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)

Uninduced rat liver microsomes and NADPH-Cytochrome P-450 reductase, purified from phenobarbital-treated rats, catalyzed an NADPH-dependent oxidation of hydroxyl radical scavenging agents. This oxidation was not stimulated by the addition of ferric ammonium sulfate, ferric citrate, or ferric-adenine nucleotide (AMP, ADP, ATP) chelates. Striking stimulation was observed when ferric-EDTA or ferric-diethylenetriamine pentaacetic acid (DTPA) was added. The iron-EDTA and iron-DTPA chelates, but not unchelated iron, iron-citrate or iron-nucleotide chelates, stimulated the oxidation of NADPH by the reductase in the absence as well as in the presence of phenobarbital-inducible cytochrome P-450. Thus, the iron chelates which promoted NADPH oxidation by the reductase were the only chelates which stimulated oxidation of hydroxyl radical scavengers by reductase and microsomes. The oxidation of aminopyrine, a typical drug substrate, was slightly stimulated by the addition of iron-EDTA or iron-DTPA to the microsomes. Catalase inhibited potently the oxidation of scavengers under all conditions, suggesting that H2O2 was the precursor of the hydroxyl radical in these systems. Very high amounts of superoxide dismutase had little effect on the iron-EDTA-stimulated rate of scavenger oxidation, whereas the iron-DTPA-stimulated rate was inhibited by 30 or 50% in microsomes or reductase, respectively. This suggests that the iron-EDTA and iron-DTPA chelates can be reduced directly by the reductase to the ferrous chelates, which subsequently interact with H2O2 in a Fenton-type reaction. Results with the reductase and microsomal systems should be contrasted with results found when the oxidation of hypoxanthine by xanthine oxidase was utilized to catalyze the production of hydroxyl radicals. In the xanthine oxidase system, ferric-ATP and -DTPA stimulated oxidation of scavengers by six- to eightfold, while ferric-EDTA stimulated 25-fold. Ferric-desferrioxamine consistently was inhibitory. Superoxide dismutase produced 79 to 86% inhibition in the absence or presence of iron, indicating an iron-catalyzed Haber-Weiss-type of reaction was responsible for oxidation of scavengers by the xanthine oxidase system. These results indicate that the ability of iron to promote hydroxyl radical production and the role that superoxide plays as a reductant of iron depends on the nature of the system as well as the chelating agent employed.
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PMID:The role of iron chelates in hydroxyl radical production by rat liver microsomes, NADPH-cytochrome P-450 reductase and xanthine oxidase. 633 21

The responses of pig aortic endothelial cells to sublethal doses of potentially toxic stimuli were investigated by monitoring K+ efflux, prostaglandin production, and the release of cytoplasmic purines. Xanthine plus xanthine oxidase reversibly stimulated these three parameters of endothelial cell function at doses that were not cytotoxic, as measured by chromium release, adenine uptake, and vital dye exclusion. The effects of xanthine plus xanthine oxidase were inhibited by catalase but not by superoxide dismutase, suggesting that H2O2 was responsible. Reagent H2O2 also reversibly stimulated K+ efflux, prostaglandin production, and the release of purines. The threshold concentration of H2O2 for these effects was approximately 10 microM, which was at least 30-fold lower than that which caused cytotoxicity. In addition to the direct effect of H2O2 in stimulating prostaglandin production (PGI2 and PGE2), prior exposure of endothelial cells to lower doses of H2O2 (less than 0.1 microM) at high oxygen tension inhibited the subsequent stimulation of prostaglandin production by ATP, A23187, and H2O2 itself. We conclude that H2O2 has substantial effects on endothelial physiology at doses up to 3,000-fold lower than those which induce cytotoxicity.
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PMID:Differential effects of hydrogen peroxide on indices of endothelial cell function. 636 99

