Bile salt export pump inhibitors are associated with bile acid-dependent drug-induced toxicity in sandwich-cultured hepatocytes
Bile salt export pump inhibitors are associated with bile acid-dependent drug-induced toxicity in sandwich-cultured hepatocytes
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DOI：
10.1016/j.bbrc.2011.11.032
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发表时间：
2011-12-16
影响因子：
3.1
通讯作者：
Horie, Toshiharu
中科院分区：
文献类型：
--
作者：
Ogimura, Eiichiro;Sekine, Shuichi;Horie, Toshiharu
药物性肝损伤（DILI）是候选化合物从药物试验中退出和药物退出临床使用的主要原因。在肝损伤的各种机制中，胆汁酸（BA）在肝细胞内的蓄积被认为是DILI发生的主要机制。虽然胆盐输出泵（BSEP）功能障碍被认为是DILI的易感因素，但对药物诱导的BSEP功能障碍与BA依赖性肝毒性之间的关系知之甚少。此外，几乎没有方法可用于BA依赖性DILI的系统和定量评价。本研究旨在利用体外培养的肝细胞（SCH）构建DILI模型。SCH可用于评估小管转运蛋白（如BSEP）的功能和代谢酶的活性。在此，研究了26种测试化合物（利托那韦、曲格列酮等）的BA依赖的细胞毒性在SCH。SCH暴露于每种化合物24小时，含或不含BA（甘氨鹅脱氧胆酸、脱氧胆酸等）。结果，在存在BA的情况下处理的SCH中，观察到11种测试化合物具有BA依赖性毒性，而在不存在BA的情况下处理的SCH中没有观察到毒性迹象。在这11种化合物中，有9种是已知的BSEP抑制剂。此外，对于某些化合物，在与细胞色素P450（CYP 450）介导的药物代谢的非选择性抑制剂1-氨基苯并三唑共处理的SCH中观察到BA依赖性毒性的严重程度增加。这些结果表明，基于SCH的模型可能被证明可用于评价BA依赖性DILI，包括药物代谢和BSEP抑制对肝损伤的影响。(C)2011 Elsevier Inc. All rights reserved.
Drug-induced liver injury (DILI) is a major reason for the dropout of candidate compounds from drug testing and the withdrawal of pharmaceuticals from clinical use. Among the various mechanisms of liver injury, the accumulation of bile acids (BAs) within hepatocytes is thought to be a primary mechanism for the development of DILI. Although bile salt export pump (BSEP) dysfunction is considered a susceptibility factor for DILI, little is known about the relationship between drug-induced BSEP dysfunction and BA-dependent hepatotoxicity. Furthermore, few methods are at hand for the systematic and quantitative evaluation of BA-dependent DILI. This study aimed to construct a model of DILI by employing sandwich-cultured hepatocytes (SCHs). SCHs can be used to assess functions of canalicular transporters such as BSEP and the activity of metabolic enzymes. Here, the impact of 26 test compounds (ritonavir, troglitazone, etc.) was investigated on BA-dependent cytotoxicity in SCHs. SCHs were exposed to each compound for 24 h with or without BAs (glycochenodeoxycholic acid, deoxycholic acid, etc.). As a result, BA-dependent toxicity was observed for 11 test compounds in SCHs treated in the presence of BAs, while no signs of toxicity were observed for SCHs treated in the absence of BAs. Of the 11 compounds, nine were known BSEP inhibitors. Moreover, for some compounds, an increase in the severity of BA-dependent toxicity was observed in SCHs that were co-treated with 1-aminobenzotriazole, a non-selective inhibitor of cytochrome P450 (CYP450)-mediated drug metabolism. These results indicate that the SCH-based model is likely to prove useful for the evaluation of BA-dependent DILI, including the effects of drug metabolism and BSEP inhibition on liver injury. (C) 2011 Elsevier Inc. All rights reserved.