The dietary charred meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine acts as both a tumor initiator and promoter in the rat ventral prostate
ABSTRACT Exposure of Fisher344 rats to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic amine in cooked meat, causes cancer in the rat ventral prostate, while sparing the dorsolateral and anterior lobes. Uncovering the molecular mechanisms of the lobe specificity of PhIP-induced rat prostate cancer may provide clues to the pathogenesis of human prostate cancer, which is also lobe selective. We examined the prostate and other organs for mutation frequencies using transgenic Fisher344 rats (Big Blue rats) after PhIP treatment. After PhIP treatment for as early as 4 weeks, the colon, spleen, seminal vesicles, and all lobes of the prostate had significantly elevated mutation frequencies compared with the saline-treated control group, and the differences became even greater after 8 weeks. G:C --> T:A transversions were the predominant type of mutation. After 8 weeks of treatment with PhIP, the Ki-67 index was increased (P < 0.001) in the ventral prostate, but not in the dorsolateral or anterior prostate. An increase in the number of stromal mast cells and macrophages was seen in the ventral prostate, but not in the other prostatic lobes. The apoptotic index also increased in the ventral lobe only. The increased proliferation and cell death in response to PhIP indicates that in addition to PhIP acting as an "initiator" of cancer, PhIP is also acting like an organ- and lobe-specific tumor "promoter." The prostate lobe-specific infiltration of mast cells and macrophages in response to PhIP suggests a potential new mechanism by which this dietary compound can increase cancer risk-by prompting inflammation.
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ABSTRACT: 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP) is a dietary mutagenic carcinogen that has been shown not only to induce the formation of DNA adducts, but is capable of inducing tumors in the colon, mammary, and prostate glands. The normal development and maturation of the prostate gland, as well as early progression of prostate cancer, is dependent on androgens acting on the androgen receptor (AR). The actual mechanism by which PhIP interacts with our biological system and its potential interaction at the AR has yet to be fully defined. Here, we describe our work in evaluating the molecular events associated with PhIP-mediated disruption of AR function in LNCaP human prostate cancer cells. We demonstrate, by molecular docking simulation, that PhIP and its metabolite can bind to the ligand-binding domain (LBD). The binding competes with dihydrotestosterone (DHT) in the native AR binding cavity of the receptor. In vitro assays show that PhIP increase AR protein expression in LNCaP cells and alters its responsiveness through PSA protein and mRNA expression. We propose that the mechanism for the tissue-specific carcinogenicity seen in the rat prostate tumors and the presumptive human prostate cancer associated with the consumption of well-done meat may be mediated by this receptor activation. Our results indicate that PhIP may play an important role in modifications of AR function.