Genotoxicity of N-acetylarylamines in the Salmonella/hepatocyte system

Coincubation of isolated, intact rat hepatocytes with Salmonella typhimurium tester strain TA 98 (Salmonella/hepatocyte system) has been employed to determine both bacterial mutagenicity and DNA damage in the hepatocytes following treatment with 2-acetylaminofluorene (AAF) and other AAF derivatives. In vivo pretreatment of rats with either 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) or 3-methylcholanthrene (MC) markedly increased both DNA damage and bacterial mutation frequency upon incubation of AAF or 2-aminofluorene (AF), in this system. The increase in damage to the hepatocyte-DNA was more pronounced after AAF treatment than by that for AF, while the increase in bacterial mutation frequency was greater after AF treatment. Hepatocytes treated with paraoxon prior to exposure to N-hydroxy-2-acetylaminofluorene (N-OH-AAF) or N-acetoxy-2-acetylaminofluorene (N-OAc-AAF) partially inhibited the DNA damage caused by these agents, as well as inhibiting the bacterial mutagenicity of N-OAc-AAF (50% inhibition) and N-OH-AAF (80% inhibition). These data indicate that metabolic processes other than those involved in activating AAF and its derivatives into a bacterial mutagen(s) may contribute to the genotoxic effects of these compounds. Thus, the Salmonella/hepatocyte system may provide a useful model in which to study the relative role of the various metabolic processes associated with the carcinogenic effects of N-acetylarylamines.