QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.105.008854v1 34/9/1582    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lang, T. Articles by Kerb, R. Search for Related Content PubMed PubMed Citation Articles by Lang, T. Articles by Kerb, R.

Genetic Variability, Haplotype Structures, and Ethnic Diversity of Hepatic Transporters MDR3 (ABCB4) and Bile Salt Export Pump (ABCB11)

EPIDAUROS Biotechnologie AG, Bernried, Germany (T.L., M.H., A.D., R.S., A.K., E.M., R.K.); Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany (T.L.); and Division of Clinical Pharmacology and Toxicology (D.J., B.S., G.A.K.-U.) and Division of Gastroenterology and Hepatology (G.A.K.-U.), Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland

Biliary excretion of bile salts and other bile constituents from hepatocytes is mediated by the apical (canalicular) transporters P-glycoprotein 3 (MDR3, ABCB4) and the bile salt export pump (ABCB11). Mutations in ABCB4 and ABCB11 contribute to cholestatic diseases [e.g., progressive familial intrahepatic cholestasis 2 (PFIC2), PFIC3, and intrahepatic cholestasis of pregnancy], and our objective was to establish genetic variability and haplotype structures of ABCB4 and ABCB11 in healthy populations of different ethnic backgrounds. All coding exons, 5 of 6 noncoding exons, 50 to 300 base pairs of the flanking intronic regions, and 2.5 to 2.8 kilobase pairs of the promoter regions of ABCB4 and ABCB11 were sequenced in 159 and 196 DNA samples of Caucasian, African-American, Japanese, and Korean origin. In total, 76 and 86 polymorphisms were identified in ABCB4 and ABCB11, respectively; among them, 14 and 28 exonic polymorphisms, and 8 and 10 protein-altering variants, of which 4 were predicted to have functional consequences. Both genes showed substantial ethnic differences with respect to allele number, frequency of common and population-specific sites, and patterns of linkage disequilibrium. Population genetic analysis suggested some selective pressure against changes in the protein, supporting the important endogenous role of these transporters. Haplotype variability was greater in ABCB11 than in ABCB4. An ABCB11 promoter haplotype was associated with significant decrease of activity compared with wild type. Our results contribute to a better understanding of the molecular basis and of ethnic differences in drug response, and provide a valuable tool for future research on the heredity of cholestatic liver injury.

This article has been cited by other articles:

				Z. Wang, J. Wang, E. Tantoso, B. Wang, A. Y.P. Tai, L. L.P.J. Ooi, S. S. Chong, and C. G.L. Lee Signatures of recent positive selection at the ATP-binding cassette drug transporter superfamily gene loci Hum. Mol. Genet., June 1, 2007; 16(11): 1367 - 1380. [Abstract] [Full Text] [PDF]