利用放射性和LC/ ms检测方法评价胆汁盐出口泵(BSEP)对膜泡的抑制作用

Lisa D. Marroquin, Paul D. Bonin, Julie Keefer, Thomas Schroeter
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引用次数: 8

摘要

胆盐输出泵(BSEP, ABCB11)属于atp结合盒转运蛋白超家族,主要存在于肝脏。BSEP是一种外排转运蛋白,在胆盐分泌到胆汁中起关键作用。药物抑制BSEP功能可导致肝脏胆盐积聚,最终导致胆汁淤积和药物性肝损伤(DILI)。DILI是药品撤出市场的一个主要原因,占急性肝衰竭的50%。因此,早期发现药物对BSEP的抑制有助于降低BSEP相关性肝损伤的可能性。本单元描述了用转染人BSEP的Hi5昆虫细胞制备的膜泡研究药物干扰BSEP功能与肝损伤之间关系的两种检测方法。描述了在384孔格式中使用放射性标记和液相色谱/质谱(LC/MS)为基础的检测方法评估BSEP抑制的综合方案。©2017 by John Wiley &儿子,Inc。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Assessment of Bile Salt Export Pump (BSEP) Inhibition in Membrane Vesicles Using Radioactive and LC/MS-Based Detection Methods

The bile salt export pump (BSEP, ABCB11) belongs to the ATP-binding-cassette superfamily of transporters and is predominately found in the liver. BSEP is an efflux transporter that plays a critical role in the secretion of bile salts into the bile. Inhibition of BSEP function by drugs can result in the buildup of bile salts in the liver and eventually leads to cholestasis and drug-induced liver injury (DILI). DILI is a major cause of withdrawal of drugs from the pharmaceutical market and accounts for >50% of acute liver failures. Therefore, early detection of BSEP inhibition by drugs can help to mitigate the possibility of BSEP-associated liver injury. This unit describes two assays that investigate the relationship between drug interference with BSEP function and liver injury using membrane vesicles prepared from Hi5 insect cells transfected with human BSEP. Comprehensive protocols for assessing BSEP inhibition in a 384-well format using radiolabeled and liquid chromatography/mass spectrometry (LC/MS)–based detection methods are described. © 2017 by John Wiley & Sons, Inc.

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