Modulation of cytotoxic and genotoxic effects of 2-acetylaminofluorene in rat and hamster hepatocytes by 3-methylcholanthrene pre-treatment

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Abstract
It is well known that 2-acetylaminofluorene (AAF)-induced liver cancer is reduced by simultaneous administration of 3-methylcholanthrene (MC) in the rat, but not in the hamster. The present report examines the effects of MC pre-treatment on the metabolism and toxkity of AAF in monolayer cultures of hepatocytes. Hepatocytes isolated from pre-treated animals of both species metabolized AAF and 2-aminofluorene (AF) to metabolites mutagenic to Salmonella typhimurium more efficiently than hepatocytes from control animals. MC-pre-treated rat hepatocytes showed increased responses to AAF-and AF-induced unscheduled DNA synthesis, while MC-pre-treated hamster hepatocytes were less responsive than the untreated hepatocytes. Increased cytotoxic effects of AAF were observed in MC-pre-treated rat hepatocytes, whereas AAF was not cytotoxic in hamster hepatocytes from either pre-treated or control animals. MC pre-treatment caused increased rates of formation of C-hydroxylated, N-hydroxylated, water-soluble and covalently macromolecular bound AAF metabolites in both species. No significant effect of MC pre-treatment was seen on the formation of AF from AAF. A large decrease in the ratio between covalently macromolecular bound (activated) metabolites and the sum of C-hydroxylated and water-soluble (detoxified) AAF metabolites, was seen after MC pre-treatment of rat hepatocytes, whereas no or only a minor decrease was observed in hamster hepatocytes. This ratio correlated much better with the in vivo carcinogen-icity data than the other parameters such as mutagenicity, DNA repair or covalent macromolecular binding. Thus, the hypothesis that A AF-induced liver cancer depends less on the rate at which AAF is activated, but more on the relative proportion of the dose which is activated, is supported by the present data.