Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism
Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism
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DOI：
10.1016/j.abb.2004.09.019
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发表时间：
2005-01-15
影响因子：
3.9
通讯作者：
Kullak-Ublick, GA
中科院分区：
文献类型：
--
作者：
Eloranta, JJ;Kullak-Ublick, GA
药物和胆汁酸被位于基底膜的特殊转运蛋白(如有机阴离子转运多肽)摄取到肝细胞。药物代谢产物被细胞色素P450(CYP)酶代谢后，通过依赖于ATP的多药耐药蛋白(MDR1和MRPs)排入胆汁或尿液。胆汁酸主要通过胆盐输出泵排出(BSEP，ABCB11)。编码药物和胆汁酸转运蛋白以及CYP酶的基因受一个复杂的转录级联网络的调控，特别是受配体激活的核受体FXR、PXR和CAR以及非配体依赖的核受体HNF-4α的调控。胆汁酸合成酶细胞色素P7A1、细胞色素P8B1和细胞色素P27A1受到胆汁酸的负反馈调节，这种负反馈调节部分是通过转录抑制因子SHP介导的。转录辅助因子，如SRC-1和PGC-1，在介导单个核受体的基因特异性效应中的作用日益明显。(C)2004 Elsevier Inc.保留所有权利。
Drugs and bile acids are taken up into hepatocytes by specialized transport proteins localized at the basolateral membrane, e.g., organic anion transporting polypeptides. Following intracellular metabolism by cytochrome P450 (CYP) enzymes, drug metabolites are excreted into bile or urine via ATP-dependent multidrug resistance proteins (MDR1 and MRPs). Bile acids are excreted mainly via the bile salt export pump (BSEP, ABCB11). The genes coding for drug and bile acid transporters and CYP enzymes are regulated by a complex network of transcriptional cascades, notably by the ligand-activated nuclear receptors FXR, PXR, and CAR and by the ligand-independent nuclear receptor HNF-4alpha. The bile acid synthesizing enzymes CYP7A1, CYP8B1, and CYP27A1 are subject to negative feedback regulation by bile acids, which is partly mediated through the transcriptional repressor SHP. The role of transcriptional cofactors, such as SRC-1 and PGC-1, in mediating the gene-specific effects of individual nuclear receptors is becoming increasingly evident. (C) 2004 Elsevier Inc. All rights reserved.