Intestinal mutagenicity of two carcinogenic food mutagens in transgenic mice: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and amino(alpha)carboline

The heterocyclic amines produced during the cooking of meat, including amino(alpha)carboline (A alpha C) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), are potent bacterial mutagens and are carcinogenic in rodents. PhIP is mutagenic in the small intestine, but its mutagenicity in the colon, where most human intestinal cancers arise, has not been reported, nor has the mutagenicity of A alpha C. In this study, A alpha C (800 p.p.m.) was fed for 30 and 45 days and PhIP (100 and 400 p.p.m.) was fed for 30, 60 and 90 days to groups of F-1 (C57BL/6xSWR) mice hemizygous for multiple tandem copies of a lad transgene (the Big Blue(TM) mouse) and heterozygous at the endogenous Dlb-1 locus, The mutant frequencies were assayed at Dlb-1 and at lad in the small intestine and at lacI in the colon, PhIP induced mutations at both loci in the small intestine and induced slightly fewer mutations in the colon, The accumulation of mutations at both loci appears to be linear with both PhIP concentration and duration of exposure and, thus, with dose(concentration x duration). The linear increase with time is in agreement with predictions about the effectiveness of chronic treatment protocols for tests of in vivo mutagenicity, Unlike PhIP, A alpha C induced mutations specifically in the colon and not in the small intestine, thereby showing a dramatic tissue specificity, The rate (mutations/p.p.m. day) was similar to PhIP.