ventricular developed pressure (DP). H2O2 was assessed using H2O2 dependent aminotriazole inactivation of myocardial catalase. Depletion of xanthine oxidase by two methods (tungsten or allopurinol inhibition) also improved recovery of function and H2O2 production. The results indicate that XO derived H2O2 contributes to myocardial reperfusion injury.
Mol Cell Biochem 1988 Dec
PMID:Hydrogen peroxide mediates reperfusion injury in the isolated rat heart. 314 10

Xanthine (X) and xanthine oxidase (XO) were injected intratracheally (IT) in hamsters at Day 0 (38 mg X, 100 micrograms XO) and Day 5 (38 mg X, 250 micrograms XO). Control hamsters received saline or X (38 mg) plus boiled XO (100, 250 micrograms). Cytoplasmic superoxide dismutase (SOD) activity increased from control of 286 to 337 and 335 units/lung at Days 12 and 19, respectively, but decreased to 228 units/lung at Day 33; mitochondrial SOD activity increased at Day 12 from control of 57 to 71 units/lung and then decreased at Days 26 and 33 to 42 and 33 units/lung, respectively. Glutathione peroxidase (GP) and glutathione reductase (GR) activities rose from their control values of 1161 and 1151 to 1561 and 2287 units/lung at Day 12, respectively; thereafter, GR activity decreased to 512 and 462 units/lung at Days 19 and 26, respectively. Glutathione transferase declined at Day 12 but increased at Day 26 after initial treatment. Glucose-6-phosphate dehydrogenase activity declined from control of 1071 to 693 units/lung at Day 2 and returned to control thereafter. Catalase activity remained unaffected. Hydroxyproline was increased from 903 micrograms/lung in control to 1080, 1301, 1195, and 1148 micrograms/lung at Days 12, 19, 26, and 33, respectively. Malonaldehyde increased from 40 nmole/lung in control to 70 and 113 nmole/lung at Days 12 and 33, respectively. The ratio of right ventricle to left ventricle and septum increased significantly from control of 0.277 to 0.318 at Day 33. Histopathology at Days 2 and 4 revealed peribronchiolar and arteriolar inflammation, and diffuse alveolitis. By Day 12 there were thickened alveolar septa and foci of fibrotic consolidation.
Exp Mol Pathol 1988 Dec
PMID:Effects of intratracheal administration of xanthine plus xanthine oxidase on lung antioxidant enzymes, lipid peroxidation, and collagen in hamsters. 319 17

The effect of oxygen free radicals, generated by xanthine and xanthine oxidase, was studied on the release of lysosomal hydrolase from rat liver lysosomes in vitro. A lysosomal enriched subcellular fraction was prepared, using differential centrifugation technique, from the homogenate of rat liver. The biochemical purity of the lysosomal fraction was established by using the markers of different cellular organelles. Oxygen free radicals were generated in vitro by the addition of xanthine and xanthine oxidase. The release of lysosomal hydrolase (beta-glucuronidase) from the lysosomal fraction was measured. There was a 3 to 4 fold increase in the release of beta-glucuronidase activity in the presence of xanthine and xanthine oxidase when compared to that in the absence of xanthine and xanthine oxidase. In the presence of superoxide dismutase (SOD), a scavenger of oxygen free radicals, the xanthine and xanthine oxidase system was unable to induce the release of beta-glucuronidase activity from the lysosomes. Sonication (2 bursts for 15 sec each) and Lubrol (2 mg/10 mg lysosomal protein) treatment, which are known to cause membrane disruption, also induced the release of beta-glucuronidase from lysosomal fraction. This release of beta-glucuronidase by sonication and lubrol treatment was not prevented by SOD. These data indicate that lysosomal disruption is a consequence of oxygen free radicals, generated by xanthine and xanthine oxidase.
Mol Cell Biochem 1988 Dec
PMID:Oxygen free radicals induced release of lysosomal enzymes in vitro. 323 Dec 25

Oxygen free radicals may participate in a variety of pathological cardiac conditions which are associated with an increased incidence of arrhythmias. However, evidence that free radicals per se can alter the electrical function of the myocardium is not convincing. Physiological solutions containing 3 mM dihydroxyfumaric acid (DHF), a compound known to generate free radicals, were superfused over calcium-tolerant cells isolated from the adult canine ventricle. The time course for changes in transmembrane action potentials was monitored using conventional microelectrode techniques. Changes were observed which could be conveniently segregated into three stages. Initially during superfusion with DHF, the voltage of the action potential plateau became more positive and the action potential duration increased (stage 1). Continued superfusion was associated with the development of both early and delayed afterdepolarizations (stage 2), which occasionally produced triggered beats. Subsequently, some cells failed to repolarize beyond -40 mV following an action potential upstroke. In cells which maintained normal levels of resting membrane potential, early and delayed afterdepolarizations ceased concomitant with the development of an increasingly more negative plateau voltage. Action potential duration decreased and plateau potential "collapsed", eventually merging with the resting level of the membrane potential. Resting membrane potential then gradually depolarized to less than -40 mV and all cells became inexcitable within 6 to 20 min (stages 3). Exposure of cells to xanthine (2 mM): xanthine oxidase (0.01 U/ml), another system known to generate free radicals, produced similar results. Superfusion with DHF solutions containing either superoxide dismutase or catalase delayed the appearance and attenuated the development of the changes in the cardiocyte action potential. The results demonstrate that isolated cardiocytes exposed to free radical generating solutions can undergo changes in their electrophysiological activity that resemble those said to underlie disturbances of cardiac rate and rhythm in the clinical setting.
J Mol Cell Cardiol 1988 Dec
PMID:Abnormal electrical activity induced by free radical generating systems in isolated cardiocytes. 324 6

