Biliary excretion of 17beta-estradiol 17beta-D-glucuronide is predominantly mediated by cMOAT/MRP2

Pharm Res. 2000 May;17(5):546-52. doi: 10.1023/a:1026412915168.


Purpose: The mechanism for the biliary excretion of 17beta-estradiol 17beta-D-glucuronide (E(2)17betaG), a cholestatic metabolite of estradiol, is still controversial. The purpose of the present study is to examine the transport of E(2)17betaG across the bile canalicular membrane.

Methods: We examined the uptake of [3H]E(2)17betaG by isolated canalicular membrane vesicles (CMVs) prepared from Sprague-Dawley (SD) rats and Eisai Hyperbilirubinemic rats (EHBR) whose canalicular multispecific organic anion transporter/multidrug resistance associated protein 2 (cMOAT/MRP2) function is hereditarily defective. Also, in vivo biliary excretion of intravenously administered [3H]E(2)17betaG was examined.

Results: In CMVs prepared from SD rats, but not from EHBR, a marked ATP-dependent uptake of [3H]E(2)17betaG was observed. Moreover, E(2)17betaG competitively inhibited the ATP-dependent uptake of [3H]2,4-dinitrophenyl-S-glutathione (DNP-SG). In addition, no significant inhibitory effect of verapamil (100 microM) and PSC-833 (5 microM) on the uptake of [3H]E(2)17betaG was observed. In vivo, the biliary excretion of intravenously administered [3H]E(2)17betaG was severely impaired in EHBR while the biliary excretion of [3H]E(2)17betaG in SD rats was reduced by administering a cholestatic dose (10 micromol/kg) unlabeled E(2)17betaG, but not by PSC-833 (3 mg/kg).

Conclusions: The transport of E(2)17betaG across the bile canalicular membrane is predominantly mediated by cMOAT/MRP2.

MeSH terms

  • Animals
  • Anion Transport Proteins
  • Bile / metabolism*
  • Bile Canaliculi / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Membrane / metabolism
  • Chromatography, Thin Layer
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacokinetics
  • Glutathione / analogs & derivatives
  • Glutathione / metabolism
  • Hyperbilirubinemia / genetics
  • Hyperbilirubinemia / metabolism
  • Injections, Intravenous
  • Male
  • Rats
  • Rats, Sprague-Dawley


  • Anion Transport Proteins
  • Carrier Proteins
  • estradiol-17 beta-glucuronide
  • S-(2,4-dinitrophenyl)glutathione
  • Estradiol
  • Glutathione