During renal ischemia, ATP is degraded to hypoxanthine. When xanthine oxidase converts hypoxanthine to xanthine in the presence of molecular oxygen, superoxide radical (O-2) is generated. We studied the role of O-2 and its reduction product OH X in mediating renal injury after ischemia. Male Sprague-Dawley rats underwent right nephrectomy followed by 60 min of occlusion of the left renal artery. The O-2 scavenger superoxide dismutase (SOD) was given 8 min before clamping and before release of the renal artery clamp. Control rats received 5% dextrose instead. Plasma creatinine was lower in SOD treated rats: 1.5, 1.0, and 0.8 mg/dl vs. 2.5, 2.5, and 2.1 mg/dl at 24, 48, and 72 h postischemia. 24 h after ischemia inulin clearance was higher in SOD treated rats than in controls (399 vs. 185 microliter/min). Renal blood flow, measured after ischemia plus 15 min of reflow, was also greater in SOD treated than in control rats. Furthermore, tubular injury, judged histologically in perfusion fixed specimens, was less in SOD treated rats. Rats given SOD inactivated by prior incubation with diethyldithiocarbamate had plasma creatinine values no different from those of control rats. The OH X scavenger dimethylthiourea (DMTU) was given before renal artery occlusion. DMTU treated rats had lower plasma creatinine than did controls: 1.7, 1.7, and 1.3 mg/dl vs. 3.2, 2.2, and 2.4 mg/dl at 24, 48, and 72 h postischemia. Neither SOD nor DMTU caused an increase in renal blood flow, urine flow rate, or solute excretion in normal rats. The xanthine oxidase inhibitor allopurinol was given before ischemia to prevent the generation of oxygen free radicals. Plasma creatinine was lower in allopurinol treated rats: 2.7, 2.2, and 1.4 mg/dl vs. 3.6, 3.5, and 2.3 mg/dl at 24, 48, and 72 h postischemia. Catalase treatment did not protect against renal ischemia, perhaps because its large size limits glomerular filtration and access to the tubular lumen. Superoxide-mediated lipid peroxidation was studied after renal ischemia. 60 min of ischemia did not increase the renal content of the lipid peroxide malondialdehyde, whereas ischemia plus 15 min reflow resulted in a large increase in kidney lipid peroxides. Treatment with SOD before renal ischemia prevented the reflow-induced increase in lipid peroxidation in renal cortical mitochondria but not in crude cortical homogenates. In summary, the oxygen free radical scavengers SOD and DMTU, and allopurinol, which inhibits free radical generation, protected renal function after ischemia. Reperfusion after ischemia resulted in lipid peroxidation; SOD decreased lipid peroxidation in cortical mitochondria after renal ischemia and reflow. We concluded that restoration of oxygen supply to ischemic kidney results in the production of oxygen free radicals, which causes renal injury by lipid peroxidation.
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PMID:Oxygen free radicals in ischemic acute renal failure in the rat. 643 91

Several reports state that oxygen uptake changed in direct correlation with changes in total oxygen delivery to the tissues in the adult respiratory distress syndrome (ARDS). Oxygen uptake appeared to be limited by oxygen delivery even at normally adequate levels so that uptake was abnormally dependent on supply. These reports are discussed with respect to whether or not such a result could have been due to errors in measurement or to mathematical coupling by relating two quantities that shared a common variable. Having rejected that proposition, animal experiments are cited in which abnormal oxygen supply dependency was produced by microembolization. The accompanying loss of reactive hyperemia and inability to extract oxygen were consistent with a progressive loss of recruitable capillaries. Evidence is presented that the potential for embolization in ARDS is greatly enhanced by activation of the complement and arachidonic acid cascades as well as by the xanthine oxidase system. The resultant use of molecular oxygen by non-ATP producing oxidase systems might also account for the increase of supply dependent oxygen demand in ARDS.
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PMID:Supply dependency of oxygen uptake in ARDS: myth or reality? 648 62

Erythrocytes of five strains of mice had ATP concentrations of ca 2.7 mumol/ml packed cells, while those of CBA mice were 23% lower, and those of BALB/C mice were 40% lower. The ratio of the concentrations of ATP and GTP were ca 3.3 in four strains but greater than 27 in three other strains. When erythrocytes from different mouse strains were incubated with radioactive precursors, appreciable strain differences were found in the apparent activities of adenine and hypoxanthine-guanine phosphoribosyltransferase, adenosine kinase, adenosine deaminase, guanine deaminase and xanthine oxidase. The activities of adenosine deaminase and guanine deaminase in sera of mice of different strains also varied.
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PMID:Variation in erythrocyte purine metabolism among mouse strains. 668 81

