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)

Methane (CH(4)) production from the anti-inflammatory agent, dimethyl sulfoxide (DMSO), was used to measure .OH from chemical reactions or human phagocytes. Reactions producing .OH (xanthine/xanthine oxidase or Fe(++)/EDTA/H(2)O(2)) generated CH(4) from DMSO, whereas reactions yielding primarily O-(2) or H(2)O(2) failed to produce CH(4). Neutrophils (PMN), monocytes, and alveolar macrophages also produced CH(4) from DMSO. Mass spectroscopy using d(6)-DMSO showed formation of d(3)-CH(4) indicating that CH(4) was derived from DMSO. Methane generation by normal but not chronic granulomatous disease or heat-killed phagocytes increased after stimulation with opsonized zymosan particles or the chemical, phorbol myristate acetate. Methane production from DMSO increased as the number of stimulated PMN was increased and the kinetics of CH(4) production approximated other metabolic activities of stimulated PMN. Methane production from stimulated phagocytes and DMSO was markedly decreased by purportedly potent .OH scavengers (thiourea or tryptophane) and diminished to lesser degrees by weaker .OH scavengers (mannitol, ethanol, or sodium benzoate). Superoxide dismutase or catalase also decreased CH(4) production but urea, albumin, inactivated superoxide dismutase, or boiled catalase had no appreciable effect. The results suggest that the production of CH(4) from DMSO may reflect release of .OH from both chemical systems and phagocytic cells. Interaction of the nontoxic, highly permeable DMSO with .OH may explain the anti-inflammatory actions of DMSO and provide a useful measurement of .OH in vitro and in vivo.
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PMID:Generation of hydroxyl radical by enzymes, chemicals, and human phagocytes in vitro. Detection with the anti-inflammatory agent, dimethyl sulfoxide. 50 Aug 30

A striking similarity exists between the pathogenetic properties of group A streptococci and those of activated mammalian professional phagocytes (neutrophils, macrophages). Both types of cells are endowed by the ability to adhere to target cells; to elaborate oxidants, hydrolases, and membrane-active agents (hemolysins, phospholipases); and to freely invade tissues and destroy cells. From the evolutionary point of view, streptococci might justifiably be considered the forefathers of "modern" leukocytes. Our earlier findings that synergy between a streptococcal hemolysin (streptolysin S, SLS) and a streptococcal thiol-dependent proteinase and between cytotoxic antibodies+complement and streptokinase-activated plasmin readily killed tumor cells, led us to hypothesize that by analogy to the pathogenetic mechanisms of streptococci, the mechanisms of tissue destruction initiated by activated leukocytes in inflammatory sites, as well as in tissues undergoing episodes of ischemia and reperfusion, might also be the result of the synergistic effects among leukocyte-derived oxidants, phospholipases, proteinases, cytokines, and cationic proteins. The current report extends our previous synergy studies with endothelial cells to two additional cell types--monkey kidney epithelial cells and rat beating heart cells. Monolayers of 51Cr-labeled cells that had been treated by combinations of sublytic amounts of hydrogen peroxide (generated either by glucose oxidase, xanthine-xanthine oxidase, or by paraquat) and with sublytic amounts of a variety of membrane-active agents (streptolysin S, phospholipases A2 and C, lysophosphatides, histone, chlorhexidine) were killed in a synergistic manner (double synergy). Crystalline trypsin markedly enhanced cell killing by combinations of oxidant and the membrane-active agents (triple synergy). Injury to the cells was characterized by the appearance of large membrane blebs that detached from the cells and floated freely in the media, looking like lipid droplets. Cytotoxicity induced by the various combinations of agonists was depressed, to a large extent, by scavengers of hydrogen peroxide (catalase, dimethyl thiourea, and by Mn2+) but not by SOD or by deferoxamine. When cationic agents were employed together with hydrogen peroxide, polyanions (heparin, polyanethole sulfonate) were also found to inhibit cell killing. It is proposed that in order to effectively combat the deleterious toxic effects of leukocyte-derived agonists on cells and tissues, antagonistic "cocktails" comprised of cationized catalase, cationized SOD, dimethylthiourea, Mn(2+)+glycine, proteinase inhibitors, putative inhibitors of phospholipases, and polyanions might be concocted. The current literature on synergistic phenomena pertaining to mechanisms of cell and tissue injury in inflammation is selectively reviewed.
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PMID:Synergism among oxidants, proteinases, phospholipases, microbial hemolysins, cationic proteins, and cytokines. 142 26

