Contribution of mrp2 in alterations of canalicular bile formation by the endothelin antagonist bosentan

J Hepatol. 2002 Aug;37(2):184-91. doi: 10.1016/s0168-8278(02)00107-1.


Background/aims: Bosentan, a dual endothelin ET(A/B) receptor antagonist, may cause dose-dependent reversible cholestatic liver injury. We herein tested whether bosentan or metabolites, both eliminated in bile, induce alterations in bile secretion.

Methods: Bile flow and output of bile constituents were monitored in pentobarbital-anesthetized rats with biliary fistulas. Normal and TR(-) rats with a genetic defect in mrp2, received bosentan intravenous injections.

Results: Bosentan bolus intravenous injections of 0.1-10mg/kg triggered a dose-dependent increase in biliary bilirubin excretion. In addition, doses (> or =10mg/kg) caused a sustained increase in canalicular bile salt-independent bile flow, combined with significant increases in the concentration and output of glutathione and of bicarbonate in bile. In rats receiving bosentan (> or =10mg/kg), both under basal conditions and under intravenous taurocholate perfusion (2micromol/min/kg), phospholipid and cholesterol secretions were profoundly inhibited and uncoupled from bile salt secretion. In TR(-) rats, the choleretic effect of bosentan was reduced to non-significant levels. The stimulation of bilirubin secretion and the uncoupling of phospholipid from bile salt secretion were absent, whereas that of cholesterol was maintained.

Conclusions: Bosentan alters canalicular bile formation in major part via mrp2-mediated mechanisms. Intermittent uncoupling of lipid from bile salt secretion may contribute to bosentan hepatic adverse reaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antihypertensive Agents / pharmacology*
  • Bile Acids and Salts / metabolism
  • Bile Canaliculi / drug effects
  • Bile Canaliculi / metabolism*
  • Bilirubin / metabolism
  • Bosentan
  • Cholesterol / metabolism
  • Endothelin Receptor Antagonists
  • Male
  • Membrane Transport Proteins*
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Phospholipids / metabolism
  • Rats
  • Rats, Mutant Strains
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Sulfonamides / pharmacology*


  • Antihypertensive Agents
  • Bile Acids and Salts
  • Endothelin Receptor Antagonists
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • Phospholipids
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Sulfonamides
  • multidrug resistance-associated protein 2
  • Cholesterol
  • Bosentan
  • Bilirubin
  • multidrug resistance-associated protein 1