*Department of Pharmacy, Uppsala University, SE-751 23 Uppsala, Sweden;
Toxicol Sci. 2013 Dec;136(2):328-43. doi: 10.1093/toxsci/kft197. Epub 2013 Sep 6.
A comprehensive analysis was performed to investigate how inhibition of the human bile salt export pump (BSEP/ABCB11) relates to clinically observed drug-induced liver injury (DILI). Inhibition of taurocholate (TA) transport was investigated in BSEP membrane vesicles for a data set of 250 compounds, and 86 BSEP inhibitors were identified. Structure-activity modeling identified BSEP inhibition to correlate strongly with compound lipophilicity, whereas positive molecular charge was associated with a lack of inhibition. All approved drugs in the data set (n = 182) were categorized according to DILI warnings in drug labels issued by the Food and Drug Administration, and a strong correlation between BSEP inhibition and DILI was identified. As many as 38 of the 61 identified BSEP inhibitors were associated with severe DILI, including 9 drugs not previously linked to BSEP inhibition. Further, among the tested compounds, every second drug associated with severe DILI was a BSEP inhibitor. Finally, sandwich-cultured human hepatocytes (SCHH) were used to investigate the relationship between BSEP inhibition, TA transport, and clinically observed DILI in detail. BSEP inhibitors associated with severe DILI greatly reduced the TA canalicular efflux, whereas BSEP inhibitors with less severe or no DILI resulted in weak or no reduction of TA efflux in SCHH. This distinction illustrates the usefulness of SCHH in refined analysis of BSEP inhibition. In conclusion, BSEP inhibition in membrane vesicles was found to correlate to DILI severity, and altered disposition of TA in SCHH was shown to separate BSEP inhibitors associated with severe DILI from those with no or mild DILI.
进行了全面分析，以研究人胆汁盐输出泵（BSEP/ABCB11）的抑制如何与临床上观察到的药物性肝损伤（DILI）相关。在 BSEP 膜囊泡中研究了牛磺胆酸钠（TA）转运的抑制作用，涉及 250 种化合物的数据组，并确定了 86 种 BSEP 抑制剂。结构-活性建模确定 BSEP 抑制与化合物脂溶性密切相关，而正分子电荷与缺乏抑制作用相关。根据食品和药物管理局发布的药物标签中的 DILI 警告，对数据集中的所有批准药物（n = 182）进行了分类，发现 BSEP 抑制与 DILI 之间存在很强的相关性。在所确定的 61 种 BSEP 抑制剂中有 38 种与严重的 DILI 相关，其中包括 9 种以前与 BSEP 抑制无关的药物。此外，在所测试的化合物中，每两种与严重 DILI 相关的药物中有一种是 BSEP 抑制剂。最后，使用三明治培养的人肝细胞（SCHH）详细研究了 BSEP 抑制、TA 转运和临床上观察到的 DILI 之间的关系。与严重 DILI 相关的 BSEP 抑制剂大大降低了 TA 胆管流出，而与较轻或无 DILI 相关的 BSEP 抑制剂导致 SCHH 中 TA 流出的减少微弱或没有。这种区别说明了 SCHH 在 BSEP 抑制的精细分析中的有用性。总之，在膜囊泡中发现 BSEP 抑制与 DILI 严重程度相关，并且 SCHH 中 TA 处置的改变表明与严重 DILI 相关的 BSEP 抑制剂与无或轻度 DILI 的 BSEP 抑制剂分离。
