title: Functional evaluation of ABCB1 (P-glycoprotein) polymorphisms: high-speed screening and structure-activity relationship analyses.
abstract: Evidence is accumulating to strongly suggest that drug transporters are one of the determinant factors governing the pharmacokinetic profile of drugs. Effort has been made to identify genetic variation in drug transporter genes. In particular, genetic variations of the human ABCB1 (MDR1) gene have been most extensively studied. Hitherto more than fifty single nucleotide polymorphisms (SNPs) and insertion/deletion polymorphisms in the ABCB1 gene have been reported. However, at the present time, information is still limited with respect to the actual effect of those genetic polymorphisms on the function of ABCB1. In this context, we have undertaken functional analyses of ABCB1 polymorphisms. To quantify the impact of genetic polymorphisms on the substrate specificity of ABCB1, we have developed a high-speed screening system and a new structure-activity relationship (SAR) analysis method. This review addresses functional aspects of the genetic polymorphism of ABCB1 and provides the standard method to evaluate the effect of polymorphisms on the function.
authors.affiliation: Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan. tishikaw@bio.titech.ac.jp
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirano
authors.forename: Yuko
authors.initials: Y
authors.lastname: Onishi
authors.forename: Aki
authors.initials: A
authors.lastname: Sakurai
authors.forename: Shigeki
authors.initials: S
authors.lastname: Tarui
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations