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Research ArticleArticle

Gestational and Pregnane X Receptor-Mediated Regulation of Placental ATP-Binding Cassette Drug Transporters in Mice

Sarabjit S. Gahir and Micheline Piquette-Miller
Drug Metabolism and Disposition March 2011, 39 (3) 465-471; DOI: https://doi.org/10.1124/dmd.110.034983
Sarabjit S. Gahir
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Micheline Piquette-Miller
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Abstract

The ATP-binding cassette (ABC) drug transporters in the placenta are involved in controlling the exchange of endogenous and exogenous moieties. Pregnane X receptor (PXR) is a nuclear receptor that regulates the hepatic expression of several key ABC transporters, but it is unclear whether PXR is involved in the regulation of these transporters in the placenta. This study explores the role of PXR in the regulation of placental drug transporters. The placental mRNA expression of Mdr1a, Bcrp, and Mrp1, 2, and 3 was examined in PXR knockout (−/−), heterozygote (+/−), and wild-type (+/+) mice by quantitative PCR. The impact of PXR activation was examined in pregnant pregnane-16α-carbonitrile (PCN)-treated mice. Compared with that in controls, the basal expression of Mdr1a, Bcrp, Mrp1, and Mrp2 was significantly higher in (+/−) and (−/−) mice. Alterations in the expression of mdr1a, bcrp, and mrp1, 2, and 3 between gestational day (GD) 10 and GD 17 was dissimilar between (+/+) and (−/−) mice. Although PCN treatment induced maternal and fetal hepatic expression of Cyp3a11; placental expression of transporters were not significantly changed. Overall, our results suggest a repressive role of PXR in the basal expression of several placental transporters and a tissue-specific induction of these target genes after PXR activation.

Footnotes

  • This work was supported by the Canadian Institutes of Health Research [Grant FRN 57688].

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

    doi:10.1124/dmd.110.034983.

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

  • ABBREVIATIONS:

    ABC
    ATP-binding cassette
    P-gp
    P-glycoprotein
    MRP/Mrp
    multidrug resistance-associated protein
    BCRP/Bcrp
    breast cancer resistance protein
    PXR
    pregnane X receptor
    GD
    gestational day
    PCN
    pregnane-16α-carbonitrile
    CAR
    constitutive androstane receptor
    RXR
    retinoid X receptor
    MDR
    multidrug resistance
    OATP
    organic anion-transporting protein
    PXR.1
    full-length PXR
    PXR.2
    PXR splice variant.

  • Received June 18, 2010.
  • Accepted December 1, 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

Gestational and Pregnane X Receptor-Mediated Regulation of Placental ATP-Binding Cassette Drug Transporters in Mice

Sarabjit S. Gahir and Micheline Piquette-Miller
Drug Metabolism and Disposition March 1, 2011, 39 (3) 465-471; DOI: https://doi.org/10.1124/dmd.110.034983

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Research ArticleArticle

Gestational and Pregnane X Receptor-Mediated Regulation of Placental ATP-Binding Cassette Drug Transporters in Mice

Sarabjit S. Gahir and Micheline Piquette-Miller
Drug Metabolism and Disposition March 1, 2011, 39 (3) 465-471; DOI: https://doi.org/10.1124/dmd.110.034983
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