GENETIC CHANGES INDUCED BY HETEROCYCLIC AMINES

Clarification of the mutational fingerprints of HCAs offers a promisin g approach in the investigation of the role of heterocyclic amines (HC As) in human carcinogenesis. We analyzed mutations in the tumor relate d genes of tumors induced by HCAs, 2-amino-3,4-dimethylimidazo[4,5-f]q uinoline (MeIQ), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), and 2-a mino-1-methyl-6-phenylimidazo[4,5-b]pyr (PhIP), which mainly yield DNA -adducts of C8-guanine. The G-->T transversion at codon 13-2nd positio n in Ha-ras was predominantly observed in mouse forestomach and rat Zy mbal gland tumors induced by MeIQ. In contrast, various types of mutat ion were detected in the ras family genes of rat Zymbal gland tumors i nduced by IQ; the presence of a methyl group at position 4 of imidazo[ 4,5-f]quinoline gave rise to a remarkable difference in the mutational fingerprint. Ape mutations were detected in PhIP- and IQ-induced rat colon tumors, with incidences of 50% (4/8) and 15% (2/13), respectivel y. All five mutations detected in the four PhIP-induced tumors consist ed of a guanine deletion from the 5'-GGGA-3' sequence, in contrast wit h T to C and C to T mutations in IQ-induced tumors. Four of these five mutations shared seven common nucleotides, -GTGGGAT- surrounding the guanine; indicating that PhIP leaves a characteristic mutational finge rprint in Ape. Colon tumors induced by PhIP were also found to have mu tations in their microsatellite sequences, and similar results were de tected in mammary gland tumors induced by PhIP, contrasting with no mu tations in IQ-induced colon tumors and a very low frequency of mutatio ns in 7,12-dimethyl-benz[ a]anthracene (DMBA)-induced mammary tumors. Although the mechanisms involved in the induction of microsatellite mu tations are not known yet, microsatellite mutations which can also be detected in sporadic human tumors, including colon and breast tumors, were indicated to be a characteristic of PhIP. Mammary tumors induced by PhIP showed loss of heterozygocity (LOH) at the distal part of chro mosome 10, which shows synteny with the distal part of human chromosom e 17, where LOH frequently occurs in human breast cancer. In conclusio n, each heterocyclic amine leave a mutational fingerprint which is spe cific to each compound. Since the tumor-related genes involved in PhIP -induced tumors have characteristics in common with those in human can cers, further detailed analysis will provide us with useful informatio n on mutational fingerprints, and on the possible contribution of PhIP to human colon cancer.