Bosentan, a dual endothelin receptor antagonist, activates the pregnane X nuclear receptor

Eur J Pharmacol. 2002 Aug 23;450(2):115-21. doi: 10.1016/s0014-2999(02)02075-7.


Recent clinical studies have shown that bosentan, a dual endothelin receptor antagonist, decreases the exposure to various substrates of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. The aim of the study was to investigate the effect of bosentan, its metabolites and glibenclamide on the activity of the pregnane X receptor, a nuclear receptor that regulates the transcription of CYP3A4. CV-1 monkey kidney cells were transiently transfected with a luciferase reporter plasmid containing three copies of the ER6 response element of CYP3A4 and the human or mouse pregnane X receptor. Subsequently, the cells were incubated with the test compounds and the activity of luciferase determined. Bosentan activated the human pregnane X receptor with an EC(50) of 19.9 microM, whereas rifampicin had an EC(50) value of 1.9 microM. Ro 47-8634 (4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-hydroxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzenesulfonamide), a metabolite of bosentan, and glibenclamide also activated the pregnane X receptor. The findings provide a molecular mechanism for the interactions observed between bosentan and several drugs.

MeSH terms

  • Animals
  • Bosentan
  • Cell Line
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism
  • Dose-Response Relationship, Drug
  • Endothelin Receptor Antagonists*
  • Glyburide / pharmacology
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Mice
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Steroid / agonists*
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacology*


  • Endothelin Receptor Antagonists
  • Hypoglycemic Agents
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Sulfonamides
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Bosentan
  • Glyburide