Eloranta Jyrki J, Meier Peter J, Kullak-Ublick Gerd A
Division of Gastroenterology and Hepatology, University Hospital, Zürich, Switzerland.
Methods Enzymol. 2005;400:511-30. doi: 10.1016/S0076-6879(05)00028-5.
Intestinal absorption and hepatic clearance of drugs, xenobiotics, and bile acids are mediated by transporter proteins expressed at the plasma membranes of intestinal epithelial cells and liver parenchymal cells in a polarized manner. Within enterocytes and hepatocytes, these exogenous or endogenous, potentially toxic compounds may be metabolized by phase I cytochrome P450 (CYP) and phase II conjugating enzymes. Many transporter proteins and metabolizing enzymes are subject to direct translational modification, enabling very rapid changes in their activity. However, to achieve intermediate and longer term changes in transport and enzyme activities, the genes encoding drug and bile acid transporters, as well as the CYP and conjugating enzymes, are regulated by a complex network of transcriptional cascades. These are typically mediated by specific members of the nuclear receptor family of transcription factors, particularly FXR, SHP, PXR, CAR, and HNF-4alpha. Most nuclear receptors are activated by specific ligands, including numerous xenobiotics (PXR, CAR) and bile acids (FXR). The fine-tuning of transcriptional control of drug and bile acid homeostasis depends on regulated interactions of specific nuclear receptors with their target genes.
药物、外源性物质和胆汁酸的肠道吸收及肝脏清除由表达于肠上皮细胞和肝实质细胞质膜上的转运蛋白以极化方式介导。在肠细胞和肝细胞内，这些外源性或内源性的潜在毒性化合物可能会被Ⅰ相细胞色素P450（CYP）和Ⅱ相结合酶代谢。许多转运蛋白和代谢酶会受到直接的翻译后修饰，从而使其活性能够非常快速地发生变化。然而，为了实现转运和酶活性的中期及长期变化，编码药物和胆汁酸转运蛋白以及CYP和结合酶的基因由一个复杂的转录级联网络调控。这些通常由转录因子核受体家族的特定成员介导，特别是法尼酯X受体（FXR）、小异二聚体蛋白（SHP）、孕烷X受体（PXR）、组成型雄烷受体（CAR）和肝细胞核因子4α（HNF-4α）。大多数核受体由特定配体激活，包括众多外源性物质（PXR、CAR）和胆汁酸（FXR）。药物和胆汁酸稳态转录调控的微调取决于特定核受体与其靶基因之间的调控相互作用。
