Studies on mammary carcinogenesis induced by a heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, in mice and rats
Article first published online: 7 MAR 2002
Copyright © 2002 Wiley-Liss, Inc.
Environmental and Molecular Mutagenesis
Volume 39, Issue 2-3, pages 158–164, 2002
How to Cite
Nagao, M., Ushijima, T., Watanabe, N., Okochi, E., Ochiai, M., Nakagama, H. and Sugimura, T. (2002), Studies on mammary carcinogenesis induced by a heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, in mice and rats. Environ. Mol. Mutagen., 39: 158–164. doi: 10.1002/em.10047
- Issue published online: 29 MAR 2002
- Article first published online: 7 MAR 2002
- Manuscript Accepted: 30 NOV 2001
- Manuscript Revised: 21 NOV 2001
- Manuscript Received: 19 OCT 2001
- Princess Takamatsu Cancer Research Fund
- Ministry of Health, Labor and Welfare, Japan
- single-nucleotide instability;
Ten heterocyclic amines (HCAs) that are produced by heating amino acids, proteins, or proteinaceous food such as fish and meat were examined for carcinogenicity in rats and mice. Three of them, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), have been shown to induce mammary cancer in female F344 and/or SD rats, but none of the HCAs induced mammary cancer in CDF1 mice. This report reviews our recent studies on mammary carcinogenesis of PhIP in various strains of mice and on the roles of genomic instability in the rat mammary carcinogenesis of PhIP. We demonstrated that the survival time from mammary adenocarcinomas was shorter in PhIP-treated BALB/c mice than that in the untreated control, and with a significantly higher incidence in the C.B-17 strain of mice compared with that of the control. To clarify mechanisms of mammary carcinogenesis, we examined genomic instability in rat mammary cancer induced by PhIP. Mammary cancers were induced in F344 × SD F1 rats harboring the lacI transgene, and two cell lines were established from two adenocarcinomas. They showed a greater than 10-fold higher frequency of spontaneous mutations than that of the primary culture of normal mammary epithelial cells, in the lacI transgene and the hprt endogenous gene during cell replication. Nucleotide sequencing revealed that almost all types of mutations were increased, with a remarkable increase of A:T C:G mutation. This genomic instability was not attributed either to alterations of mismatch-repair enzymes or to p53. These mutational characteristics were also observed in the original tumors. Single-nucleotide instability (SNI) might be implicated in the mammary cancer induced by PhIP. Environ. Mol. Mutagen. 39:158–164, 2002. © 2002 Wiley-Liss, Inc.