Artículo
Induction of hepatic multidrug resistance-associated protein 3 by ethynylestradiol is independent of cholestasis and mediated by estrogen receptor
Ruiz, Maria Laura
; Rigalli, Juan Pablo
; Arias, Agostina
; Villanueva, Silvina Stella Maris
; Banchio, Claudia Elena
; Vore, Mary; Mottino, Aldo Domingo
; Catania, Viviana Alicia
Fecha de publicación:
02/2013
Editorial:
American Society for Pharmacology and Experimental Therapeutics
Revista:
Drug Metabolism and Disposition
ISSN:
0090-9556
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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.
Palabras clave:
Mrp3·
,
Estrogen Receptor
,
Cholestasis
,
Ethynylestradiol
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Identificadores
Colecciones
Articulos(CCT - ROSARIO)
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - ROSARIO
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - ROSARIO
Articulos(IFISE)
Articulos de INST.DE FISIOLOGIA EXPERIMENTAL (I)
Articulos de INST.DE FISIOLOGIA EXPERIMENTAL (I)
Citación
Ruiz, Maria Laura; Rigalli, Juan Pablo; Arias, Agostina; Villanueva, Silvina Stella Maris; Banchio, Claudia Elena; et al.; Induction of hepatic multidrug resistance-associated protein 3 by ethynylestradiol is independent of cholestasis and mediated by estrogen receptor; American Society for Pharmacology and Experimental Therapeutics; Drug Metabolism and Disposition; 41; 2; 2-2013; 275-280
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