The Cooked Meat Carcinogen 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine Activates the Extracellular Signal–Regulated Kinase Mitogen-Activated Protein Kinase Pathway

Abstract

During the cooking of meat, mutagenic and carcinogenic heterocyclic amines are formed, the most abundant of which, 2-amino-1-methyl-6-phenylimidazo [4-5-b ]pyridine (PhIP), induces tumors of the prostate, colon, and mammary gland in rats. Humans consuming cooked meat are exposed to PhIP on a daily basis, yet few studies have assessed the effects of PhIP at dietary relevant concentrations. In addition to its genotoxic properties, recent studies have shown that PhIP can activate estrogen receptor-mediated signaling pathways at doses that are similar to those that may be present in the body following consumption of a cooked meat meal. In the present study, we examined whether such doses of PhIP can affect estrogen receptor-independent signal transduction via the mitogen-activated protein kinase (MAPK) extracellular signal-related kinase (ERK) pathway to influence proliferation and migration in the human mammary epithelial cell line MCF10A and the prostate cancer cell line PC-3. At doses shown to have a proliferative effect on MCF10A cells (10 À11 -10 À7 mol/L), PhIP induced a rapid, transient increase in phosphorylation of both MAPK/ERK kinase 1/2 and ERKs. Inhibition of this pathway significantly reduced the PhIPinduced proliferation of MCF10A cells and the migration of PC-3 cells. The data presented here show that levels of PhIP that approximate to human dietary exposure stimulate cellular signaling pathways and result in increased growth and migration, processes linked to the promotion and progression of neoplastic disease. These findings provide strong evidence that PhIP acts as a tumor initiator and promoter and that dietary exposure to this compound could contribute

The cooked meat-derived mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) elicits estrogenic-like microRNA responses in breast cancer cells

“…However, it should be noted that PhIP has also been reported to affect cellular pathways by mechanisms that are independent of ERα (Creton et al, 2007).…”

Nutrigenetics: The Relevance of Polymorphisms

“…The most prevalent HCA found in meats is 2-amino-1-methyl-6-phenylimidazo [4,5-b]-pyridine (PhIP). Following metabolic activation, PhIP, along with other HCAs, causes the production of DNA adducts and is carcinogenic in rat colon, mammary, and prostate tissues (119)(120)(121). In rodents and cell lines, PhIP has been shown to stimulate signaling pathways resulting in increased cellular proliferation (119,120,122,123).…”

Heterocyclic Aromatic Amine [HCA] Intake and Prostate Cancer Risk: Effect Modification by Genetic Variants

“…However, the intake of grilled meat is thought to be related to PCa risk since high-temperature cooking of meat leads to formation of mutagenic heterocyclic aromatic amines (HCA), which have been shown to induce tumours in experimental animal models [3][4] . Cooking at higher temperatures and for longer periods of time both result in formation of more HCA [3][4] . To date, several observational studies have evaluated the association of intake of meat cooked at high temperature and PCa risk, but results are inconsistent [5][6][7][8][9] .…”

“…However, experimental studies have shown that levels of PhIP approximating human dietary exposure stimulate cellular signalling pathways and result in increased growth and migration, suggesting a link with the promotion and progression of neoplastic disease 4,12 . One of the reasons for our null-findings might be that the association between HCA intake and PCa risk is modified by different genotypes/polymorphisms in genes encoding for HCA-metabolizing enzymes.…”