Solvo Biotechnology, Hungary.
Toxicol In Vitro. 2012 Dec;26(8):1294-9. doi: 10.1016/j.tiv.2011.11.002. Epub 2011 Nov 18.
Bile salt export pump (BSEP, ABC11) is a membrane protein that is localized in the cholesterol-rich canalicular membrane of hepatocytes. Its function is to eliminate unconjugated and conjugated bile acids/salts from hepatocyte into the bile. In humans there is no compensatory mechanism for the loss of this transporter. Mutations of BSEP result in a genetic disease, called progressive familial intrahepatic cholestasis type 2 (PFIC2), that is characterized with decreased biliary bile salt secretion, leading to decreased bile flow and accumulation of bile salts inside the hepatocyte, inflicting damage. BSEP inhibitor drugs produce similar bile salt retention that may lead to severe cholestasis and liver damage. Drug-induced liver injury is a relevant clinical issue, in severe cases ending in liver transplantation. Therefore, measurement of BSEP inhibition by candidate drugs has high importance in drug discovery and development. Although several methods are suitable to detect BSEP-drug interactions, due to interspecies differences in bile acid composition, differences in hepatobiliary transporter modulation, they have limitations. This review summarizes appropriate in vitro methods that could be able to predict BSEP-drug candidate interactions in humans before the start of clinical phases.
胆盐输出泵（BSEP，ABC11）是一种膜蛋白，位于肝细胞的富含胆固醇的胆小管膜中。其功能是将未结合和结合的胆汁酸/盐从肝细胞中排出到胆汁中。在人类中，没有这种转运蛋白丢失的代偿机制。BSEP 的突变导致一种称为进行性家族性肝内胆汁淤积症 2 型（PFIC2）的遗传疾病，其特征是胆汁中胆汁盐分泌减少，导致胆汁流量减少和胆汁盐在肝细胞内积聚，造成损伤。BSEP 抑制剂药物会产生类似的胆汁盐潴留，可能导致严重的胆汁淤积和肝损伤。药物性肝损伤是一个相关的临床问题，在严重的情况下，最终需要进行肝移植。因此，候选药物对 BSEP 的抑制作用的测量在药物发现和开发中具有重要意义。尽管有几种方法适用于检测 BSEP-药物相互作用，但由于胆汁酸组成的种间差异，以及肝胆转运蛋白调节的差异，它们存在局限性。本文综述了合适的体外方法，这些方法可能能够在临床前阶段开始之前预测人类的 BSEP-候选药物相互作用。
