Laboratory of Molecular Pharmacology, CHUQ Research Center and Faculty of Pharmacy, Laval University, Québec, Canada.
Drug Metab Rev. 2010 Feb;42(1):110-22. doi: 10.3109/03602530903219220.
Recent progresses in molecular pharmacology approaches have allowed the identification and characterization of a series of nuclear receptors (NR) which efficiently control the level UDP-glucuronosyltransferase (UGT) genes expression. These regulatory processes ensure optimized UGT expression in response to specific endogenous and/or exogenous stimuli. Interestingly, numerous endogenous activators of these NRs are conjugated by the UGT enzymes they regulate. In such a case, the NR-dependent regulation of UGT genes corresponds to a feedforward/feedback mechanism by which a bioactive molecule controls its own concentrations. In the present review, we will discuss i) how bilirubin reduces its circulating levels by activating AhR in the liver; ii) how bile acids modulate their hepatic glucuronidation via PXR- and FXR-dependent processes in enterohepatic tissues; and iii) how androgens inhibit their cellular metabolism in prostate cancer cells through an AR-dependent mechanism. Subsequently, with further discussion of the same examples (bilirubin and bile acids), we will illustrate how NR-dependent regulation of UGT enzymes may contribute to the beneficial effects of pharmacological activators of nuclear receptors, such as CAR and PPARa.
近年来，分子药理学方法的进展使得一系列核受体（NR）得以被鉴定和表征，这些核受体能够有效地控制尿苷二磷酸葡萄糖醛酸转移酶（UGT）基因的表达水平。这些调控过程确保了 UGT 表达的优化，以响应特定的内源性和/或外源性刺激。有趣的是，这些 NR 的许多内源性激活剂都被它们调节的 UGT 酶所共轭。在这种情况下，NR 依赖的 UGT 基因调控对应于一种正反馈/负反馈机制，其中一种生物活性分子控制其自身的浓度。在本综述中，我们将讨论：i）胆红素如何通过在肝脏中激活 AhR 来降低其循环水平；ii）胆汁酸如何通过 PXR 和 FXR 依赖的过程在肠肝组织中调节其肝葡萄糖醛酸化；以及 iii）雄激素如何通过 AR 依赖的机制抑制前列腺癌细胞中的细胞代谢。随后，通过进一步讨论相同的例子（胆红素和胆汁酸），我们将说明 NR 依赖的 UGT 酶的调控如何有助于核受体药理学激活剂（如 CAR 和 PPARa）的有益作用。
