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This Article Full Text Full Text (PDF) All Versions of this Article: 288/2/G327    most recent 00227.2004v1 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 (14) Citing Articles via Google Scholar Google Scholar Articles by Mottino, A. D. Articles by Vore, M. Search for Related Content PubMed PubMed Citation Articles by Mottino, A. D. Articles by Vore, M.

LIVER AND BILIARY TRACT

Role of microtubules in estradiol-17-D-glucuronide-induced alteration of canalicular Mrp2 localization and activity

¹Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky; and ²Institute of Experimental Physiology, National University of Rosario, Rosario, Argentina

Submitted 18 May 2004 ; accepted in final form 8 September 2004

Estradiol-17-D-glucuronide (E₂-17G) induces a marked but reversible inhibition of bile flow in the rat together with endocytic retrieval of multidrug resistance-associated protein 2 (Mrp2) from the canalicular membrane to intracellular structures. We analyzed the effect of pretreatment (100 min) with the microtubule inhibitor colchicine or lumicholchicine, its inactive isomer (1 µmol/kg iv), on changes in bile flow and localization and function of Mrp2 induced by E₂-17G (15 µmol/kg iv). Bile flow and biliary excretion of bilirubin, an endogenous Mrp2 substrate, were measured throughout, whereas Mrp2 localization was examined at 20 and 120 min after E₂-17G by confocal immunofluorescence microscopy and Western analysis. Colchicine pretreatment alone did not affect bile flow or Mrp2 localization and activity over the short time scale examined (3–4 h). Administration of E₂-17G to colchicine-pretreated rats induced a marked decrease (85%) in bile flow and biliary excretion of bilirubin as well as internalization of Mrp2 at 20 min. These alterations were of a similar magnitude as in rats pretreated with lumicolchicine followed by E₂-17G. Bile flow and Mrp2 localization and activity were restored to control levels within 120 min of E₂-17G in animals pretreated with lumicolchicine. In contrast, in colchicine-pretreated rats followed by E₂-17G, bile flow and Mrp2 activity remained significantly inhibited by 60%, and confocal and Western studies revealed sustained internalization of Mrp2 120 min after E₂-17G. We conclude that recovery from E₂-17G cholestasis, associated with exocytic insertion of Mrp2 in the canalicular membrane, but not its initial E₂-17G-induced endocytosis, is a microtubule-dependent process.

bile secretion; endocytic compartment; colchicine; bilirubin

This article has been cited by other articles:

				A. D. Mottino, T. Hoffman, F. A. Crocenzi, E. J. Sanchez Pozzi, M. G. Roma, and M. Vore Disruption of function and localization of tight junctional structures and Mrp2 in sustained estradiol-17beta-D-glucuronide-induced cholestasis Am J Physiol Gastrointest Liver Physiol, July 1, 2007; 293(1): G391 - G402. [Abstract] [Full Text] [PDF]

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