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, 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.

Original languageEnglish (US)
Pages (from-to)1315-1319
Number of pages5
JournalDrug Metabolism and Disposition
Volume31
Issue number11
DOIs
StatePublished - Nov 2003

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Phenobarbital
Retinoid X Receptors
Cytochrome P-450 Enzyme System
Cytochrome P-450 CYP2B1
Rats
Liver
Inbred WKY Rats
constitutive androstane receptor
multidrug resistance protein 3
Enzymes
Hepatocytes
Messenger RNA
stilbene oxide
oltipraz
allyl sulfide

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Cherrington, N. J., Slitt, A. L., Maher, J. M., Zhang, X. X., Zhang, J., Huang, W., ... Klaassen, C. D. (2003). Induction of multidrug resistance protein 3 (MRP3) in vivo is independent of constitutive androstane receptor. Drug Metabolism and Disposition, 31(11), 1315-1319. https://doi.org/10.1124/dmd.31.11.1315

Induction of multidrug resistance protein 3 (MRP3) in vivo is independent of constitutive androstane receptor. / Cherrington, Nathan J.; Slitt, Angela L.; Maher, Jonathan M.; Zhang, Xiao Xue; Zhang, Jun; Huang, Wendong; Wan, Yu-Jui Yvonne; Moore, David D.; Klaassen, Curtis D.

In: Drug Metabolism and Disposition, Vol. 31, No. 11, 11.2003, p. 1315-1319.

Research output: Contribution to journalArticle

Cherrington, NJ, Slitt, AL, Maher, JM, Zhang, XX, Zhang, J, Huang, W, Wan, Y-JY, Moore, DD & Klaassen, CD 2003, 'Induction of multidrug resistance protein 3 (MRP3) in vivo is independent of constitutive androstane receptor', Drug Metabolism and Disposition, vol. 31, no. 11, pp. 1315-1319. https://doi.org/10.1124/dmd.31.11.1315
Cherrington, Nathan J. ; Slitt, Angela L. ; Maher, Jonathan M. ; Zhang, Xiao Xue ; Zhang, Jun ; Huang, Wendong ; Wan, Yu-Jui Yvonne ; Moore, David D. ; Klaassen, Curtis D. / Induction of multidrug resistance protein 3 (MRP3) in vivo is independent of constitutive androstane receptor. In: Drug Metabolism and Disposition. 2003 ; Vol. 31, No. 11. pp. 1315-1319.
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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.",
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AU - Cherrington, Nathan J.

AU - Slitt, Angela L.

AU - Maher, Jonathan M.

AU - Zhang, Xiao Xue

AU - Zhang, Jun

AU - Huang, Wendong

AU - Wan, Yu-Jui Yvonne

AU - Moore, David D.

AU - Klaassen, Curtis D.

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AB - 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.

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