Generation of H2O2 by rat liver mitochondria with choline, glycerol 1-phosphate and proline as substrates has been shown by using high-concentration phosphate buffer. Rates obtained under these conditions were higher and more consistent as compared with the earlier reports with high-concentration mannitol/sucrose/Tris buffer. Sulphate ions could replace phosphate indicating a requirement for a high concentration of oxygen-containing anions. H2O2 generation was dependent on the presence of native mitochondria and substrate. Maximal rates with various substrates were found to be the same as with succinate. Values of Km and Vmax for H2O2 generation were considerably less than those obtained for respective dehydrogenase activities, measured by dye reduction. Scavengers of O2-. and OH. inhibited generation of H2O2. ATP, ADP, thyronine derivatives and a number of phenolic compounds also showed very potent inhibitory effects of H2O2 generation, whereas phenyl compound had no effect. Phenolic compounds did not have any effect on mitochondrial superoxide dismutase and choline dehydrogenase activities as well as on O2-. generation by the xanthine-xanthine oxidase system. Inhibition by phenolic compounds may have potential for regulation of the intracellular concentration of H2O2, that is not considered to have a "second messenger' function.
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PMID:Inhibition of H2O2 generation in rat liver mitochondria by radical quenchers and phenolic compounds. 730 14

Oxygen-derived free radicals (FRs) and other reactive oxygen species (ROS) have been implicated in the deleterious aspects of myocardial infarction, neutrophil infiltration and post-ischaemic reperfusion. We studied their actions on the main intracellular organelles of Ca-compartmentation and force production (the sarcoplasmic reticulum (SR) and myofilaments) in rat heart preparations by using two forms of chemical 'skinning'. We recorded Ca(2+)-activated isometric tension or, in saponin-treated trabeculae where SR function is maintained, either tension alone or tension and [Ca2+] transients evoked by caffeine. A single, brief application of xanthine/xanthine oxidase (generating superoxide; O2-) rapidly and irreversibly inhibits Ca(2+)-activated force with a dose- and time-dependent action. The kinetics of residual force production are slowed. Rigor induction (by ATP withdrawal) before and during exposure to .O2- prevents this action, suggesting the .O2(-)-sensitive site is occluded in rigor. Myofilament Ca-sensitivity and SR function were unaffected by .O2- or physiologically relevant [H2O2] (< 10 microM). Briefly applying 10-50 microM hypochlorous acid (HOCl) increased Ca-sensitivity and resting tension, but reduced Ca-activated force, in a manner consistent with 'rigor-like' crossbridges being involved. HOCl also provoked spontaneous Ca-release but reduced net SR Ca-uptake. Electron microscopy reveals that the myofilament lattice suffers a characteristic disruption by HOCl but not by .O2-. We conclude that FRs and ROS associated with myocyte dysfunction, reperfusion and inflammation could contribute to post-ischaemic myocardial dysfunction.
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PMID:Intracellular effects of free radicals and reactive oxygen species in cardiac muscle. 747 29

Hypoxia-induced hepatocyte injury results not only from ATP depletion but also from reductive stress and oxygen activation. Thus the NADH/NAD+ ratio was markedly increased in isolated hepatocytes maintained under 95% N2/5% CO2 in Krebs-Henseleit buffer well before plasma membrane disruption occurred. Glycolytic nutrients fructose, dihydroxyacetone or glyceraldehyde prevented cytotoxicity, restored the NADH/NAD+ ratio, and prevented complete ATP depletion. However, the NADH generating nutrients sorbitol, xylitol, glycerol and beta-hydroxybutyrate enhanced hypoxic cytotoxicity even though ATP depletion was not affected. On the other hand, NADH oxidising metabolic intermediates oxaloacetate or acetoacetate prevented hypoxic cytotoxicity but did not affect ATP depletion. Restoring the cellular NADH/NAD+ ratio with the artificial electron acceptors dichlorophenolindophenol and Methylene blue also prevented hypoxic injury and partly restored ATP levels. Ethanol which further increased the cellular NADH/NAD+ ratio increased by hypoxia also markedly increased toxicity whereas acetaldehyde which restored the normal cellular NADH/NAD+ ratio, prevented toxicity even though hypoxia induced ATP depletion was little affected by ethanol or acetaldehyde. The viability of hypoxic hepatocytes is therefore more dependent on the maintenance of normal redox homeostasis than ATP levels. GSH may buffer these redox changes as hypoxia caused cell injury much sooner with GSH depleted hepatocytes. Hypoxia also caused an intracellular release of free iron and cytotoxicity was prevented by desferoxamine. Furthermore, increasing the cellular NADH/NAD+ ratio markedly increased the intracellular release of iron. Hypoxia-induced hepatocyte injury was also prevented by oxypurinol, a xanthine oxidase inhibitor. Polyphenolic antioxidants or the superoxide dismutase mimic, TEMPO partly prevented cytotoxicity suggesting that reactive oxygen species contributed to the cytotoxicity. The above results suggests that hypoxia induced hepatocyte injury results from sustained reductive stress and oxygen activation.
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PMID:Modulating hypoxia-induced hepatocyte injury by affecting intracellular redox state. 748 48

