Regulation of androgen metabolism by the nuclear receptor CAR

描述(由申请人提供)： 前列腺癌是美国男性癌症死亡的第二大原因。激素代谢紊乱导致的雄激素水平异常与前列腺癌的发生和发展密切相关。然而，调节雄激素，特别是睾酮代谢和失活的机制仍不清楚。构造性雄烷受体(CAR)是外源和内生物质包括类固醇激素代谢和解毒的主要调节因子。有多种证据表明CAR可能调节雄激素代谢：1.参与睾酮氧化的两种P450酶--CYP2B和CYP3A是CAR调控的主要靶基因。2.产前和新生儿暴露于苯巴比妥，一种典型的CAR激活剂，会导致P450酶印记，并永久改变睾酮水平。3.CAR在肝脏和前列腺中表达，这两个部位是雄激素代谢的两个主要部位。我们的长期目标是描绘雄激素代谢的调节途径及其对前列腺癌发生的影响。我们假设CAR控制着肝脏和前列腺中雄激素代谢的一个重要途径，而这一途径的解除调控会改变雄激素的生物利用度，从而影响前列腺癌的发生。我们提出了三个具体的目标来检验我们的假设：特定的目标1。确定CAR在肝脏和前列腺睾酮代谢中的作用。在用CAR激活剂处理后，我们将比较野生型和我们的CAR基因敲除小鼠，以确定CAR在雄激素代谢中的作用。具体目的2.探讨CAR在睾酮代谢P450酶早期发育印记中的作用及其在前列腺癌发生中的作用。我们将首先确定CAR在介导P450酶印迹中的作用，然后研究这种早期发育印迹在前列腺癌发生中的影响。具体目的3.研究CAR对GSTP1基因在前列腺中的转录调控作用。这里概述的实验结果将阐明雄激素代谢的一条重要途径，并提供更好的了解雄激素稳态的分子机制。通过小分子调控CAR活性可能成为前列腺癌预防和治疗的新途径。

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.