sequential activation of classic pkc and estrogen receptor α is involved in estradiol 17？-d-glucuronide-induced cholestasis经典的顺序激活pkc和雌激素受体α参与雌二醇17 -d-glucuronide-induced胆汁淤积.pdfVIP

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sequential activation of classic pkc and estrogen receptor α is involved in estradiol 17？-d-glucuronide-induced cholestasis经典的顺序激活pkc和雌激素受体α参与雌二醇17 -d-glucuronide-induced胆汁淤积.pdf

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sequential activation of classic pkc and estrogen receptor α is involved in estradiol 17？-d-glucuronide-induced cholestasis经典的顺序激活pkc和雌激素受体α参与雌二醇17 -d-glucuronide-induced胆汁淤积

Sequential Activation of Classic PKC and Estrogen Receptor a Is Involved in Estradiol 17ß-D-Glucuronide- Induced Cholestasis ´ Ismael R. Barosso, Andres E. Zucchetti, Andrea C. Boaglio, M. Cecilia Larocca, Diego R. Taborda, ´ Marcelo G. Luquita, Marcelo G. Roma, Fernando A. Crocenzi, Enrique J. Sanchez Pozzi* ´ ´ ´ Instituto de Fisiologıa Experimental (IFISE), Facultad de Ciencias Bioquımicas y Farmaceuticas (CONICET – U.N.R.), Rosario, Argentina Abstract Estradiol 17ß-D-glucuronide (E17G) induces acute cholestasis in rat with endocytic internalization of the canalicular transporters bile salt export pump (Abcb11) and multidrug resistance-associated protein 2 (Abcc2). Classical protein kinase C (cPKC) and PI3K pathways play complementary roles in E17G cholestasis. Since non-conjugated estradiol is capable of activating these pathways via estrogen receptor alpha (ERa), we assessed the participation of this receptor in the cholestatic manifestations of estradiol glucuronidated-metabolite E17G in perfused rat liver (PRL) and in isolated rat hepatocyte couplets (IRHC). In both models, E17G activated ERa. In PRL, E17G maximally decreased bile flow, and the excretions of dinitrophenyl-glutathione, and taurocholate (Abcc2 and Abcb11 substrates, respectively) by 60% approximately; preadministration of ICI 182,780 (ICI, ERa inhibitor) almost totally prevented these decreases. In IRHC, E17G decreased the canalicular vacuolar accumulation of cholyl-glycylamido-fluorescein (Abcb11 substrate) with an IC50 of 91 61 mM. ICI increased the IC50