Prediction of drug-induced intrahepatic cholestasis: in vitro screening and QSAR analysis of drugs inhibiting the human bile salt export pump.
Drug-induced intrahepatic cholestasis is one of the major causes of hepatotoxicity, which often occur during the drug discovery and development process. Human ATP-binding cassette transporter ABCB11 (sister of P-glycoprotein/bile salt export pump) mediates the elimination of cytotoxic bile salts from liver cells to bile, and, therefore, plays a critical role in the generation of bile flow. The authors have recently developed in vitro high-speed screening and quantitative structure-activity relationship analysis methods to investigate the interaction of ABCB11 with a variety of compounds. Based on the extent of inhibition of the bile salt export pump, the authors analysed the quantitative structure-activity relationship to identify chemical groups closely associated with the inhibition of ABCB11. This approach provides a new tool to predict compounds with a potential risk of drug-induced intrahepatic cholestasis.
Sakurai
Aki
A
Tokyo Institute of Technology, Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, 4259-B-60 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan.
Kurata
Atsuo
A
Onishi
Yuko
Y
Hirano
Hiroyuki
H
Ishikawa
Toshihisa
T
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001647:Bile Acids and Salts / Q000037:antagonists & inhibitors / Q000378:metabolism; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship
C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D004364:Pharmaceutical Preparations