Role of the intestinal bile acid transporters in bile acid and drug disposition.
Role of the intestinal bile acid transporters in bile acid and drug disposition.
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DOI：
10.1007/978-3-642-14541-4_4
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发表时间：
2011
影响因子：
--
通讯作者：
Dawson, Paul A
中科院分区：
文献类型：
--
作者：
Dawson, Paul A
由肝细胞和肠上皮细胞表达的膜转运蛋白在维持胆汁酸的肝肠循环中起关键作用，这是一种有效的再循环和保护机制，在很大程度上将这些潜在的细胞毒性去污剂限制在肠和肝胆隔室中。在这样做的过程中，肝脏和肠细胞运输系统确保了胆汁酸的持续供应，以在一天中的多餐消化过程中重复使用。胆汁酸从肠腔吸收并输出到门静脉循环中是由肠上皮细胞顶膜和基底外侧膜上表达的一系列转运蛋白介导的。回肠顶端钠依赖性胆汁酸协同转运蛋白（缩写为ASBT;基因符号，SLC 10A 2）负责胆汁酸穿过肠上皮细胞刷状缘膜的初始摄取。然后胆汁酸通过异聚体有机溶质转运蛋白OSTα-OSTβ有效地穿梭于细胞并穿过基底外侧膜输出。本章简要综述了ASBT和OSTα-OSTα的组织表达、生理学、遗传学、病理生理学和转运特性。此外，本章讨论了肠道胆汁酸转运蛋白和药物代谢之间的关系，包括开发ASBT抑制剂作为新的降胆固醇或保肝药物，前药靶向的ASBT，以增加口服生物利用度，并参与肠道胆汁酸转运蛋白在药物吸收和药物相互作用。
Membrane transporters expressed by the hepatocyte and enterocyte play critical roles in maintaining the enterohepatic circulation of bile acids, an effective recycling and conservation mechanism that largely restricts these potentially cytotoxic detergents to the intestinal and hepatobiliary compartments. In doing so, the hepatic and enterocyte transport systems ensure a continuous supply of bile acids to be used repeatedly during the digestion of multiple meals throughout the day. Absorption of bile acids from the intestinal lumen and export into the portal circulation is mediated by a series of transporters expressed on the enterocyte apical and basolateral membranes. The ileal apical sodium-dependent bile acid cotransporter (abbreviated ASBT; gene symbol, SLC10A2) is responsible for the initial uptake of bile acids across the enterocyte brush border membrane. The bile acids are then efficiently shuttled across the cell and exported across the basolateral membrane by the heteromeric Organic Solute Transporter, OSTα-OSTβ. This chapter briefly reviews the tissue expression, physiology, genetics, pathophysiology, and transport properties of the ASBT and OSTα-OSTα. In addition, the chapter discusses the relationship between the intestinal bile acid transporters and drug metabolism, including development of ASBT inhibitors as novel hypocholesterolemic or hepatoprotective agents, prodrug targeting of the ASBT to increase oral bioavailability, and involvement of the intestinal bile acid transporters in drug absorption and drug-drug interactions.