title: High-speed screening and QSAR analysis of human ATP-binding cassette transporter ABCB11 (bile salt export pump) to predict drug-induced intrahepatic cholestasis.
abstract: 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.
authors.affiliation: Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirano
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kurata
authors.forename: Yuko
authors.initials: Y
authors.lastname: Onishi
authors.forename: Aki
authors.initials: A
authors.lastname: Sakurai
authors.forename: Hikaru
authors.initials: H
authors.lastname: Saito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Nagakura
authors.forename: Shigeki
authors.initials: S
authors.lastname: Tarui
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kanamori
authors.forename: Masato
authors.initials: M
authors.lastname: Kitajima
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active; D002462:Cell Membrane / Q000378:metabolism; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced* / Q000175:diagnosis; D006801:Humans; D021281:Quantitative Structure-Activity Relationship; D018411:Spodoptera; D013656:Taurocholic Acid / Q000378:metabolism; D014162:Transfection
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D013656:Taurocholic Acid; D000255:Adenosine Triphosphate