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Disruption of function and localization of tight junctional structures and Mrp2 in sustained estradiol-17-D-glucuronide-induced cholestasis

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

Submitted 24 October 2006 ; accepted in final form 25 April 2007

Estradiol-17-D-glucuronide (E₂17G) induces immediate and profound but transient cholestasis in rats when administered as a single bolus dose. Here, we examined the consequence of sustained E₂17G cholestasis and assessed the function and localization of the tight junctional proteins zonula occludens-1 (ZO-1) and occludin and of the canalicular transporter multidrug resistance-associated protein-2 (Mrp2). An initial dose of E₂17G (15 µmol/kg iv) followed by five subsequent doses of 7.5 µmol/kg from 60 to 240 min induced a sustained 40–70% decrease in bile flow. Following their biliary retrograde administration, cholera toxin B subunit-FITC or horseradish peroxidase were detected at the sinusoidal domain, indicating opening of the paracellular route; this occurred as early as 15 min after the first dose as well as 15 min after the last dose of E₂17G, but not following the administration of vehicle in controls. Localization of ZO-1 and occludin was only slightly affected under acute cholestatic conditions but was severely disrupted under sustained cholestasis, with their appearance suggesting a fragmented structure. Endocytic internalization of Mrp2 to the pericanalicular region was apparent 20 min after a single E₂17G administration; however, Mrp2 was found more deeply internalized and partially redistributed to the basolateral membrane under sustained cholestasis. In conclusion, acute E₂17G-induced cholestasis increased permeability of the tight junction, while sustained cholestasis provoked a significant redistribution of ZO-1, occludin, and Mrp2 in addition to increased permeability of the tight junction. Altered tight junction integrity likely contributes to impaired bile secretion and may be causally related to changes in Mrp2 localization.

bile secretion; endocytic compartment; estrogen; paracellular permeability