Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan.
Curr Drug Targets. 2009 Nov;10(11):1156-1163. doi: 10.2174/138945009789735174.
Cholestasis results in the intrahepatic retention of cytotoxic bile acid and it can thus lead to liver injury and/or liver fibrosis. Cholestatic liver damage is counteracted by a variety of intrinsic hepatoprotective mechanisms including a complex network of drug metabolizing enzymes and transporters. During the last decade, much progress has been made in dissecting the mechanisms which regulate the hepatic xeno- and endobiotic metabolism by nuclear receptors. The xenobiotic receptors CAR and PXR are two important members of the NR1I nuclear receptor family. They function as sensors of toxic byproducts derived from the endogenous metabolism and of exogenous chemicals, in order to enhance their elimination. Ligands for both receptors, including phenobarbital, have already been used to treat cholestatic liver diseases before the mechanisms of these receptors were revealed. Furthermore, Yin Zhi Huang, a traditional Chinese herbal medicine, which has been used to prevent and treat neonatal jaundice, was identified to be a CAR ligand which also accelerates bilirubin clearance. Therefore, CAR and PXR have a protective effect on cholestasis by activating both detoxification enzymes and transporters. As a result, novel compounds targeting CAR and PXR with specific effects and fewer side effects will therefore be useful for the treatment of cholestatic liver diseases. This article will review the current knowledge on xenobiotic-sensing nuclear receptors CAR and PXR, while also discussing their potential role in the treatment of cholestatic liver diseases.
胆汁淤积导致细胞毒性胆汁酸在肝内蓄积，从而导致肝损伤和/或肝纤维化。多种内在的肝保护机制可对抗胆汁淤积性肝损伤，包括药物代谢酶和转运体的复杂网络。在过去的十年中，人们在解析核受体调节肝外源性和内源性代谢的机制方面取得了很大进展。外源性受体 CAR 和 PXR 是 NR1I 核受体家族的两个重要成员。它们作为内源性代谢和外源性化学物质产生的毒性副产物的传感器发挥作用，以增强其消除。这两种受体的配体，包括苯巴比妥，在这些受体的机制被揭示之前，已经被用于治疗胆汁淤积性肝病。此外，茵栀黄，一种用于预防和治疗新生儿黄疸的中药，被鉴定为 CAR 配体，也能加速胆红素清除。因此，CAR 和 PXR 通过激活解毒酶和转运体对胆汁淤积具有保护作用。因此，针对 CAR 和 PXR 的具有特定作用和较少副作用的新型化合物将有助于治疗胆汁淤积性肝病。本文将综述外源性受体 CAR 和 PXR 的最新知识，并讨论其在胆汁淤积性肝病治疗中的潜在作用。
