Species differences in the metabolism of 2-acetylaminofluorene by hepatocytes in primary monolayer culture.

Monolayers of hepatocytes from mouse, hamster, rat, and guinea pig metabolized 2-acetylaminofluorene (AAF) to ether-extractable, water-soluble as well as covalently macromolecular bound products. Hamster hepatocytes showed the highest rate of formation of ether-extractable metabolites, rat and guinea pig the lowest. These species differences reflected mainly differences in the formation of 2-aminofluorene, the dominating ether-extractable metabolite formed. Detectable levels of N-hydroxy-AAF (greater than 1 nmol/10(6) cells) were only obtained with hamster hepatocytes. The major C-hydroxylated metabolites in the species tested were 7- and 9-hydroxy-AAF. Hepatocytes from guinea pig and hamster showed the highest rate of formation of C-hydroxylated and water-soluble metabolites, rat hepatocytes the lowest. The highest rate of covalent macromolecular binding by AAF metabolites was found with hamster hepatocytes, followed by hepatocytes from rat, guinea pig, and mouse. The balance between activation and detoxification reactions of AAF in hepatocytes may be expressed as the ratio between covalently bound metabolites and the sum of C-hydroxylated and stable water-soluble metabolites. This ratio was far greater in rat hepatocytes followed by hamster, guinea pig, and mouse, and it correlated better with the species susceptibility to liver cancer than covalent binding as such. Thus, AAF-induced liver cancer may depend more on the relative degree of activation versus detoxification of the administered dose than on the absolute capacity of the liver to activate the carcinogen.