Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan,
Arch Toxicol. 2015 Jul;89(7):1045-55. doi: 10.1007/s00204-015-1522-9. Epub 2015 May 16.
The constitutive androstane receptor (CAR), a member of the nuclear receptor superfamily, is a well-known xenosensor that regulates hepatic drug metabolism and detoxification. CAR activation can be elicited by a large variety of xenobiotics, including phenobarbital (PB) which is not a directly binding CAR ligand. The mechanism of CAR activation is complex and involves translocation from the cytoplasm into the nucleus, followed by further activation steps in the nucleus. Recently, epidermal growth factor receptor (EGFR) has been identified as a PB-responsive receptor, and PB activates CAR by inhibiting the EGFR signaling. In addition to regulation of drug metabolism, activation of CAR has multiple biological end points such as modulation of xenobiotic-elicited liver injury, and the role of CAR in endobiotic functions such as glucose metabolism and cholesterol homeostasis is increasingly recognized. Thus, investigations on the molecular mechanism of CAR activation are critical for the real understanding of CAR-mediated processes. Here, we summarize the current understanding of mechanisms by which CAR activators regulate gene expression through cellular signaling pathways and the roles of CAR on xenobiotic-elicited hepatocellular carcinoma, liver injury, glucose metabolism and cholesterol homeostasis.
组成型雄烷受体（CAR）是核受体超家族的一员，是一种众所周知的外源性物质传感器，可调节肝脏的药物代谢和解毒。CAR 的激活可由多种外源物质引起，包括苯巴比妥（PB），而 PB 不是直接结合 CAR 的配体。CAR 激活的机制很复杂，涉及从细胞质到细胞核的易位，然后在细胞核中进行进一步的激活步骤。最近，表皮生长因子受体（EGFR）被鉴定为 PB 反应性受体，而 PB 通过抑制 EGFR 信号来激活 CAR。除了调节药物代谢外，CAR 的激活还具有多种生物学终点，如调节外源物质引起的肝损伤，以及 CAR 在葡萄糖代谢和胆固醇稳态等内源性功能中的作用，越来越受到认可。因此，研究 CAR 激活的分子机制对于真正理解 CAR 介导的过程至关重要。在这里，我们总结了目前对 CAR 激活剂通过细胞信号通路调节基因表达的机制的理解，以及 CAR 在诱导肝细胞癌、肝损伤、葡萄糖代谢和胆固醇稳态的外源物质中的作用。
