Genetic changes induced by heterocyclic amines.
Clarification of the mutational fingerprints of HCAs offers a promising approach in the investigation of the role of heterocyclic amines (HCAs) in human carcinogenesis. We analyzed mutations in the tumor related genes of tumors induced by HCAs, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which mainly yield DNA-adducts of C8-guanine. The G-->T transversion at codon 13-2nd position in Ha-ras was predominantly observed in mouse forestomach and rat Zymbal gland tumors induced by MeIQ. In contrast, various types of mutation were detected in the ras family genes of rat Zymbal gland tumors induced 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. Apc mutations were detected in PhIP- and IQ-induced rat colon tumors, with incidences of 50% (4/8) and 15% (2/13), respectively. All five mutations detected in the four PhIP-induced tumors consisted of a guanine deletion from the 5'-GGGA-3' sequence, in contrast with 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 fingerprint in Apc. Colon tumors induced by PhIP were also found to have mutations in their microsatellite sequences, and similar results were detected in mammary gland tumors induced by PhIP, contrasting with no mutations in IQ-induced colon tumors and a very low frequency of mutations in 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. Although the mechanisms involved in the induction of microsatellite mutations 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 chromosome 10, which shows synteny with the distal part of human chromosome 17, where LOH frequently occurs in human breast cancer. In conclusion, each heterocyclic amine leave a mutational fingerprint which is specific to each compound. Since the tumor-related genes involved in PhIP-induced tumors have characteristics in common with those in human cancers, further detailed analysis will provide us with useful information on mutational fingerprints, and on the possible contribution of PhIP to human colon cancer.
Nagao
M
M
National Cancer Center Research Institute, Tokyo, Japan.
Ushijima
T
T
Toyota
M
M
Inoue
R
R
Sugimura
T
T
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000588:Amines / Q000633:toxicity*; D000818:Animals; D004260:DNA Repair; D017491:Genes, APC; D011905:Genes, ras; D005819:Genetic Markers; D006571:Heterocyclic Compounds / Q000633:toxicity*; D006579:Heterozygote; D006801:Humans; D007093:Imidazoles / Q000633:toxicity*; D007546:Isoquinolines / Q000633:toxicity*; D051379:Mice; D016296:Mutagenesis / Q000187:drug effects*; D009152:Mutagenicity Tests; D011804:Quinolines / Q000633:toxicity*; D051381:Rats; D017384:Sequence Deletion
D000588:Amines; D005819:Genetic Markers; D006571:Heterocyclic Compounds; D007093:Imidazoles; D007546:Isoquinolines; D011804:Quinolines; D015127:9,10-Dimethyl-1,2-benzanthracene; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C036989:2-amino-3,4-dimethylimidazo(4,5-f)quinoline