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This Article Full Text Full Text (PDF) All Versions of this Article: 285/2/G449    most recent 00508.2002v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (33) Citing Articles via Google Scholar Google Scholar Articles by Crocenzi, F. A. Articles by Roma, M. G. Search for Related Content PubMed PubMed Citation Articles by Crocenzi, F. A. Articles by Roma, M. G.

LIVER AND BILIARY TRACT

Estradiol-17-D-glucuronide induces endocytic internalization of Bsep in rats

Fernando A. Crocenzi,¹ Aldo D. Mottino,¹ Jingsong Cao,² Luis M. Veggi,¹ Enrique J. Sánchez Pozzi,¹ Mary Vore,² Roger Coleman,^,3 and Marcelo G. Roma¹

¹Instituto de Fisiología Experimental, Universidad Nacional de Rosario, S2002LRL, Rosario, Argentina; ²Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536-0305; and ³School of Biosciences, The University of Birmingham, Birmingham B15 2TT, United Kingdom

Submitted 2 December 2002 ; accepted in final form 11 April 2003

Endocytic internalization of the multidrug resistance-associated protein 2 (Mrp2) was previously suggested to be involved in estradiol-17-D-glucuronide (E₂17G)-induced cholestasis. Here we evaluated in the rat whether a similar phenomenon occurs with the bile salt export pump (Bsep) and the ability of DBcAMP to prevent it. E₂17G (15 µmol/kg iv) impaired bile salt (BS) output and induced Bsep internalization, as assessed by confocal microscopy and Western blotting. Neither cholestasis nor Bsep internalization occurred in TR^- rats lacking Mrp2. DBcAMP (20 µmol/kg iv) partially prevented the decrease in bile flow and BS output and substantially prevented E₂17G-induced Bsep internalization. In hepatocyte couplets, E₂17G (50 µM) diminished canalicular accumulation of a fluorescent BS and decreased Bsep-associated fluorescence in the canalicular membrane; DBcAMP (10 µM) fully prevented both effects. In conclusion, our results suggest that changes in Bsep localization are involved in E₂17G-induced impairment of bile flow and BS transport and that DBcAMP prevents this effect by stimulating insertion of canalicular transporter-containing vesicles. Mrp2 is required for E₂17G to induce its harmful effect.

bile salt; cholestasis; dibutyryl-adenosine 3',5'-cyclic monophosphate; F-actin; TR^- rats

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