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Research ArticleArticle

INDUCTION OF MULTIDRUG RESISTANCE PROTEIN 3 (MRP3) IN VIVO IS INDEPENDENT OF CONSTITUTIVE ANDROSTANE RECEPTOR

Nathan J. Cherrington, Angela L. Slitt, Jonathan M. Maher, Xiao-Xue Zhang, Jun Zhang, Wendong Huang, Yu-Jui Yvonne Wan, David D. Moore and Curtis D. Klaassen
Drug Metabolism and Disposition November 2003, 31 (11) 1315-1319; DOI: https://doi.org/10.1124/dmd.31.11.1315
Nathan J. Cherrington
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Angela L. Slitt
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Jonathan M. Maher
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Xiao-Xue Zhang
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Jun Zhang
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Wendong Huang
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Yu-Jui Yvonne Wan
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David D. Moore
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Curtis D. Klaassen
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Abstract

We previously demonstrated that multidrug resistance protein 3 (Mrp3/ABCC3) is induced in rat liver by phenobarbital (PB) and several other microsomal enzyme inducers that induce cytochrome P450 2B (CYP2B). CYP2B is induced by constitutive androstane receptor (CAR)-retinoid X receptor (RXR) heterodimer binding to a phenobarbital-responsive promoter element in the CYP2B promoter. Hepatic mRNA levels of CYP2B and Mrp3 were measured in three models of altered CAR activity to determine whether CAR is also involved in the induction of Mrp3. In Wistar Kyoto rats, where males express higher CAR protein levels than females, the induction of CYP2B1/2 was significantly higher in males than in females by PB, diallyl sulfide, and trans-stilbene oxide but not oltipraz. Mrp3 was induced by each of these treatments, but in contrast to CYP2B1/2, to a similar magnitude in males and females. In male hepatocyte-specific RXRα-/- mice, CYP2B10 was not induced by diallyl sulfide or oltipraz but remained inducible by PB and trans-stilbene oxide after considering the decrease in basal CYP2B10 expression. Mrp3, however, was induced by PB, diallyl sulfide, trans-stilbene oxide and oltipraz in both wild-type and RXRα-/- mice. Additionally, constitutive expression of Mrp3 was significantly reduced in RXRα-/- mice. In CAR-/- mice, the robust induction of CYP2B10 by PB was completely absent. However, Mrp3 was equally induced both in wild-type and CAR-/- mice by PB. These data clearly demonstrate that induction of hepatic Mrp3 by PB and other microsomal enzyme inducers is CAR-independent and implies a role for RXRα in the constitutive expression of Mrp3.

Footnotes

  • ↵1 Abbreviations used are: Mrp3, multidrug resistance protein 3; CAR, constitutive androstane receptor; PB, phenobarbital; RXR, retinoid X receptor; WKY, Wistar Kyoto; DAS, diallyl sulfide; TSO, trans-stilbene oxide; OPZ, oltipraz; EST, expressed sequence tag; TCPOBOP, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene.

  • This work was supported by National Institutes of Health Grants ES-09716 and ES-03192 (to C.D.K.), CA53596 and AA014147 (to Y.-J.Y.W.) and DK46546 (to D.D.M.).

    • Received February 28, 2003.
    • Accepted July 24, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (11)
Drug Metabolism and Disposition
Vol. 31, Issue 11
1 Nov 2003
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Research ArticleArticle

INDUCTION OF MULTIDRUG RESISTANCE PROTEIN 3 (MRP3) IN VIVO IS INDEPENDENT OF CONSTITUTIVE ANDROSTANE RECEPTOR

Nathan J. Cherrington, Angela L. Slitt, Jonathan M. Maher, Xiao-Xue Zhang, Jun Zhang, Wendong Huang, Yu-Jui Yvonne Wan, David D. Moore and Curtis D. Klaassen
Drug Metabolism and Disposition November 1, 2003, 31 (11) 1315-1319; DOI: https://doi.org/10.1124/dmd.31.11.1315

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Research ArticleArticle

INDUCTION OF MULTIDRUG RESISTANCE PROTEIN 3 (MRP3) IN VIVO IS INDEPENDENT OF CONSTITUTIVE ANDROSTANE RECEPTOR

Nathan J. Cherrington, Angela L. Slitt, Jonathan M. Maher, Xiao-Xue Zhang, Jun Zhang, Wendong Huang, Yu-Jui Yvonne Wan, David D. Moore and Curtis D. Klaassen
Drug Metabolism and Disposition November 1, 2003, 31 (11) 1315-1319; DOI: https://doi.org/10.1124/dmd.31.11.1315
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