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Research ArticleArticle

In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice

Nico Scheer, Jillian Ross, Yury Kapelyukh, Anja Rode and C. Roland Wolf
Drug Metabolism and Disposition July 2010, 38 (7) 1046-1053; DOI: https://doi.org/10.1124/dmd.109.031872
Nico Scheer
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Jillian Ross
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Yury Kapelyukh
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Anja Rode
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C. Roland Wolf
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Abstract

Dexamethasone (DEX) is a potent and widely used anti-inflammatory and immunosuppressant glucocorticoid. It can bind and activate the pregnane X receptor (PXR), which plays a critical role as xenobiotic sensor in mammals to induce the expression of many enzymes, including cytochromes P450 in the CYP3A family. This induction results in its own metabolism. We have used a series of transgenic mouse lines, including a novel, improved humanized PXR line, to compare the induction profile of PXR-regulated drug-metabolizing enzymes after DEX administration, as well as looking at hepatic responses to rifampicin (RIF). The new humanized PXR model has uncovered further intriguing differences between the human and mouse receptors in that RIF only induced Cyp2b10 in the new humanized model. DEX was found to be a much more potent inducer of Cyp3a proteins in wild-type mice than in mice humanized for PXR. To assess whether PXR is involved in the detoxification of DEX in the liver, we analyzed the consequences of high doses of the glucocorticoid on hepatotoxicity on different PXR genetic backgrounds. We also studied these effects in an additional mouse model in which functional mouse Cyp3a genes have been deleted. These strains exhibited different sensitivities to DEX, indicating a protective role of the PXR and CYP3A proteins against the hepatotoxicity of this compound.

Footnotes

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

  • Conflict of interest: N.S. and A.R. receive income from TaconicArtemis, and J.R., Y.K., and C.R.W. receive income from CXR Biosciences. The authors have declared that no conflict of interest exists.

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

    doi:10.1124/dmd.109.031872.

  • ABBREVIATIONS:

    DEX
    dexamethasone
    P450
    cytochrome P450
    GR
    glucocorticoid receptor
    PXR
    pregnane X receptor
    CAR
    constitutive androstane receptor
    ET-743
    ecteinascidin 743
    huPXR
    humanized pregnane X receptor mice
    PCR
    polymerase chain reaction
    ES cell
    embryonic stem cell
    FLPe
    efficient FLP
    PXR KO
    pregnane X receptor knockout mice
    huPXRi
    improved humanized pregnane X receptor mice
    WT
    wild-type
    RIF
    rifampicin
    qRT
    quantitative reverse transcriptase
    hPXR
    human pregnane X receptor
    PAGE
    polyacrylamide gel electrophoresis
    PROD
    pentoxyresorufin dealkylation
    BQ
    7-benzyloxyquinoline
    ALT
    alanine aminotransferase
    AUC
    area under the concentration versus time curve
    SET
    sucrose/EDTA/Tris-HCl.

  • Received December 18, 2009.
  • Accepted March 30, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (7)
Drug Metabolism and Disposition
Vol. 38, Issue 7
1 Jul 2010
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Research ArticleArticle

In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice

Nico Scheer, Jillian Ross, Yury Kapelyukh, Anja Rode and C. Roland Wolf
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1046-1053; DOI: https://doi.org/10.1124/dmd.109.031872

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Research ArticleArticle

In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice

Nico Scheer, Jillian Ross, Yury Kapelyukh, Anja Rode and C. Roland Wolf
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1046-1053; DOI: https://doi.org/10.1124/dmd.109.031872
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