The oxidative demethylenation reactions of (methylendioxy)phenyl compounds (MDPs), (methylenedioxy)benzene (MDB), (methylenedioxy)amphetamine (MDA), and (methylenedioxy)methamphetamine (MDMA), were evaluated by using two hydroxyl radical generating systems, the autoxidation of ascorbate in the presence of iron-EDTA and the iron-catalyzed Haber-Weiss reaction conducted by xanthine/xanthine oxidase with iron-EDTA. Reaction products generated when MDB, MDA, and MDMA were incubated with the ascorbate or xanthine oxidase system were catechol, dihydroxyamphetamine (DHA), and dihydroxymethamphetamine (DHMA), respectively. The reaction required the presence of either ascorbic acid or xanthine oxidase. Levels of each catechol increased in proportion to ferric ion concentration and were suppressed by desferrioxamine B methanesulfonate (desferal). Catalase (CAT) inhibited the oxidation by the ascorbate system whereas superoxide dismutase (SOD) had little effect. The addition of hydrogen peroxide to the reaction mixture stimulated the oxidation, but the reaction was not initiated by hydrogen peroxide alone, suggesting that hydrogen peroxide acts as a precursor of hydroxyl radical. SOD and CAT suppressed the demethylenation reactions in the xanthine oxidase system. Hydroxyl radical scavenging agents such as ethanol, benzoate, DMSO, and thiourea effectively inhibited the oxidation by both systems. Urea, which has little effect on hydroxyl radical, was without any effect. These results indicated that hydroxyl radical can effect the cleavage of methylenedioxy group on MDPs.
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PMID:Hydroxyl radical mediated demethylenation of (methylenedioxy)phenyl compounds. 168 Apr 77

This study was designed to probe the hypothesis that oxygen-derived free radicals are involved in initiation of the no-reflow phenomenon. We developed a reproducible model of no reflow in the rat hind limb. Laser Doppler studies confirmed that the hind limbs perfused well after 2 or 4 hours of ischemia, but perfusion ceased in the first 10 minutes after 6 hours of ischemia. Venous blood samples and biopsy specimens of skin and muscle were taken after 2 and 4 hours of ischemia to study tissue injury. Blood samples were evaluated for xanthine oxidase (XO), xanthine dehydrogenase, and creatine phosphokinase (CPK) activities. Conjugated dienes and iodine 125-labeled albumin extravasation were quantified in tissue samples. Groups of animals were treated with inhibitors of XO (allopurinol), antioxidant enzymes (superoxide dismutase plus catalase), and free radical scavengers (dimethyl sulfoxide and dimethyl thiourea) to assess the roles of free radicals in ischemia-reperfusion injury in the hind limbs. After 4 hours of ischemia followed by reperfusion, plasma XO activity rose threefold over preischemia levels (p less than 0.05). Xanthine dehydrogenase activity did not change; conjugated diene levels in muscle rose twofold; CPK levels rose sixfold, and 125I albumin extravasation rose twofold (p less than 0.05). Pretreatment with the XO inhibitor allopurinol reduced XO activity to negligible levels and significantly attenuated conjugated diene levels, CPK levels, and albumin extravasation. Albumin extravasation was also significantly attenuated by pretreating animals with superoxide dismutase together with catalase, dimethyl thiourea, and dimethyl sulfoxide. In all animals pretreated with allopurinol or superoxide dismutase and catalase, reperfusion persisted after 6 hours of ischemia. These data suggest that, in ischemia followed by reperfusion, tissue injury is related to oxygen products derived from XO activity.
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PMID:Xanthine oxidase: its role in the no-reflow phenomenon. 173 87

