Oxygen-mediated cell injury in the killing of cultured hepatocytes by acetaminophen.
Sensitivity of cultured hepatocytes to acetaminophen was induced by pretreatment of the rat with 3-methylcholanthrene. Under these conditions, 10 uM B-naphthoflavone but not SKF-525A prevented the cell killing, indicating dependence on metabolism. Inhibition of glutathione reductase by 50 uM bis-chloro-nitrosourea, shown previously to increase the sensitivity of hepatocytes to an oxidative stress, potentiated the toxicity of acetaminophen without increasing the covalent binding of acetaminophen metabolites. Pretreatment of the hepatocytes with the ferric iron chelator deferoxamine, known to reduce the sensitivity of hepatocytes to an oxidative stress, prevented the cell killing without reducing covalent binding. Addition of ferric chloride to the culture medium restored the sensitivity of the cells to acetaminophen, again without effect on the extent of covalent binding. These data demonstrate that the toxicity of acetaminophen can be dissociated from the covalent binding of its metabolites and support the conclusion that the hepatocytes were lethally injured by an oxidative stress accompanying the mixed function oxidase-dependent biotransformation of acetaminophen.
D000082:Acetaminophen / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D000975:Antioxidants; D000082:Acetaminophen; D005978:Glutathione; D003676:Deferoxamine; D010100:Oxygen