期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 285, 期 2, 页码 G449-G459出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00508.2002
关键词
bile salt; cholestasis; dibutyryl-adenosine 3 '; 5 '-cyclic monophosphate; F-actin; TR- rats
Endocytic internalization of the multidrug resistance-associated protein 2 (Mrp2) was previously suggested to be involved in estradiol-17beta-D-glucuronide (E(2)17G)-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. E(2)17G (15 mumol/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 mumol/kg iv) partially prevented the decrease in bile flow and BS output and substantially prevented E(2)17G-induced Bsep internalization. In hepatocyte couplets, E(2)17G (50 muM) diminished canalicular accumulation of a fluorescent BS and decreased Bsep-associated fluorescence in the canalicular membrane; DBcAMP (10 muM) fully prevented both effects. In conclusion, our results suggest that changes in Bsep localization are involved in E(2)17G-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 E(2)17G to induce its harmful effect.
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