By correlating lactate/pyruvate ratios and ATP levels, cytotoxicity induced by the mitochondrial respiratory inhibitors or hypoxia:reoxygenation injury can be attributed not only to ATP depletion but also to reductive stress and oxygen activation. Thus hypoxia, cyanide or antimycin markedly increases reductive stress, non-heme Fe release and H2O2 formation in hepatocytes. Cytotoxicity was partly prevented with the ferric chelator desferoxamine, the xanthine oxidase inhibitor oxypurinol and the hydrogen peroxide scavenger glutathione. No lipid peroxidation could be detected and phenolic anti-oxidants had little effect. However, polyphenolic antioxidants or the superoxide dismutase mimics TEMPO or TEMPOL partly prevented cytotoxicity. Furthermore, increasing the hepatocyte NADH/NAD+ ratio with NADH generating compounds such as ethanol, glycerol, or beta-hydroxybutyrate markedly increased cytotoxicity (prevented by desferoxamine) and further increased the intracellular release of non-heme iron. Cytotoxicity could be prevented by glycolytic substrates (eg. fructose, dihydroxyacetone, glyceraldehyde) or the NADH utilising substrates acetoacetate or acetaldehyde which decreased the reductive stress and prevented intracellular iron release. These results suggest that liver injury resulting from insufficient respiration involves reductive stress which releases intracellular Fe, converts xanthine dehydrogenase to xanthine oxidase and causes mitochondrial oxygen activation. The cell's antioxidant defences are compromised and ATP catabolism contributes to oxygen activation.
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PMID:Hepatocyte injury resulting from the inhibition of mitochondrial respiration at low oxygen concentrations involves reductive stress and oxygen activation. 758 49

While the free radical-generating enzyme xanthine oxidase is a central mechanism of injury in postischemic tissues, questions remain regarding how xanthine oxidase-mediated radical generation is triggered during ischemia and reperfusion. There is controversy regarding whether radical generation is caused by enzyme formation of that of its substrates xanthine and hypoxanthine. Therefore, studies were performed in isolated rat hearts correlating the magnitude and time course of radical generation with alteration in xanthine oxidase and its substrates. Radical generation was measured by electron paramagnetic resonance spectroscopy and correlated with spectrophotometric assays of tissue xanthine oxidase activity and chromatographic measurements of tissue and effluent concentrations of xanthine oxidase substrates and products. Xanthine oxidase was present in preischemic hearts and slightly increased during 30-min global ischemia. Hypoxanthine and xanthine were not present prior to ischemia but accumulated greatly during ischemia due to ATP degradation. These substrate concentrations rapidly declined over the first 5 min of reperfusion matching the observed time course of radical generation, whereas xanthine oxidase activity was largely unchanged. Both substrates were also observed in the coronary effluent during the first 5 min of reflow along with the product uric acid. Thus, the burst of xanthine oxidase-mediated free radical generation upon reperfusion is triggered and its time course controlled by a large increase in substrate formation that occurs secondary to the degradation of ATP during ischemia.
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PMID:Substrate control of free radical generation from xanthine oxidase in the postischemic heart. 764 30


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