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Species differences in hepatic glutathione depletion, covalent binding and hepatic necrosis after acetaminophen
Authors:D C Davis  W Z Potter  D J Jollow  J R Mitchell
Affiliation:Laboratory of Chemical Pharmacology, National Heart and Lung Institute, Bethesda, Md., USA
Abstract:Acetaminophen, a widely prescribed analgesic that causes fulminant hepatic necrosis in overdosed humans, produced varying degrees of hepatotoxixity in mice, rats, hamsters, guinea pigs and rabbits. The severity of hepatic injury paralleled the rate of activation of acetaminophen by hepatic microsomal enzymes to a potent arylating agent. The severity of hepatic damage in various species also correlated directly with the rate of hepatic glutathione depletion after acetaminophen. These findings support the hypothesis that the electrophilic arylating agent formed from acetaminophen invibo is preferentially detoxified by conjugation with glutathione and that arylation of hepatic macromolecules occurs only when glutathione availability is exceeded. Since N-hydroxylation of another N-acetylarylamine (2-acetylaminofluorene) occurs to a much greater extent in the species that are susceptible to acetaminophen-induced hepatic necrosis, the data also are consistent with the hypothesis that the toxic metabolite of acetaminophen results from N-hydroxylation.
Keywords:Send reprint requests to Dr. Jerry R. Mitchell   Laboratory of Chemical Pharmacology   National Heart and Lung Institute   Bethesda   Maryland 20014   USA.
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