Genotoxicity of heterocyclic amines in the hepatocyte/DNA repair assay using hepatocytes of rats or mice pretreated with 3-methylcholanthrene

Abstract

The genotoxicity of 4 heterocyclic amines, 3-amino-1,4-dimethyl-5 H-pyrido[4,3- b]indole (Trp-P-1), 3-amino-1-methyl-5 H-pyrido[4,3- b]indole (Trp-P-2), 2-amino-6-methyldipyrido[1,2- a:3′,2′- d]imidazole (Glu-P-1) and 2-aminodipyrido[1,2- a:3′,2′- d]imidazole (Glu-P-2) was examined in the hepatocyte primary culture (HPC)/DNA-repair assay using hepatocytes of rats and mice pretreated with 3-methylcholanthrene (MC), and the results were compared with those obtained in a previous assay with hepatocytes of normal rodents. All of these heterocyclic amines clearly elicited positive responses of DNA repair in the assay with hepatocytes of the rodents given MC, although in the regular HPC/DNA-repair test without MC pretreatment Tyr-P-2 and Glu-P-2 were negative in rat hepatocytes, and Try-P-2 was also negative in mouse hepatocytes. The level of unscheduled DNA synthesis induced by these positive compounds in the assay with hepatocytes of MC-treated rodents was much higher than that in the assay with hepatocytes of normal rodents. These results are basically in agreement with the reports that this class of compounds is highly activated metabolically by the cytochrome P-450 system from liver microsomes.