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Rapid CommunicationSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

Induction of Hepatic Multidrug Resistance-Associated Protein 3 by Ethynylestradiol Is Independent of Cholestasis and Mediated by Estrogen Receptor

María L. Ruiz, Juan P. Rigalli, Agostina Arias, Silvina Villanueva, Claudia Banchio, Mary Vore, Aldo D. Mottino and Viviana A. Catania
Drug Metabolism and Disposition February 2013, 41 (2) 275-280; DOI: https://doi.org/10.1124/dmd.112.047357
María L. Ruiz
Instituto de Fisiología Experimenta(M.L.R., J.P.R., A.A., S.V., A.D.M., V.A.C.) and Instituto de Biología Molecular y Celular de Rosario (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Rosario, Argentina (C.B.); and Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky (M.V.)
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Juan P. Rigalli
Instituto de Fisiología Experimenta(M.L.R., J.P.R., A.A., S.V., A.D.M., V.A.C.) and Instituto de Biología Molecular y Celular de Rosario (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Rosario, Argentina (C.B.); and Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky (M.V.)
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Agostina Arias
Instituto de Fisiología Experimenta(M.L.R., J.P.R., A.A., S.V., A.D.M., V.A.C.) and Instituto de Biología Molecular y Celular de Rosario (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Rosario, Argentina (C.B.); and Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky (M.V.)
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Silvina Villanueva
Instituto de Fisiología Experimenta(M.L.R., J.P.R., A.A., S.V., A.D.M., V.A.C.) and Instituto de Biología Molecular y Celular de Rosario (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Rosario, Argentina (C.B.); and Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky (M.V.)
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Claudia Banchio
Instituto de Fisiología Experimenta(M.L.R., J.P.R., A.A., S.V., A.D.M., V.A.C.) and Instituto de Biología Molecular y Celular de Rosario (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Rosario, Argentina (C.B.); and Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky (M.V.)
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Mary Vore
Instituto de Fisiología Experimenta(M.L.R., J.P.R., A.A., S.V., A.D.M., V.A.C.) and Instituto de Biología Molecular y Celular de Rosario (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Rosario, Argentina (C.B.); and Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky (M.V.)
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Aldo D. Mottino
Instituto de Fisiología Experimenta(M.L.R., J.P.R., A.A., S.V., A.D.M., V.A.C.) and Instituto de Biología Molecular y Celular de Rosario (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Rosario, Argentina (C.B.); and Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky (M.V.)
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Viviana A. Catania
Instituto de Fisiología Experimenta(M.L.R., J.P.R., A.A., S.V., A.D.M., V.A.C.) and Instituto de Biología Molecular y Celular de Rosario (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Rosario, Argentina (C.B.); and Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky (M.V.)
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Abstract

Multidrug resistance–associated protein 3 (Mrp3; Abcc3) expression and activity are up-regulated in rat liver after in vivo repeated administration of ethynylestradiol (EE), a cholestatic synthetic estrogen, whereas multidrug resistance-associated protein 2 (Mrp2) is down-regulated. This study was undertaken to determine whether Mrp3 induction results from a direct effect of EE, independent of accumulation of any endogenous common Mrp2/Mrp3 substrates resulting from cholestasis and the potential mediation of estrogen receptor (ER). In in vivo studies, male rats were given a single, noncholestatic dose of EE (5 mg/kg s.c.), and basal bile flow and the biliary excretion rate of bile salts and glutathione were measured 5 hours later. This treatment increased Mrp3 mRNA by 4-fold, detected by real-time polymerase chain reaction, despite the absence of cholestasis. Primary culture of rat hepatocytes incubated with EE (1–10 µM) for 5 hours exhibited a 3-fold increase in Mrp3 mRNA (10 µM), consistent with in vivo findings. The increase in Mrp3 mRNA by EE was prevented by actinomycin D, indicating transcriptional regulation. When hepatocytes were incubated with an ER antagonist [7α,17β-[9-[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol (ICI182/780), 1 µM], in addition to EE, induction of Mrp3 mRNA was abolished, implicating ER as a key mediator. EE induced an increase in ER-α phosphorylation at 30 minutes and expression of c-Jun, a well-known ER target gene, at 60 minutes, as detected by Western blotting of nuclear extracts. These increases were prevented by ICI182/780. In summary, EE increased the expression of hepatic Mrp3 transcriptionally and independently of any cholestatic manifestation and required participation of an ER, most likely ER-α, through its phosphorylation.

Footnotes

  • This work was supported by Agencia Nacional de Promoción Científica y Tecnológica [PICT 2007 04-1637 and PICT 2010-1072]; Consejo Nacional de Investigaciones Científicas y Técnicas [PIP 112-2008-01-00029/00691]; Universidad Nacional de Rosario [BIO 214], and Fundación Alberto J. Roemmers, Argentina; and by the National Institutes of Health The Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant HD58299].

  • dx.doi.org/10.1124/dmd.112.047357.

  • Received June 19, 2012.
  • Accepted October 17, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (2)
Drug Metabolism and Disposition
Vol. 41, Issue 2
1 Feb 2013
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Rapid CommunicationSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

Estrogen Receptor Mediates Mrp3 Induction by Ethynylestradiol

María L. Ruiz, Juan P. Rigalli, Agostina Arias, Silvina Villanueva, Claudia Banchio, Mary Vore, Aldo D. Mottino and Viviana A. Catania
Drug Metabolism and Disposition February 1, 2013, 41 (2) 275-280; DOI: https://doi.org/10.1124/dmd.112.047357

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Rapid CommunicationSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

Estrogen Receptor Mediates Mrp3 Induction by Ethynylestradiol

María L. Ruiz, Juan P. Rigalli, Agostina Arias, Silvina Villanueva, Claudia Banchio, Mary Vore, Aldo D. Mottino and Viviana A. Catania
Drug Metabolism and Disposition February 1, 2013, 41 (2) 275-280; DOI: https://doi.org/10.1124/dmd.112.047357
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