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)

Free radical generation and the mobilization of catalytic iron are important in the pathogenesis of alcohol-induced liver injury. Cimetidine is a free radical scavenger in thermal skin injury and cobra venom-induced lung injury, and was therefore investigated as a scavenger of ethanol-induced free radicals. In vitro cimetidine inhibited iron-mediated cleavage of DNA as well as the potentiation of such cleavage by bleomycin. Peroxidation of microsomes by xanthine-xanthine oxidase, acetaldehyde-xanthine oxidase, as well as by the addition of low-molecular weight iron chelates were inhibited (17-100%) by cimetidine (0.1-1 mM). Free radical generation due to ethanol in isolated rat hepatocytes was studied by measuring ethane and pentane production. Cimetidine (1 mM) significantly decreased ethane and pentane production due to ethanol: 1 mM (2.2 +/- 0.3 vs. 1.0 +/- 0.2 pmol ethane per 10(6) cells/h; p less than 0.01, 4.2 +/- 0.4 versus 1.6 +/- 0.3 pmole per 10(6) cells/h pentane; p less than 0.001). Similar inhibitions were observed in the isolated perfused liver. Studies of superoxide reduction of ferricytochrome-C as well as hydroxyl radical generation by Fe(+)+/EDTA/ascorbate revealed that cimetidine was an effective hydroxyl radical scavenger. In summary, in a variety of in vitro systems, as well as in isolated hepatocytes and perfused liver, cimetidine inhibits ethanol-induced free radical injury. These findings may warrant its investigation as a therapeutic agent.
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PMID:Cimetidine as a scavenger of ethanol-induced free radicals. 141 59

This study investigated whether or not oxygen-derived free radicals are implicated in the mechanism of recurrence of duodenal ulceration. To this end, allopurinol (50 mg qds)--a hydroxyl scavenger and an inhibitor of xanthine oxidase which forms superoxide radicals--and dimethyl sulphoxide (DMSO, 500 mg qds)--a hydroxyl scavenger--were given orally. Three hundred and two consecutive patients with previous symptomatic, endoscopy-proven duodenal ulceration which had been shown endoscopically to have healed and who were smokers and social drinkers, were randomized to receive for one year either placebo, cimetidine 400 mg at bedtime, allopurinol, or DMSO. In two hundred and twenty patients evaluable for efficacy, the cumulative relapse at one year was: placebo 65%, cimetidine 30%, allopurinol 12% and DMSO 13%. Cimetidine was significantly effective (p less than 0.01); however, allopurinol and DMSO were equally efficacious and superior to cimetidine (p less than 0.05). In patients who relapsed, the ulcer recurrence tended to occur early on placebo and to be evenly distributed over the year on active therapy. In all the groups, the relative frequency of symptomatic to silent relapses was similar in the first and second halves of the year and was comparable among the groups. The results suggest that oxygen-derived free radicals are directly implicated in the mechanism of duodenal ulcer relapse and that removing the radicals reduces recurrence of this ulceration.
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PMID:Oxygen-derived free radicals and the prevention of duodenal ulcer relapse: a new approach. 216 71

Reactive oxygen species are a major cause of damage occurring in ischemic tissue after reperfusion. During reperfusion transitional metals such as iron are required for reactive oxygen species to mediate their major toxic effects. Xanthine oxidase is an important source of reactive oxygen species during ischemia-reperfusion injury, but not in all organs or species. Because cytochrome P-450 enzymes are an important pulmonary source of superoxide anion (O2-.) generation under basal conditions and during hyperoxia, and provide iron catalysts necessary for hydroxyl radical (.OH) formation and propagation of lipid peroxidation, we postulated that cytochrome P-450 might have a potential role in mediating ischemia-reperfusion injury. In this report, we explored the role of cytochrome P-450 enzymes in a rabbit model of reperfusion lung injury. The P-450 inhibitors 8-methoxypsoralen, piperonyl butoxide, and cimetidine markedly decreased lung edema from transvascular fluid flux. Cimetidine prevented the reperfusion-related increase in lung microvascular permeability, as measured by movement of 125I-albumin from the vascular space into lung water and alveolar fluid. P-450 inhibitors also prevented the increase in lung tissue levels of thiobarbituric acid reactive products in the model. P-450 inhibitors did not block enhanced O2-. generation by ischemic reperfused lungs, measured by in vivo reduction of succinylated ferricytochrome c in lung perfusate, but did prevent the increase in non-protein-bound low molecular weight chelates of iron after reperfusion. Thus, cytochrome P-450 enzymes are not likely a major source of enhanced O2-. generation, but serve as an important source of iron in mediating oxidant injury to the rabbit lung during reperfusion. These results suggest an important role of cytochrome P-450 in reperfusion injury to the lung and suggest potential new therapies for the disorder.
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PMID:Role of cytochrome P-450 in reperfusion injury of the rabbit lung. 217 18

Paraxanthine (PX; 1,7-dimethylxanthine) is the major metabolite of caffeine in humans. Despite the continuous exposure of a large proportion of the population to PX, little is known about PX disposition in humans. The present study was performed to define the metabolic partial clearances of PX in humans and, by determining the effects of cimetidine and allopurinol pretreatments on PX disposition, assess the relative importance of cytochrome P-450 and xanthine oxidase in PX biotransformation. The combined formation of the 7-demethylated products 1-methylxanthine (1-MX), 1-methyluric acid (1-MU) and 5-acetyl-amino-6-formylamino-3-methyluracil (AFMU) accounted for 67% of PX clearance. Formation of 7-methylxanthine (7-MX) and 1,7-dimethyluric acid and renal excretion of unchanged PX comprised 6, 8 and 9% of PX clearance, respectively. Allopurinol pretreatment had no effect on PX plasma clearance but decreased 1-MU excretion and increased 1-MX excretion, with the combined excretion of these metabolites remaining constant. Cimetidine pretreatment decreased PX plasma clearance by 30%. Metabolic partial clearances to 1-MX + 1-MU and to AFMU were reduced to a similar extent (ca. 40%) in the cimetidine treatment phase, but other pathways were not significantly affected. These data are consistent with 1-MX and AFMU being derived from a common intermediate, the formation of which is mediated by cytochrome P-450. Xanthine oxidase catalyzes only the secondary conversion of 1-MX to 1-MU.
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PMID:Paraxanthine metabolism in humans: determination of metabolic partial clearances and effects of allopurinol and cimetidine. 291 77

The effects of cimetidine, a potent histamine-H2-receptor antagonist and a good -OH scavenger, on the kinetics of ferricytochrome c and NBT reduction by superoxide anions were studied. The drug dose-dependently inhibited ferricytochrome c and NBT reduction by O2- radicals, generated either in xanthine oxidase system or photochemically or directly by KO2. The inhibitory effect of cimetidine remained unchanged in the presence of catalase or mannitol. Cimetidine and its complexes with Cu(II) and Fe(III) ions inhibited ferricytochrome c and NBT reduction even when metal chelators were added to the reaction medium. The results suggest the reaction of cimetidine with O2-radicals.
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PMID:Effects of cimetidine and its metal complexes on nitroblue tetrazolium and ferricytochrome c reduction by superoxide radicals. 1048 Jun 60