High-speed screening and QSAR analysis of human ATP-binding cassette transporter ABCB11 (bile salt export pump) to predict drug-induced intrahepatic cholestasis.
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.
Hirano
Hiroyuki
H
Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
Kurata
Atsuo
A
Onishi
Yuko
Y
Sakurai
Aki
A
Saito
Hikaru
H
Nakagawa
Hiroshi
H
Nagakura
Makoto
M
Tarui
Shigeki
S
Kanamori
Yoichi
Y
Kitajima
Masato
M
Ishikawa
Toshihisa
T
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
C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D013656:Taurocholic Acid; D000255:Adenosine Triphosphate