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Research ArticleArticle

The Glucocorticoid Receptor Is Essential for Induction of Cytochrome P-4502B by Steroids but Not for Drug or Steroid Induction of CYP3A or P-450 Reductase in Mouse Liver

Erin G. Schuetz, Wolfgang Schmid, Gunther Schutz, Cynthia Brimer, Kazuto Yasuda, Tetsuya Kamataki, Lester Bornheim, Kathy Myles and Timothy J. Cole
Drug Metabolism and Disposition March 2000, 28 (3) 268-278;
Erin G. Schuetz
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Wolfgang Schmid
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Gunther Schutz
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Cynthia Brimer
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Kazuto Yasuda
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Tetsuya Kamataki
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Lester Bornheim
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Kathy Myles
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Timothy J. Cole
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Abstract

Cytochrome P-4503A, CYP2B, and P-450 reductase are induced by glucocorticoids, antiglucocorticoids such as pregnenolone 16α-carbonitrile, and drugs such as rifampin and phenobarbital. Although the pregnane X receptor is reported to mediate steroid and drug activation of CYP3A via a conserved cis-element in CYP3A genes, discrepancies exist between the induction of the endogenous CYP3A genes and the activation of the pregnane X receptor. It is a formal possibility that the glucocorticoid receptor may account for some of these discrepancies. To determine the requirement in vivo of the glucocorticoid receptor in expression of CYP3A and CYP2B, we compared the induction of these proteins in the livers of normal mice and mice with a targeted mutation in the glucocorticoid receptor. Mice lacking the glucocorticoid receptor show no difference in constitutive hepatic expression of CYP3A but show a decrease in the level of CYP2B. Glucocorticoid receptor-deficient mice challenged with either dexamethasone or pregnenolone 16α-carbonitrile failed to induce CYP2B proteins, whereas CYP2B was readily induced in (+/+) mice. In contrast, CYP3A and P-450 reductase proteins were induced by either inducer in wild-type and glucocorticoid receptor-null mice. Similarly, rifampin induced CYP3A in either wild-type or glucocorticoid receptor-null mice. Despite reports that rifampin is a nonsteroidal ligand for the human glucocorticoid receptor, rifampin failed to induce tyrosine aminotransferase in mice regardless of glucocorticoid receptor genotype, and rifampin did not compete for ligand binding to either mouse or human glucocorticoid receptor. Phenobarbital induced CYP3A, CYP2B, and P-450 reductase in all mice, but the amplitude of induction was diminished 37% in glucocorticoid receptor-null mice. Thus, there are distinctly different essential requirements of CYP3A, CYP2B, and P-450 reductase genes for the glucocorticoid receptor in their induction by steroids and drugs.

Footnotes

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

  • This work was supported by National Institutes of Health Research Grants ES08658, ES05851, P30-CA21765, and DA04265 (L.M.B.); a block grant from the National Health and Medical Research Council of Australia; and the American Lebanese Syrian Associated Charities (ALSAC).

  • Abbreviations used are::
    PXR
    pregnane X receptor
    DMEM
    Dulbecco's modified Eagle's medium
    TAT
    tyrosine aminotransferase
    GRE
    glucocorticoid response element
    PCN
    pregnenolone 16α-carbonitrile
    • Received August 11, 1999.
    • Accepted November 9, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (3)
Drug Metabolism and Disposition
Vol. 28, Issue 3
1 Mar 2000
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Research ArticleArticle

The Glucocorticoid Receptor Is Essential for Induction of Cytochrome P-4502B by Steroids but Not for Drug or Steroid Induction of CYP3A or P-450 Reductase in Mouse Liver

Erin G. Schuetz, Wolfgang Schmid, Gunther Schutz, Cynthia Brimer, Kazuto Yasuda, Tetsuya Kamataki, Lester Bornheim, Kathy Myles and Timothy J. Cole
Drug Metabolism and Disposition March 1, 2000, 28 (3) 268-278;

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Research ArticleArticle

The Glucocorticoid Receptor Is Essential for Induction of Cytochrome P-4502B by Steroids but Not for Drug or Steroid Induction of CYP3A or P-450 Reductase in Mouse Liver

Erin G. Schuetz, Wolfgang Schmid, Gunther Schutz, Cynthia Brimer, Kazuto Yasuda, Tetsuya Kamataki, Lester Bornheim, Kathy Myles and Timothy J. Cole
Drug Metabolism and Disposition March 1, 2000, 28 (3) 268-278;
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