Species differences in the cytotoxic and genotoxic effects of 2-acetylaminofluorene and its primary metabolites 2-aminofluorene and N-OH-2-acetylaminofluorene

2-Acetylaminofluorene (AAF), 2-aminofluorene (AF) and N-hydroxy-2-acetylaminofluorene (N-OH-AAF) could be activated to mutagens in S. typhimurium using either 9000 g supernatant (S9) or hepatocytes isolated from rats, mice, hamsters or guinea pigs. Their relative mutagenic potency was generally N-OH-AAF greater than AF greater than AAF. Monolayer cultures of hepatocytes exposed to AAF/AF/N-OH-AAF showed evidence of DNA damage measured as unscheduled DNA repair synthesis. The order of activity in rat and hamster was N-OH-AAF greater than AAF greater than AF, in guinea pig and mouse N-OH-AAF greater than AF greater than AAF. Only N-OH-AAF caused observable cytotoxicity, and the rat hepatocytes were the far more sensitive species. Neither the resistance of guinea pig liver nor the greater susceptibility of the rat liver to the carcinogenic effects of AAF and N-OH-AAF could be readily explained by the species differences in activating these compounds to mutagens in Salmonella or to DNA damaging agents in the hepatocytes. It is possible that cytotoxic effects of N-OH-AAF may be of some importance for the observed species differences in the liver carcinogenic effects of AAF and N-OH-AAF.