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-D-GLUCURONIDE INDUCES ENDOCYTIC INTERNALIZATION OF BSEP IN THE RAT
1 Instituto de Fisiologia Experimental, Universidad Nacional de Rosario, Rosario, Santa Fe, Argentina
2 Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky, USA
3 School of Biosciences, The University of Birmingham, Birmingham, United Kingdom
* To whom correspondence should be addressed. E-mail: ifise1{at}citynet.net.ar.
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 dibutyryl-cAMP (DBcAMP) to prevent it. E217G (15 µmol/kg, i.v.) 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, i.v.) 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.
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