Carcinogenesis Advance Access published online on August 19, 2004
Carcinogenesis, doi:10.1093/carcin/bgh268
© 2004 by Oxford University Press
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1 Molecular Toxicology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London SW7 2AZ, UK; Biomedical Sciences, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London SW7 2AZ, UK
* To whom correspondence should be addressed. E-mail: n.gooderham{at}ic.ac.uk.
The cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), induces tumours of the breast, colon and prostate in rats. Here we show that in addition to it's well-established genotoxicity, which can be detected at concentrations >10-6 M, PhIP is also oestrogenic. In COS-1 cells transiently transfected with an oestrogen-responsive reporter gene, PhIP (10-10 - 10-6 M) mediated transcription through oestrogen receptor-
Revised July 15, 2004
Accepted August 10, 2004
CARCINOGENESIS
The cooked food derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is potently oestrogenic: a mechanistic basis for it's tissue specific carcinogenicity
2 Cancer Medicine, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London SW7 2AZ, UK
Abstract 
(ER-), but not ER-
, and inhibition by the pure ER antagonist ICI 182 780 demonstrated a requirement for a functional ER. In contrast, the structurally related food-derived carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) failed to induce reporter gene transcription. Additionally we show that in a hormonally responsive breast cancer cell line (MCF-7 cells), PhIP induced transcriptional activation using endogenously expressed ER. Examination of the genotoxic potential of PhIP using a model mammalian cell mutation assay (hprt- locus) demonstrated that the genetic toxicology of PhIP was readily detectable, but separate, in terms of effective concentration, from it's oestrogenic activity. To determine if PhIP's oestrogenicity could mediate oestrogen-dependent responses such as cell growth, we examined the growth of hormonally-responsive cells (MCF-7 cells). We show that PhIP can stimulate cell proliferation and again this was dependent upon a functional ER. Using ligand blotting, we further show that PhIP, can stimulate the expression of progesterone receptor (PR-A and PR-B) and c-MYC and activate the MAPK signal transduction pathway. These responses were similar to that produced by oestradiol, in terms of temporal aspects, potency and a requirement for a functional ER. Each of these dose-dependent mitogenic responses occurred at concentrations of PhIP (
10-9-10-11 M) that are likely to be equivalent to systemic human exposure via consumption of cooked meat food. Thus PhIP can induce cellular responses that encompass altered gene expression and mitogenesis. We suggest that the combination of genetic toxicology and oestrogen-like promotion of genomic and cellular events, provide a mechanism for the compound's tissue specific tumourigenicity.
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