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Research ArticleArticle

Cloning and Expression of Murine Sister of P-Glycoprotein Reveals a More Discriminating Transporter ThanMDR1/P-Glycoprotein

Valerie Lecureur, Daxi Sun, Philip Hargrove, Erin G. Schuetz, Richard B. Kim, Lu-Bin Lan and John D. Schuetz
Molecular Pharmacology January 2000, 57 (1) 24-35;
Valerie Lecureur
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Daxi Sun
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Philip Hargrove
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Erin G. Schuetz
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Richard B. Kim
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Lu-Bin Lan
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John D. Schuetz
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Abstract

Sister of P-glycoprotein (SPGP), a novel murine cDNA and member of the ATP-binding cassette superfamily highly homologous to P-glycoprotein (Pgp), was cloned. Moreover, its genomic clone was isolated and localized to chromosome 2 by fluorescence in situ hybridization. SPGP was functionally evaluated relative to MDR1 after subcloning SPGP cDNA into a retroviral bicistronic vector capable of expressing both SPGP and the green fluorescent protein. LLC-PK1 and MDCKII cells were transduced with this retrovirus and SPGP-positive clones were isolated. Drug uptake and efflux was compared in cells ectopically expressing either SPGP or human MDR1. SPGP cells had decreased uptake of taurocholate and vinblastine compared with LLC-PK1 cells. Additional studies revealed that vinblastine efflux was accelerated by SPGP compared with LLC-PK1. Further comparison revealed that although MDR1 easily impaired uptake of vincristine, daunomycin, paclitaxel, and digoxin, SPGP had no effect on uptake of these drugs. However, further studies demonstrated that, like MDR1, SPGP effluxed calcein-acetoxymethyl ester (AM). Unlike MDR1, SPGP was incapable of effluxing rhodamine 123. Although cyclosporine A and reserpine blocked calcein-AM transport by MDR1, these drugs had either minimal or no effect, respectively, on blocking SPGP efflux of calcein-AM. In contrast, ditekiren, a linear hexapeptide, readily and preferentially inhibited SPGP efflux of calcein-AM. Further studies with three structural analogs of ditekiren revealed that one analog inhibited SPGP efflux of calcein-AM, although not as potently as ditekiren. These are the first studies to reveal that SPGP has distinct transport properties compared with MDR1.

Footnotes

  • Send reprint requests to: Dr. John D. Schuetz, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale Ave., Memphis, TN 38105. E-mail:john.schuetz{at}stjude.org

  • This work was supported by National Institutes of Health Grants ES/GM 5851, ES/GM 8568, CA 21765, CA 23099, and GM 31304, and by the American Lebanese Syrian Associated Charities.

  • Abbreviations:
    Pgp
    P-glycoprotein
    SPGP
    sister of P-glycoprotein
    ABC
    ATP-binding cassette
    MDR
    multidrug resistance
    AM
    acetoxymethyl ester
    kb
    kilobase
    EST
    expressed sequence tag
    BAC
    bacterial artificial chromosome
    PCR
    polymerase chain reaction
    FISH
    fluorescence in situ hybridization
    GST
    glutathione transferase
    GFP
    green fluorescence protein
    BSEP
    bile salt export pump
    CsA
    cyclosporine A
    TM
    transmembrane
    • Received July 6, 1999.
    • Accepted September 23, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 57 (1)
Molecular Pharmacology
Vol. 57, Issue 1
1 Jan 2000
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Research ArticleArticle

Cloning and Expression of Murine Sister of P-Glycoprotein Reveals a More Discriminating Transporter ThanMDR1/P-Glycoprotein

Valerie Lecureur, Daxi Sun, Philip Hargrove, Erin G. Schuetz, Richard B. Kim, Lu-Bin Lan and John D. Schuetz
Molecular Pharmacology January 1, 2000, 57 (1) 24-35;

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Research ArticleArticle

Cloning and Expression of Murine Sister of P-Glycoprotein Reveals a More Discriminating Transporter ThanMDR1/P-Glycoprotein

Valerie Lecureur, Daxi Sun, Philip Hargrove, Erin G. Schuetz, Richard B. Kim, Lu-Bin Lan and John D. Schuetz
Molecular Pharmacology January 1, 2000, 57 (1) 24-35;
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