The Cooked Meat–Derived Genotoxic Carcinogen 2-Amino-3-Methylimidazo[4,5-b]Pyridine Has Potent Hormone-Like Activity: Mechanistic Support for a Role in Breast Cancer

Abstract

The cooked meat-derived heterocyclic amine 2-amino-3-methylimidazo [4,5-b]pyridine (PhIP) is activated by CYP1A2 to the N-hydroxy metabolite, then esterified by acetyl transferase and sulfur transferase into unstable DNA-reactive products that can lead to mutation. The genotoxicity of PhIP has been implicated in its carcinogenicity. Yet, CYP1A2-null mice are still prone to PhIP-mediated cancer, inferring that alternative mechanisms must be operative in tumor induction. PhIP induces tumors of the breast, prostate, and colon in rats and lymphoma in mice. This profile of carcinogenicity is indicative of hormonal involvement. We recently reported that PhIP has potent estrogenic activity inducing transcription of estrogen (E 2 )-regulated genes, proliferation of E 2 -dependent cells, up-regulation of progesterone receptor, and stimulation of mitogen-activated protein kinase signaling. In this report, we show for the first time that PhIP at doses as low as of 10 À11 mol/L has direct effects on a rat pituitary lactotroph model (GH3 cells) and is able to induce cell proliferation and the synthesis and secretion of prolactin. This PhIP-induced pituitary cell proliferation and synthesis and secretion of prolactin can be attenuated by an estrogen receptor (ER) inhibitor, implying that PhIP effects on lactotroph responses are ERA mediated. In view of the strong association between estrogen, progesterone, prolactin, and breast cancer, the PhIP repertoire of hormone-like activities provides further mechanistic support for the tissue-specific carcinogenicity of the chemical. Furthermore, the recent epidemiology studies that report an association between consumption of cooked red meat and premenopausal and postmenopausal human breast cancer are consonant with these observations. [Cancer Res 2007;67(19):9597-602]

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

“…Two published studies have questioned the ability of PhIP to induce oestrogenic responses in breast cancer cells (Evans et al, 2010;Immonen et al, 2009) (Lauber et al, 2004;Lauber and Gooderham, 2007). The ability of PhIP to induce oestrogenicdependent responses is also supported by the work of independent labs (Bennion et al, 2005;Okudaira et al, 2013).…”

“…Whilst the former studies investigating the hormonelike properties of PhIP were based on cell line models (Lauber et al, 2004;Lauber and Gooderham, 2007), importantly, Okudaira et al,(Okudaira et al, 2013 used transgenic mice to detect in vivo ERα-dependent genomic instability caused by PhIP exposure, supporting the biological relevance of this mechanism. The data generated in the present study support these previous reports and demonstrate that in MCF-7 breast cancer cells PhIP exposure can also drive the deregulation of miRNA expression (Fig.2-3).…”

Curcumin inhibits PhIP induced cytotoxicity in breast epithelial cells through multiple molecular targets

“…Amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) is the most abundantly found HCA in the human diet [3]. Several studies have shown that PhIP can induce tumors in breast, prostate and colon tissue [6][7][8] and rodent models [9][10][11][12]. N-Hydroxy derivatives are formed by the oxidation of PhIP by cytochrome P-450 1A2 (CYP1A2) [13].…”

Curcumin Inhibit PhIP-Induced Carcinogenicity by Regulating Expression of Nrf2 and FOXO Targets, and BRCA-1 and P16 Expression in Breast Epithelial Cells

“…HCA causes multifold cytotoxic effect, for example metabolism of PhIP leads to ROS production, and PhIP metabolites produce DNA adduct and DNA strand breaks [1][2][3][4]. Breast epithelial cells contain all the machinery to metabolize HCA and the genotoxic effects of these metabolites may lead to breast cancer [1].The prevention of cancer through diet is categorized as one of the most effective ways to reduce cancer incidence [5]. We hypothesized that curcumin may be a potential food additive that may be inhibitory to PhIP-induced carcinogenicity by inhibiting ROS production, DNA adduct formation and DNA strand breaks.…”

“…PhIP is known for its genotoxic and carcinogenic effects causing several types of cancer, including breast cancer. HCA causes multifold cytotoxic effect, for example metabolism of PhIP leads to ROS production, and PhIP metabolites produce DNA adduct and DNA strand breaks [1][2][3][4]. Breast epithelial cells contain all the machinery to metabolize HCA and the genotoxic effects of these metabolites may lead to breast cancer [1].…”