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Research ArticleArticle

Generation and Characterization of a Novel Multidrug Resistance Protein 2 Humanized Mouse Line

Nico Scheer, Praveen Balimane, Michael D. Hayward, Sandra Buechel, Gunther Kauselmann and C. Roland Wolf
Drug Metabolism and Disposition November 2012, 40 (11) 2212-2218; DOI: https://doi.org/10.1124/dmd.112.047605
Nico Scheer
TaconicArtemis, Koeln, Germany (N.S., S.B., G.K.); Bristol-Myers Squibb, Princeton, New Jersey (P.B.); Taconic Biosciences, Cranbury, New Jersey (M.D.H.); CXR Biosciences Limited, Dundee, United Kingdom (C.R.W.); and Cancer Research United Kingdom Molecular Pharmacology Unit, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (C.R.W.)
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Praveen Balimane
TaconicArtemis, Koeln, Germany (N.S., S.B., G.K.); Bristol-Myers Squibb, Princeton, New Jersey (P.B.); Taconic Biosciences, Cranbury, New Jersey (M.D.H.); CXR Biosciences Limited, Dundee, United Kingdom (C.R.W.); and Cancer Research United Kingdom Molecular Pharmacology Unit, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (C.R.W.)
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Michael D. Hayward
TaconicArtemis, Koeln, Germany (N.S., S.B., G.K.); Bristol-Myers Squibb, Princeton, New Jersey (P.B.); Taconic Biosciences, Cranbury, New Jersey (M.D.H.); CXR Biosciences Limited, Dundee, United Kingdom (C.R.W.); and Cancer Research United Kingdom Molecular Pharmacology Unit, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (C.R.W.)
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Sandra Buechel
TaconicArtemis, Koeln, Germany (N.S., S.B., G.K.); Bristol-Myers Squibb, Princeton, New Jersey (P.B.); Taconic Biosciences, Cranbury, New Jersey (M.D.H.); CXR Biosciences Limited, Dundee, United Kingdom (C.R.W.); and Cancer Research United Kingdom Molecular Pharmacology Unit, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (C.R.W.)
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Gunther Kauselmann
TaconicArtemis, Koeln, Germany (N.S., S.B., G.K.); Bristol-Myers Squibb, Princeton, New Jersey (P.B.); Taconic Biosciences, Cranbury, New Jersey (M.D.H.); CXR Biosciences Limited, Dundee, United Kingdom (C.R.W.); and Cancer Research United Kingdom Molecular Pharmacology Unit, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (C.R.W.)
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C. Roland Wolf
TaconicArtemis, Koeln, Germany (N.S., S.B., G.K.); Bristol-Myers Squibb, Princeton, New Jersey (P.B.); Taconic Biosciences, Cranbury, New Jersey (M.D.H.); CXR Biosciences Limited, Dundee, United Kingdom (C.R.W.); and Cancer Research United Kingdom Molecular Pharmacology Unit, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (C.R.W.)
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Abstract

The multidrug resistance protein (MRP) 2 is predominantly expressed in liver, intestine, and kidney, where it plays an important role in the excretion of a range of drugs and their metabolites or endogenous compounds into bile, feces, and urine. Mrp knockout [Mrp2(−/−)] mice have been used recently to study the role of MRP2 in drug disposition. Here, we describe the first generation and initial characterization of a mouse line humanized for MRP2 (huMRP2), which is nulled for the mouse Mrp2 gene and expresses the human transporter in the organs and cell types where MRP2 is normally expressed. Analysis of the mRNA expression for selected cytochrome P450 and transporter genes revealed no major changes in huMRP2 mice compared with wild-type controls. We show that human MRP2 is able to compensate functionally for the loss of the mouse transporter as demonstrated by comparable bilirubin levels in the humanized mice and wild-type controls, in contrast to the hyperbilirubinemia phenotype that is observed in MRP2(−/−) mice. The huMRP2 mouse provides a model to study the role of the human transporter in drug disposition and in assessing the in vivo consequences of inhibiting this transporter by compounds interacting with human MRP2.

Footnotes

  • This work was supported in part by ITI Life Sciences, Scotland.

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

    http://dx.doi.org/10.1124/dmd.112.047605.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    MRP
    multidrug resistance protein
    ABC
    ATP-binding cassette
    WT
    wild type
    kb
    kilobase
    PCR
    polymerase chain reaction
    ES
    embryonic stem
    huMRP
    humanized multidrug resistance protein
    PXR
    pregnane X receptor
    huPXR
    humanized PXR
    RT
    reverse transcription
    Ct
    cycle threshold
    BSA
    bovine serum albumin
    HRP
    horseradish peroxidase.

  • Received July 3, 2012.
  • Accepted August 23, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (11)
Drug Metabolism and Disposition
Vol. 40, Issue 11
1 Nov 2012
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Research ArticleArticle

MRP2 HUMANIZED MICE

Nico Scheer, Praveen Balimane, Michael D. Hayward, Sandra Buechel, Gunther Kauselmann and C. Roland Wolf
Drug Metabolism and Disposition November 1, 2012, 40 (11) 2212-2218; DOI: https://doi.org/10.1124/dmd.112.047605

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Research ArticleArticle

MRP2 HUMANIZED MICE

Nico Scheer, Praveen Balimane, Michael D. Hayward, Sandra Buechel, Gunther Kauselmann and C. Roland Wolf
Drug Metabolism and Disposition November 1, 2012, 40 (11) 2212-2218; DOI: https://doi.org/10.1124/dmd.112.047605
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