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Research ArticleArticle

Decreased Hepatic Breast Cancer Resistance Protein Expression and Function in Multidrug Resistance-Associated Protein 2-Deficient (TR−) Rats

Wei Yue, Jin Kyung Lee, Koji Abe, Yuichi Sugiyama and Kim L. R. Brouwer
Drug Metabolism and Disposition March 2011, 39 (3) 441-447; DOI: https://doi.org/10.1124/dmd.110.035188
Wei Yue
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Jin Kyung Lee
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Koji Abe
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Yuichi Sugiyama
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Kim L. R. Brouwer
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Abstract

Multidrug resistance-associated protein (Mrp) 2-deficient (TR−) Wistar rats have been used to elucidate the role of Mrp2 in drug disposition. Decreased breast cancer resistance protein (Bcrp) levels were reported in sandwich-cultured hepatocytes (SCH) from TR− rats compared with those from wild-type (WT) rats. This study was designed to characterize hepatic Bcrp expression and function in TR− rats, using nitrofurantoin and pitavastatin as substrates. Bcrp was knocked down by RNA interference in rat SCH. Antibody BXP53, but not BXP21, specifically detected Bcrp knockdown in SCH. Bcrp protein levels were decreased markedly in TR− but not Mrp2-deficient Sprague-Dawley [Eisai hyperbilirubinemic rats (EHBR)] rats. Bcrp mRNA levels were decreased significantly in TR− livers as determined by TaqMan real-time reverse transcriptase-polymerase chain reaction. Biliary excretion of nitrofurantoin, a specific Bcrp substrate, was decreased significantly in SCH and isolated perfused livers from TR− rats compared with those from WT controls, indicating that hepatic Bcrp function is decreased in TR− rats. In Bcrp knockdown SCH, the biliary excretion index and in vitro biliary clearance of pitavastatin were decreased significantly to ∼58 and ∼52% of control, respectively, indicating that Bcrp plays a role in pitavastatin biliary excretion. Pitavastatin biliary excretion was decreased significantly in perfused livers from TR− compared with those from WT rats. In conclusion, expression and function of hepatic Bcrp are decreased significantly in TR− rats. The potential role of both Bcrp and Mrp2 should be considered when data generated in TR− rats are interpreted. TR− and EHBR rats in combination may be useful in differentiating the role of Mrp2 and Bcrp in drug/metabolite disposition.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM41935] (to K.L.R.B.); and a scholarship from Daiichi-Sankyo (to K.A.).

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

    doi:10.1124/dmd.110.035188.

  • ABBREVIATIONS:

    ABC
    ATP-binding cassette
    BCRP/Bcrp
    breast cancer resistance protein
    Mrp/MRP
    multidrug resistance-associated protein
    EHBR
    Eisai hyperbilirubinemic rats
    RNAi
    RNA interference
    SCH
    sandwich-cultured hepatocytes
    IPL
    isolated perfused liver
    WT
    wild-type
    UNC
    University of North Carolina
    SD
    Sprague-Dawley
    RT
    reverse transcriptase
    PCR
    polymerase chain reaction
    HBSS
    Hanks' balanced salt solution
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    AUC
    area under the perfusate concentration-time curve
    BEI
    biliary excretion index.

  • Received June 30, 2010.
  • Accepted November 19, 2010.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (3)
Drug Metabolism and Disposition
Vol. 39, Issue 3
1 Mar 2011
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Research ArticleArticle

Decreased Hepatic Breast Cancer Resistance Protein Expression and Function in Multidrug Resistance-Associated Protein 2-Deficient (TR−) Rats

Wei Yue, Jin Kyung Lee, Koji Abe, Yuichi Sugiyama and Kim L. R. Brouwer
Drug Metabolism and Disposition March 1, 2011, 39 (3) 441-447; DOI: https://doi.org/10.1124/dmd.110.035188

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Research ArticleArticle

Decreased Hepatic Breast Cancer Resistance Protein Expression and Function in Multidrug Resistance-Associated Protein 2-Deficient (TR−) Rats

Wei Yue, Jin Kyung Lee, Koji Abe, Yuichi Sugiyama and Kim L. R. Brouwer
Drug Metabolism and Disposition March 1, 2011, 39 (3) 441-447; DOI: https://doi.org/10.1124/dmd.110.035188
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