We have assessed whether oxygen-derived free radicals produced by xanthine oxidase may be an important trigger mechanism in the genesis of reperfusion-induced arrhythmias. We have examined (i) the effects of inhibition of xanthine oxidase by both folic acid solution and amflutizole; (ii) the effects of the inhibitor of xanthine dehydrogenase to xanthine oxidase conversion, soybean trypsin inhibitor; (iii) the effects of administration of superoxide dismutase and catalase, both singly and in combination and (iv) in an isolated rat heart preparation we have investigated the ability of free radical scavengers to reduce reperfusion arrhythmias caused by the infusion of xanthine oxidase and hypoxanthine. The prior administration of folic acid solution, amflutizole, superoxide dismutase, catalase, and superoxide dismutase plus catalase all reduced the incidence of reperfusion-induced arrhythmias and resultant mortality, caused by reperfusion after a transient period of coronary artery occlusion in the anaesthetised rat. Prior administration of soybean trypsin inhibitor significantly reduced mortality. In an isolated, perfused rat heart preparation with temporary coronary artery occlusion, addition of xanthine oxidase-hypoxanthine to the perfusion medium increased the incidence of reperfusion arrhythmias and decreased the total duration of sinus rhythm during reperfusion. Further addition of superoxide dismutase or L-methionine increased significantly the total duration of sinus rhythm. These results suggest that in the rat heart xanthine oxidase may be involved in the genesis of reperfusion-induced arrhythmias.
J Mol Cell Cardiol 1988 Jan
PMID:Reperfusion-induced arrhythmias: a study of the role of xanthine oxidase-derived free radicals in the rat heart. 336 77

Porfiromycin was reductively metabolized by NADPH cytochrome P-450 reductase and xanthine oxidase under anaerobic conditions. The production of metabolites varied with the pH and the contents of the reaction buffer. In Tris buffer, two major metabolites were produced at pH 7.5 and above, whereas one major metabolite was produced at pH 6.5. The three major metabolites were separated and isolated by HPLC. Identification by californium-252 plasma desorption mass spectrometry showed that the two major metabolites from pH 7.5 were (trans) and (cis)-forms of 7-amino-1-hydroxyl-2-methylaminomitosene and the major metabolite from pH 6.5 was 7-amino-2-methylaminomitosene. All three major metabolites showed substitutions at the C-1 position. DNA was alkylated readily by enzyme-activated porfiromycin. Digestion of porfiromycin-alkylated DNA by DNase, snake venom phosphodiesterase, and alkaline phosphatase resulted in an insoluble nuclease-resistant fraction and a soluble fraction. The nuclease-resistant fraction reflected a high content of cross-linked adducts. Upon HPLC analysis, the solubilized fraction contained two monofunctionally linked porfiromycin adducts and a possibly cross-linked dinucleotide. The major adduct was isolated by HPLC and identified by NMR, as N2-(2'-deoxyguanosyl)-7-amino-2-methylaminomitosene. The N2 position of deoxyguanosine appeared as the major monofunctional alkylating site for DNA alkylation by porfiromycin. Thus, mitomycin C and porfiromycin (which differs from mitomycin C only by the addition of a methyl group to the aziridine nitrogen) share the same enzymatic activating mechanism that leads to the formation of the same types of metabolites and the same specificity of DNA alkylation.
Mol Pharmacol 1988 Aug
PMID:Metabolites and DNA adduct formation from flavoenzyme-activated porfiromycin. 341 25

We used isolated, buffer-perfused rabbit hearts to evaluate whether global, normothermic ischemia altered mitochondrial hydrogen peroxide (H2O2) generation and mitochondrial activities of the major enzymes responsible for degrading H2O2 and superoxide anion (O2-.): glutathione peroxidase (GPD) and superoxide dismutase (SOD), respectively. This preparation lacks exogenous neutrophils and endogenous xanthine oxidase, which are other potential sources of oxygen metabolites. Ischemia depressed mitochondrial oxidative phosphorylation parameters, State 4 succinate-supported H2O2 generation rates, and the relative flux of State 4 oxygen consumption that was diverted to H2O2 formation. The production of H2O2 was not abolished. Ischemia and reperfusion significantly reduced the activities of SOD (by 43%) and GPD (by 39%) in the mitochondrial fraction. Cytosolic GPD activity was also depressed. The results suggest that the myocardial cell's ability to enzymatically degrade H2O2 and O2-. is compromised, particularly in the mitochondrion. Although mitochondrial H2O2 production is decreased, the mitochondria may persist as a source of this oxygen metabolite following ischemia. Collectively, the data may help explain why mitochondria are vulnerable targets of free radical-mediated damage due to ischemia.
J Mol Cell Cardiol 1987 Dec
PMID:Mitochondrial hydrogen peroxide generation and activities of glutathione peroxidase and superoxide dismutase following global ischemia. 344 86


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