The new water-soluble ammonium-analog of alpha-tocopherol (vitamin E) (compound 1: 3,4-dihydro-6-hydroxy-N,N, N-2,5,7,8-heptamethyl-2H-1-benzopyran-2-ethanaminium 4-methylbenzenesulfonate) and its tertiary amine derivative (compound 2: 3,4-dihydro-2-(2-dimethylaminoethyl)-2,5,7,8-tetramethyl-2H-1-benzopyran -6-ol hydrochloride) were investigated as scavengers of oxygen-derived free radicals. Compounds 1 and 2 were at least 40 times more potent inhibitors of Fe-driven heart microsomal lipid peroxidation than Trolox. While the alpha-tocopherol analogs had the same potency as scavengers of xanthine/xanthine oxidase-generated superoxyl radicals, the thiol compounds D,L-penicillamine and N-2-mercaptopropionyl glycine reacted at a much slower rate. The O-acetyl derivatives of compounds 1 and 2 were not scavengers of superoxyl radicals. Considerable differences between the alpha-tocopherol analogs were observed in their competition with 2-deoxyribose for hydroxyl radicals (OH.). Compound 2 was equipotent with Trolox and thiourea, whereas the reactivity of these substances was diminished by more than 30% as compared to compound 1. Although showing lower reactivity, the O-acetyl derivatives of compounds 1 and 2 were active nevertheless as OH.-scavengers. The previously reported high potency of compound 1 in reducing infarct size during myocardial ischemia/reperfusion appears to be due to its radical-scavenging properties, likely to be enhanced by its previously described cardioselectivity.
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PMID:A water-soluble quaternary ammonium analog of alpha-tocopherol, that scavenges lipoperoxyl, superoxyl and hydroxyl radicals. 177 7

Thiourea and superoxide dismutase were effective antidotes to paraquat toxicity in an HL60 cell culture system, whereas other hydroxyl scavengers were ineffective. The efficacy of thioureas was not due to blockage of intracellular paraquat uptake, inhibition of NADPH-P-450 reductase, or reaction with the paraquat radical. Thiourea also competitively inhibited the reduction of cytochrome c by the xanthine/xanthine oxidase superoxide-generating system, and the release of iron from ferritin by superoxide radicals. The reaction of superoxide with thiourea produced a sulfhydryl compound distinct from products formed by hydrogen peroxide or hydroxyl radicals. Spectrophotometric and chromatographic studies indicated the carbon-sulfide double bond was converted to a sulfhydryl group which reacted with Ellman's reagent. Additional confirmatory evidence for the sulfhydryl compound was obtained with carbon-13 NMR and mass spectroscopies. Thus, thioureas are direct scavengers of superoxide radicals as well as hydroxyl radicals and hydrogen peroxide. The rate constant for the reduction of thiourea by superoxide was estimated at 1.1 x 10(3) M-1 s-1. The implication of this finding on free radical studies, the mechanism of paraquat toxicity, and the metabolism of thioureas is discussed.
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PMID:Thioureas react with superoxide radicals to yield a sulfhydryl compound. Explanation for protective effect against paraquat. 215 25

The changes in short circuit current (electrogenic Cl- secretion) of rat colon brought about by xanthine/xanthine oxidase in the Ussing chamber were inhibited by catalase and diethyldithiocarbamate, but not by superoxide dismutase. These results, the reproduction of the response with glucose/glucose oxidase and with exogenous H2O2, and the lack of effect of preincubation with deferoxamine or thiourea implicate H2O2, and not O2- or OH., as the important reactive oxygen metabolite altering intestinal electrolyte transport. 1 mM H2O2 stimulated colonic PGE2 and PGI2 production 8- and 15-fold, respectively, inhibited neutral NaCl absorption, and stimulated biphasic electrogenic Cl secretion with little effect on enterocyte lactic dehydrogenase release, epithelial conductance, or histology. Cl- secretion was reduced by cyclooxygenase inhibition. Also, the Cl- secretion, but not the increase in prostaglandin production, was reduced by enteric nervous system blockade with tetrodotoxin, hexamethonium, or atropine. Thus, H2O2 appears to alter electrolyte transport by releasing prostaglandins that activate the enteric nervous system. The change in short circuit current in response to Iloprost, but not PGE2, was blocked by tetrodotoxin. Therefore, PGI2 may be the mediator of the H2O2 response. H2O2 produced in nontoxic concentrations in the inflamed gut could have significant physiologic effects on intestinal water and electrolyte transport.
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PMID:Hydrogen peroxide stimulates rat colonic prostaglandin production and alters electrolyte transport. 216 49

