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Research ArticleArticle

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

Thomas Lang, Michael Haberl, Diana Jung, Anja Drescher, Robert Schlagenhaufer, Andrea Keil, Esther Mornhinweg, Bruno Stieger, Gerd A. Kullak-Ublick and Reinhold Kerb
Drug Metabolism and Disposition September 2006, 34 (9) 1582-1599; DOI: https://doi.org/10.1124/dmd.105.008854
Thomas Lang
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Michael Haberl
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Diana Jung
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Anja Drescher
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Robert Schlagenhaufer
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Andrea Keil
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Esther Mornhinweg
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Bruno Stieger
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Gerd A. Kullak-Ublick
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Reinhold Kerb
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Abstract

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.

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  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • Supported by Grants 01GG9846 and 01GG9848 from the German Federal Ministry for Education and Science (Bundesministerium für Bildung und Forschung).

  • doi:10.1124/dmd.105.008854.

  • ABBREVIATIONS: ABC, ATP-binding cassette; MDR, multidrug resistance; BSEP, bile salt export pump; DIC, drug-induced cholestasis; PFIC, progressive familial intrahepatic cholestasis; ICP, intrahepatic cholestasis of pregnancy; SNP, single nucleotide polymorphism; LD, linkage disequilibrium; PCR, polymerase chain reaction; kb, kilobase(s); bp, base pair(s); EC, evolutionarily conserved; EU, evolutionarily unconserved; CDCA, chenodeoxycholic acid; UTR, untranslated region; SIFT, sorting intolerant from tolerant; PolyPhen, Polymorphism Phenotyping; wt, wild type; AA, African American; CA, Caucasian; JA, Japanese, KO, Korean; PSIC, position-specific independent count.

    • Received December 7, 2005.
    • Accepted June 7, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (9)
Drug Metabolism and Disposition
Vol. 34, Issue 9
1 Sep 2006
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Research ArticleArticle

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

Thomas Lang, Michael Haberl, Diana Jung, Anja Drescher, Robert Schlagenhaufer, Andrea Keil, Esther Mornhinweg, Bruno Stieger, Gerd A. Kullak-Ublick and Reinhold Kerb
Drug Metabolism and Disposition September 1, 2006, 34 (9) 1582-1599; DOI: https://doi.org/10.1124/dmd.105.008854

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Research ArticleArticle

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

Thomas Lang, Michael Haberl, Diana Jung, Anja Drescher, Robert Schlagenhaufer, Andrea Keil, Esther Mornhinweg, Bruno Stieger, Gerd A. Kullak-Ublick and Reinhold Kerb
Drug Metabolism and Disposition September 1, 2006, 34 (9) 1582-1599; DOI: https://doi.org/10.1124/dmd.105.008854
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