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Biliary excretion of 17beta-estradiol 17beta-D-glucuronide is predominantly mediated by cMOAT/MRP2
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan.
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.