Several experimental and theoretical lines of evidence implicate oxidant mechanisms in the diffuse lung injury which leads to the clinical syndrome called the adult respiratory distress syndrome (ARDS). The fact that the injury is characterized by diffuse lung inflammation and that neutrophils can injure lung cells by producing reactive oxygen species provide all of the events necessary for extracellular oxidant stress as an important mechanism of injury. In experimental models and in the clinical syndrome, biochemical evidence of oxidant injury can be measured in the form of lipid peroxidation products. In some models, antioxidants, even antioxidant enzymes which do not access cell interiors, can protect the lungs from injury. There is also evidence that reactive oxygen species generated within lung cells may provide an additional oxidant mechanism of injury. Gram negative bacterial endotoxin can directly injure lung endothelial cells in culture. This injury is unaffected by superoxide dismutase or catalase (antioxidant enzymes which do not enter cells), but is prevented by several antioxidants which penetrate cells (including dimethyl sulphoxide, dimethyl thiourea and allopurinol). The fact that allopurinol can inhibit direct lung cell injury by endotoxin suggests that xanthine oxidase may be a source of oxidant generation in lung endothelial cells. Current data suggest a two stage oxidant process of lung cell injury where there is both direct injury of the cell by intracellular generation of toxic oxidants and triggering of the inflammatory response. Activated inflammatory cells adherent to lung cells then enhance the injury by the generation and release of extracellular oxidants.
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PMID:Oxidant stress and adult respiratory distress syndrome. 227 7

The effect of oxidant stress on the active transport of serotonin (5-HT) into mouse platelets was examined. Oxidant stress was produced using either H2O2 or the xanthine-xanthine oxidase generating system that yields both superoxide anion and H2O2. H2O2 (6.25-100 microM) caused a rapid (2-4 min) stimulation of platelet 5-HT transport that returned to control levels after 15 min of incubation. Catalase (1500 U/ml) completely prevented the stimulation, and the hydroxyl radical trapping agents mannitol (1 nM) and thiourea (1 mM) failed to alter the stimulation. Fluoxetine (1 microM) totally blocked all 5-HT uptake into stimulated platelets. The xanthine-xanthine oxidase (3.12-25 mU/ml) generating system produced a response similar to that of H2O2. In this system, superoxide dismutase (250 U/ml) did not alter the stimulatory response, whereas catalase (1500 U/ml) totally prevented the stimulation. The kinetics of 5-HT transport showed that oxidant stress did not alter the Km of 5-HT transport (Km control = 8.0 +/- 1.0 x 10(-7) M versus Km H2O2 = 9.5 +/- 1.1 x 10(-7) M) but markedly increased the maximal rate of transport (Vmax control = 36.1 +/- 4.8 pmol/10(8) platelets/4 min versus Vmax H2O2 = 79.9 +/- 9.1 pmol/10(8) platelets/4 min). Washed platelets failed to be stimulated by H2O2; however, the addition of small amounts of plasma to the buffer medium fully restored the stimulating response to H2O2. These data suggest that a plasma factor regulates the active transport of 5-HT by platelets that are oxidatively stressed.
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PMID:Oxidant stress stimulates active transport of serotonin by platelets. 253 34

The lysis of sheep and rabbit red blood cells (SRBC and RRBC, respectively) upon exposure to PMA-activated human polymorphonuclear leukocytes (PMN) was investigated. The lysis of these target cells, which was measured by the release of 51Cr, showed different kinetics and scavenger-sensitivity. The lysis of RRBC, which was already detectable within 45 min of incubation, was sensitive to superoxide dismutase (SOD), but was only poorly influenced by scavengers of hydroxyl radical formation, such as desferal or thiourea. In contrast, lysis of SRBC was first detectable after 90 to 135 min of incubation and sensitive to desferal and thiourea, but not to SOD. Finally, only RRBC were sensitive to the artificial superoxide-generating system hypoxanthine/xanthine oxidase. Taken together, these data point at a cytolytic activity of superoxide anion O2- towards RRBC. SRBC are relatively resistant to O2-, but are lysed by an H2O2- and hydroxyl radical-dependent process.
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PMID:Evidence that superoxide-anion, produced by PMA-activated human polymorphonuclear leukocytes, is the cytolytic agent for rabbit, but not for sheep red blood cells. 284 Dec 39


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