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.