Oxidative stress by acute acetaminophen administration in mouse liver.
Acetaminophen was given to mice at a single dose of 375 mg/kg. In situ liver chemiluminescence, H2O2 steady-state concentration, and the liver concentrations of total and oxidized glutathione were measured 15, 30, and 60 min after acetaminophen administration. Increases of 145% and 72% in spontaneous chemiluminescence and H2O2 concentration were observed 15 min after the injection, respectively. Total glutathione was decreased by acetaminophen administration at all the times studied. The maximal decrease, 83%, was found 60 min postinjection. The ratio GSH/GSSG was found significantly decreased at all the times studied. Microsomal superoxide production was increased by 2.4-fold by addition of acetaminophen. The activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase were determined. Catalase was slightly inhibited (30%) 15 min after acetaminophen administration. No significant changes were found in superoxide dismutase activity. Se and non-Se glutathione peroxidase activities were decreased by 40% and 53% respectively, 15 min after acetaminophen administration. The decrease in catalase and glutathione peroxidase would result in an increased steady state level of H2O2 and hydroperoxides, contributing to cell injury. Damaged hepatocytes were observed, and severe lesions and necrosis appeared 60 min after acetaminophen administration. Our results indicate the occurrence of oxidative stress as a possible mechanism for acetaminophen-induced hepatotoxicity.
Lores Arnaiz
S
S
Instituto de Química y Fisicoquímica Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina.
Llesuy
S
S
Cutrín
J C
JC
Boveris
A
A
D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D006861:Hydrogen Peroxide / Q000378:metabolism; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008163:Luminescent Measurements; D051379:Mice; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000633:toxicity*; D013481:Superoxides / Q000378:metabolism
D017382:Reactive Oxygen Species; D013481:Superoxides; D000082:Acetaminophen; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D019803:Glutathione Disulfide