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

Abstract

Endocytic internalization of the multidrug resistance-associated protein 2 (Mrp2) was previously suggested to be involved in estradiol-17beta-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 micromol/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 micromol/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 microM) diminished canalicular accumulation of a fluorescent BS and decreased Bsep-associated fluorescence in the canalicular membrane; DBcAMP (10 microM) 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.

• Authors: Fernando A Crocenzi, Aldo D Mottino, Jingsong Cao, Luis M Veggi, Enrique J Sánchez Pozzi, Mary Vore, Roger Coleman, Marcelo G Roma
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 285 Issue 2 Pg. G449-59 (Aug 2003) ISSN: 0193-1857 [Print] United States
• PMID: 12702498 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters
• Abcb11 protein, rat
• Abcc2 protein, rat
• Actins
• Bile Acids and Salts
• Carrier Proteins
• estradiol-17 beta-glucuronide
• Estradiol
• Bucladesine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters (analysis, metabolism)
• Actins (analysis)
• Animals
• Bile (physiology)
• Bile Acids and Salts (metabolism)
• Bile Canaliculi (chemistry)
• Blotting, Western
• Bucladesine (pharmacology)
• Carrier Proteins (genetics, physiology)
• Cell Membrane (chemistry)
• Cholestasis (metabolism)
• Endocytosis (drug effects)
• Estradiol (analogs & derivatives, pharmacology)
• Female
• Fluorescent Antibody Technique
• Liver (chemistry, drug effects, metabolism)
• Microscopy, Confocal
• Mutation
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar