Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability.

Ho RH, Leake BF, Kilkenny DM, Meyer Zu Schwabedissen HE, Glaeser H, Kroetz DL, Kim RB
Pharmacogenet Genomics. 2010 20 (1): 45-57

PMID: 20010382 · PMCID: PMC2883163 · DOI:10.1097/FPC.0b013e3283349eb0

OBJECTIVES - Our aims were to identify and functionally characterize coding region nonsynonymous single nucleotide polymorphisms in the hepatic efflux transporter, bile salt export pump (BSEP; ABCB11), and to assess interindividual variability in BSEP expression.

METHODS - We identified 24 single nucleotide polymorphisms, including nine nonsynonymous variants, in ABCB11 from genomic DNA of approximately 250 ethnically diverse healthy individuals using denaturing high-performance liquid chromatography analysis and DNA sequencing. Wild type and variant BSEP were generated and functionally characterized for taurocholate transport activity in vitro in HeLa cells using a recombinant vaccinia-based method. BSEP expression was assessed by real-time mRNA analysis, western blot analysis, and immunofluorescence confocal microscopy.

RESULTS - For the most part, polymorphisms were rare and ethnic-dependent. In vitro functional studies revealed several rare variants, including 616A>G, 1674G>C, 1772A>G, and 3556G>A, to be associated with significantly impaired taurocholate transport activity while the 890A>G variant trended towards impaired function but was not statistically significant. The 3556G>A variant was associated with reduced cell surface to total protein expression compared with wild-type BSEP. Expression of BSEP by mRNA and protein analysis was determined from a bank of human liver samples. Wide interindividual variability was noted in both mRNA (19-fold) and protein (31-fold) expression levels. The common variant 1331T>C was associated with significantly reduced hepatic BSEP mRNA levels.

CONCLUSION - Accordingly, our study indicates there are functionally relevant polymorphisms in ABCB11 which may be of potential relevance in the predisposition to acquired liver disorders such as drug-induced cholestasis.

MeSH Terms (16)

ATP-Binding Cassette Transporters ATP Binding Cassette Transporter, Subfamily B, Member 11 Bile Acids and Salts Cell Line Cell Membrane Gene Expression HeLa Cells Humans Liver Microscopy, Confocal Mutagenesis, Site-Directed Polymerase Chain Reaction Polymorphism, Single Nucleotide Recombinant Fusion Proteins RNA, Messenger Vaccinia virus

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