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

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.