Superoxide dismutase and catalase protect cultured hepatocytes from the cytotoxicity of acetaminophen.
Superoxide dismutase, catalase and mannitol prevent the killing of cultured hepatocytes by acetaminophen in the presence of an inhibitor of glutathione reductase, BCNU. Under these conditions, the cytotoxicity of acetaminophen depends upon its metabolism, since beta-naphthoflavone, an inhibitor of mixed function oxidation, prevents the cell killing. In hepatocytes made resistant to acetaminophen by pretreatment with the ferric iron chelator, deferoxamine, addition of ferric or ferrous iron restores the sensitivity to acetaminophen. In such a situation, both superoxide dismutase and catalase prevent the killing by acetaminophen in the presence of ferric iron. By contrast, catalase, but not superoxide dismutase, prevents the cell killing dependent upon addition of ferrous iron. These results document the participation of both superoxide anion and hydrogen peroxide in the killing of cultured hepatocytes by acetaminophen and suggest that hydroxyl radicals generated by an iron catalyzed Haber-Weiss reaction mediate the cell injury.
D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology*; D002712:Chlorides; D003676:Deferoxamine / Q000494:pharmacology; D004351:Drug Resistance; D005290:Ferric Compounds / Q000494:pharmacology; D005296:Ferrous Compounds / Q000494:pharmacology; D005609:Free Radicals; D008099:Liver / Q000187:drug effects*; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D008748:Methylcholanthrene / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013482:Superoxide Dismutase / Q000494:pharmacology*; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D002712:Chlorides; D005290:Ferric Compounds; D005296:Ferrous Compounds; D005609:Free Radicals; D000082:Acetaminophen; D008353:Mannitol; D008748:Methylcholanthrene; D019324:beta-Naphthoflavone; D006899:Mixed Function Oxygenases; D002374:Catalase; D013482:Superoxide Dismutase; D003676:Deferoxamine; C029451:ferrous chloride; C024555:ferric chloride; D002330:Carmustine