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Molecular Pharmacology

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Research ArticleArticle

Altered Expression of Hepatic Cytochromes P-450 in Mice Deficient in One or More mdr1 Genes

Erin G. Schuetz, Diane R. Umbenhauer, Kazuto Yasuda, Cynthia Brimer, Lan Nguyen, Mary V. Relling, John D. Schuetz and Alfred H. Schinkel
Molecular Pharmacology January 2000, 57 (1) 188-197;
Erin G. Schuetz
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Diane R. Umbenhauer
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Kazuto Yasuda
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Cynthia Brimer
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Lan Nguyen
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Mary V. Relling
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John D. Schuetz
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Alfred H. Schinkel
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This article has a correction. Please see:

  • Correction for Volume 57, p. 188 - June 01, 2000

Abstract

We hypothesized that the drug efflux protein P-glycoprotein (Pgp), the product of the multidrug resistance gene MDR1, might influence hepatic expression of CYP3A or other cytochromes P-450 (P-450s) because Pgp can transport endogenous regulators of these cytochromes. We began with variants of a CF-1 mouse strain containing a defective mdr1a gene that is inherited in a Mendelian fashion. The amount of CYP3A protein in liver was inversely related to the gene dose of the normal mdr1a allele in these mice.mdr1a knockout mice of either mixed (FVB × 129/Ola) or pure FVB genetic background and housed in Amsterdam display an increased expression of CYP2B and CYP3A proteins. However, becausemdr1a ablation causes a compensatory increase in hepaticmdr1b (which can efflux intracellular glucocorticoids), we reasoned that mdr1b might mask the overall effect ofmdr1a absence on P-450 gene expression. Targeted inactivation of the mdr1b gene increased P-450 expression, but the effect was modest compared withmdr1a ablation. Mice nullizygous for bothmdr1a and mdr1b-type Pgps and kept in Amsterdam had dramatically increased levels of CYP3A protein as well as other P-450s examined and of the electron donor P-450 reductase. Consistent with the protein results, CYP3A catalytic activity measured as midazolam 1′- and 4-hydroxylation in liver microsomes from these knockout mice revealed a rank order of activities withmdr1a/1b > mdr1a >mdr1b > (+/+) mice. In contrast to results in mice housed in Amsterdam, in the genetically identical mdr1aor mdr1a/1b (−/−) male mice housed in the United States, hepatic P-450 expression was unaffected by mdr1genotype or actually showed a slight decrease in mdr1a(−/−) mice. These results provide a revealing picture ofmdr1-type Pgp as an upstream regulator of hepatic P-450 expression, and demonstrate that these pharmacologically relevant phenotypes in knockout mice depend not only on the genetic make-up of the mice but also on the environment.

Footnotes

  • Send reprint requests to: Dr. Erin Schuetz, Dept. 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 Institute of Health Grants ES/GM 5851 and 8568, CA51001, and Core Grant CA21765, and by the American Lebanese Syrian Associated Charities.

  • Abbreviations:
    P-450
    cytochrome P-450
    PXR
    pregnane X receptor
    P-450 reductase
    NADPH cytochrome P-450 reductase
    Pgp
    P-glycoprotein, the product of the human MDR1 and mousemdr1a and mdr1b genes
    MDR1
    multidrug resistance gene
    • Received July 1, 1999.
    • Accepted September 14, 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

Altered Expression of Hepatic Cytochromes P-450 in Mice Deficient in One or More mdr1 Genes

Erin G. Schuetz, Diane R. Umbenhauer, Kazuto Yasuda, Cynthia Brimer, Lan Nguyen, Mary V. Relling, John D. Schuetz and Alfred H. Schinkel
Molecular Pharmacology January 1, 2000, 57 (1) 188-197;

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Research ArticleArticle

Altered Expression of Hepatic Cytochromes P-450 in Mice Deficient in One or More mdr1 Genes

Erin G. Schuetz, Diane R. Umbenhauer, Kazuto Yasuda, Cynthia Brimer, Lan Nguyen, Mary V. Relling, John D. Schuetz and Alfred H. Schinkel
Molecular Pharmacology January 1, 2000, 57 (1) 188-197;
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