Genotoxic activity of the N-acetylated metabolites of the food mutagens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3, 4-dimethylimidazo[4,5-f]quinoline (MeIQ)

Abstract

The genotoxic potential of the food mutagens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,4-di-methylimidazo[4,5-f]quinoline (MelQ) and their N-acetylated metabolites (AcIQ and AcMelQ, respectively) has been studied, in order to evaluate whether an initial N-acetylation of IQ or MelQ is important for the overall in vivo genotoxicity of the compounds. When incubated with uninduced (control) rat hepatocytes, both the acetylated and the unacetylated compounds appeared to be relatively stable, whereas water-soluble metabolites (i.e. not extractable by ethyl acetate at alkaline pH) were rapidly formed with hepatocytes from PCB-induced animals. No DNA damage was induced by IQ or MelQ in hepatocytes isolated from control rats, as measured by alkaline elution. In hepatocytes from PCB-pretreated rats, IQ, MelQ, AcIQ and AcMelQ induced DNA damage at low (10⁻⁶ M) concentrations, with AcIQ being more potent than IQ whereas AcMelQ was less potent than MelQ. Similar patterns were observed when unscheduled DNA synthesis was measured in hepatocytes. The compounds induced sister chromatid exchanges in Chinese hamster V79 cells with PCB-induced hepatocytes as activation system; IQ and AcIQ were equal while AcMelQ had less activity than MelQ. The compounds were also compared in bacterial mutagenesis test systems (Salmonella typhimurium TA98). With hepatocyte activation, AcIQ was slightly more potent than IQ, whereas AcMelQ was markedly less mutagenic than MelQ. With sub-cellular fractions as activation system (rat liver S9 or micro-somes), the N-acetylated compounds were similar to or less mutagenic than their parent compounds. The mutagenic effects of AcIQ and AcMelQ in bacteria with microsomal activation were markedly reduced by the deacetylase inhibitor paraoxon. Paraoxon also reduced the DNA strand breaks induced by AcIQ or AcMelQ in PCB-induced hepatocytes, but did not affect IQ- or MelQ-induced DNA damage. The results show that an initial N-acetylation of IQ or MelQ does not dramatically change the overall genotoxicity of these hetrocyclic aromatic amines.