Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo: the protective effect of allopurinol.
Acetaminophen (500 mg/kg i.p.) induced hepatotoxicity in fasted ICR mice in vivo. Acetaminophen also caused a long-lasting 50% reduction of the hepatic ATP content, an irreversible loss of hepatic xanthine dehydrogenase activity and a transient increase of the xanthine oxidase activity. All effects occurred before parenchymal cell damage, i.e., the release of cellular enzymes. The hepatic content of GSH and GSSG was initially depleted by acetaminophen without affecting the GSSG:GSH ratio (1:200), however, during the recovery phase of the hepatic GSH levels the GSSG content increased faster than GSH, resulting in a GSSG:GSH ratio of 1:18 24 h after acetaminophen administration. The mitochondrial GSSG content increased from 2% in controls to greater than 20% in acetaminophen-treated mice. The extremely elevated tissue GSSG levels were accompanied by a 4-fold increase of the plasma GSSG concentrations but not by an enhanced biliary efflux, although hepatic GSSG formation and biliary excretion were not affected by acetaminophen. Allopurinol protected dose-dependently against acetaminophen-induced cell injury, the loss of ATP and the increase of the GSSG content in the total liver and in the mitochondrial compartment without inhibiting reactive metabolite formation. High, protective as well as low, nonprotective doses of allopurinol almost completely inhibited hepatic xanthine oxidase and dehydrogenase activity, but only high doses prevented the increase of the mitochondrial GSSG content. The data indicate a long-lasting, primarily intracellular oxidant stress during the progression phase of acetaminophen-induced cell necrosis. The protective effect of allopurinol is unlikely to involve the inhibition of reactive oxygen formation by xanthine oxidase but could be the result of its antioxidant property.
Jaeschke
H
H
Center for Experimental Therapeutics, Baylor College of Medicine, Houston, Texas.
D000082:Acetaminophen / Q000633:toxicity*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000493:Allopurinol / Q000627:therapeutic use*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008107:Liver Diseases / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D014968:Xanthine Dehydrogenase / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
D000082:Acetaminophen; D000493:Allopurinol; D000255:Adenosine Triphosphate; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; D000410:Alanine Transaminase; D010100:Oxygen