Potentiation in the intact rat of the hepatotoxicity of acetaminophen by 1,3-bis(2-chloroethyl)-1-nitrosourea.
Studies of the killing of cultured hepatocytes by acetaminophen indicate that the cells are injured by an oxidative stress that accompanies the metabolism of the toxin (J. L. Farber et al. (1988) Arch. Biochem. Biophys. 267, 640-650). The present report documents that the essential features of the killing of cultured hepatocytes by acetaminophen are reproduced in the intact animal. Male rats had no evidence of liver necrosis 24 h after administration of up to 1000 mg/kg of acetaminophen. Induction of mixed function oxidase activity by 3-methylcholanthrene increased the hepatotoxicity of acetaminophen. Inhibition of glutathione reductase by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) potentiated the hepatotoxicity of acetaminophen in male rats induced with 3-methylcholanthrene. Whereas the pretreatment with BCNU reduced the GSH content by 40%, a comparable depletion of GSH by diethylmaleate did not potentiate the toxicity of acetaminophen. The antioxidant diphenylphenylenediamine (25 mg/kg) and the ferric iron chelator deferoxamine (1000 mg/kg) prevented the liver necrosis produced by 500 mg/kg acetaminophen in rats pretreated with BCNU. Neither protective agent prevented the fall in GSH produced by acetaminophen. It is concluded the conditions of the irreversible injury of cultured hepatocytes by acetaminophen previously reported are not necessarily different from those that obtain in the intact rat with this toxin.
Nakae
D
D
Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Oakes
J W
JW
Farber
J L
JL
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002330:Carmustine / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003676:Deferoxamine / Q000494:pharmacology; D004357:Drug Synergism; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000082:Acetaminophen; D008748:Methylcholanthrene; D005980:Glutathione Reductase; D003676:Deferoxamine; D002330:Carmustine