Regional mutagenicity of heterocyclic amines in the intestine: mutation analysis of the cII gene in lambda/ lacZ transgenic mice

Abstract

Transgenic mouse assays have revealed that the mouse intestine, despite its resistance to carcinogenesis, is sensitive to the mutagenicity of some heterocyclic amines (HCAs). Little is known, however, about the level and localization of that sensitivity. We assessed the mutagenicity of four orally administered (20 mg/kg per day for 5 days) HCAs—2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) hydrochloride, 2-amino-3-methylimidazo[4,5- f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5- f]quinoline (MeIQ), and 3-amino-1-methyl-5 H-pyrido[4,3- b]indole (Trp-P-2) acetate—in the intestine of male Muta™Mice. Two weeks after the last administration, we isolated epithelium from the small intestine, cecum, and colon and analyzed lacZ and cII transgene mutations. PhIP increased the lacZ mutant frequency (MF) in all the samples, and in the small intestine, cII and lacZ MFs were comparable. In the cII gene, G:C to T:A and G:C to C:G transversions were characteristic PhIP-induced mutations (which has also been reported for the rat colon, where PhIP is carcinogenic). In the small intestine, PhIP increased the cII MF to four-fold that of the control, but IQ, MeIQ, and Trp-P-2 did not have a significant mutagenic effect. In the cecum, cII MFs induced by IQ and MeIQ were 1.9 and 2.7 times those in the control, respectively. The MF induced by MeIQ in the colon was 3.1 times the control value. Mutagenic potency was in the order PhIP>MeIQ>IQ; Trp-P-2 did not significantly increase the MF in any tissue. The cecum was the most susceptible organ to HCA mutagenicity.