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

Am J Physiol Gastrointest Liver Physiol. 2003 Aug;285(2):G449-59. doi: 10.1152/ajpgi.00508.2002. Epub 2003 Apr 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • 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