Regulation of androgen metabolism by the nuclear receptor CAR

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DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer death among men in the United States. Abnormal levels of androgen due to deregulation of hormone metabolism have been implicated in the initiation and progression of prostate cancer. However, the mechanism of regulating androgen, particularly testosterone metabolism and inactivation is still unknown. Constitutive Androstane Receptor (CAR) is a master regulator in the metabolism and detoxification of both xenobiotics and endobiotics including steroid hormones. Several lines of evidence suggest that CAR may regulate the androgen metabolism: 1. Two P450 enzymes involved in testosterone oxidation, CYP2B and CYP3A, are primary target genes regulated by CAR. 2. Prenatal and neonatal exposure to Phenobarbital, a prototypical CAR activator, results in P450 enzyme imprinting and permanently changes the levels of testosterone. 3. CAR is expressed in the liver and prostate, the two major sites for androgen metabolism. Our long-term goal is to delineate the regulatory pathway of androgen metabolism and its impact on prostate carcinogenesis. We hypothesize that CAR controls an important pathway of androgen metabolism in liver and prostate and deregulation of this pathway changes the bioavailability of androgen, thus affecting prostate carcinogenesis. We propose three specific aims to test our hypothesis: Specific Aim1. Determine the role of CAR in testosterone metabolism in liver and prostate. We will compare the wild type and our CAR knockout mice after treating the animals with CAR activators to determine the role of CAR in androgen metabolism. Specific Aim 2. Investigate the role of CAR in early developmental imprinting of P450 enzymes in testosterone metabolism and its effect on prostate carcinogenesis. We will first determine the role of CAR in mediating the P450 enzyme imprinting and then investigate the impact of this early developmental imprinting on prostate carcinogenesis. Specific Aim 3. Study the transcriptional regulation of GSTP1 gene by CAR in the prostate. Results from experiments outlined here will illustrate an important pathway in androgen metabolism and provide better understanding of the molecular mechanism of androgen homeostasis. Manipulation of CAR activity by small molecules may be a novel approach for prostate cancer prevention and therapy.