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High-Speed Screening and QSAR Analysis of Human ATP-Binding Cassette Transporter ABCB11 (Bile Salt Export Pump) To Predict Drug-Induced Intrahepatic Cholestasis

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Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan, GS platZ Co. Ltd., Tokyo 103-0027, Japan, BioTec Co. Ltd., Tokyo 113-0034, Japan, Bio Research Laboratories, Nosan Corporation, Tsukuba 300-2615, Japan, and Life Science Systems Department, PLM Solutions Division, Fujitsu Kyushu System Engineering Co. Ltd., Fukuoka 814-8589, Japan
Cite this: Mol. Pharm. 2006, 3, 3, 252–265
Publication Date (Web):April 28, 2006
https://doi.org/10.1021/mp060004w
Copyright © 2006 American Chemical Society

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    Abstract

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    Human ATP-binding cassette transporter ABCB11 (SPGP/BSEP) mediates the elimination of bile salts from liver cells and thereby plays a critical role in the generation of bile flow. In the present study, we have developed in vitro high-speed screening and quantitative structure−activity relationship (QSAR) analysis methods to investigate the interaction of ABCB11 with a variety of drugs. Plasma membrane vesicles prepared from insect cells overexpressing human ABCB11 were used to measure the ATP-dependent transport of [14C]taurocholate. Over 40 different drugs and natural compounds were tested to evaluate their interaction with ABCB11-mediated taurocholate transport. On the basis of the extent of inhibition, we have analyzed the QSAR to identify one set of chemical fragmentation codes closely associated with the inhibition of ABCB11. This approach can be used to predict compounds with a potential risk of drug-induced intrahepatic cholestasis.

    Keywords: ABC transporter; ABCB11; bile salt; intrahepatic cholestasis; troglitazone

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     Tokyo Institute of Technology.

     GS platZ Co., Ltd.

    §

     BioTec Co., Ltd.

     Nosan Corporation.

     Fujitsu Kyushu System Engineering Co. Ltd.

    *

     Author to whom correspondence should be addressed. Mailing address:  Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Nagatsuta 4259-B-60, Yokohama 226-8501, Japan. Tel:  045-924-5800. Fax:  045-924-5838. E-mail:  [email protected].

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