Human exposure to carcinogenic heterocyclic amines and their mutational fingerprints in experimental animals

Heterocyclic amines (HCAs) are mutagens/carcinogens to which humans are exposed on almost a daily basis. 2-Amino-1-melhyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant of the various carcinogenic HCAs (present at a level of 0.56 to 69.2 ng/g of cooked meat or fish), with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) following it at 0.64 to 6.44 ng/g. HCAs have been found in the urine of healthy people who consume ordinary diets, while patients receiving parenteral alimentation lack, for example, PhIP and MeIOx in their urine. Based on the concentrations of PhIP and MeIOx in urine samples from 10 healthy volunteers, daily intake of MeIQx in Japanese was calculated to be 0.3 to 3.9 mu g/person, while that of PhIP was 0.005 to 0.3 mu g. The Japanese consume more MeIQx than Americans, whereas Japanese intake of PhIP was about one-third that of Americans. MeIQx-DNA adducts have also been detected in Japanese kidney, colon, and rectum samples using the P-32-postlabeling method followed by identification using high-performance liquid chromatography (HPLC) analysis; the levels were 0.18, 1.8, and 1.4 per 10(9) nucleotides, respectively. In addition, we elucidated the mutational fingerprints of PhIP by analyzing Apc mutations in rat colon cancers induced by this carcinogen. Four of eight tumors had a total of five mutations in the Apc gene, four of which featured a guanine deletion from 5'-GTGGGAT-3' sequences. This specific mutation spectrum may be used as a fingerprint of PhIP in evaluating its risk potential for human colon carcinogenesis. Mutations were not found in similar 2-amino-3-methylimidazo[4,5-f]quinoline-induced colon lesions. Microsatellite instability was detected in both colon and mammary tumors induced by PhIP. The mechanisms involved in this development of microsatellite instability in PhIP-induced cancers remain to be elucidated.