Biliary Excretion of 17β-Estradiol 17β-d-Glucuronide Is Predominantly Mediated by cMOAT/MRP2

Purpose. The mechanism for the biliary excretion of 17β-estradiol17β0-d-glucuronide (E217βG), a cholestatic metabolite of estradiol, isstill controversial. The purpose of the present study is to examine thetransport of E217βG across the bile canalicular membrane. Methods. We examined the uptake of [3H]E217βG by isolatedcanalicular membrane vesicles (CMVs) prepared from Sprague-Dawley (SD)rats and Eisai Hyperbilirubinemic rats (EHBR) whose canalicularmultispecific organic anion transporter/multidrug resistance associatedprotein 2 (cMOAT/MRP2) function is hereditarily defective. Also,in vivo biliary excretion of intravenously administered [3H]E217βGwas examined. Results. In CMVs prepared from SD rats, but not from EHBR, amarked ATP-dependent uptake of [3H]E217βG was observed.Moreover, E217βG competitively inhibited the ATP-dependent uptake of[3H]2,4-dinitrophenyl-S-glutathione (DNP-SG). In addition, nosignificant inhibitory effect of verapamil (100 μM) and PSC-833 (5 μM) onthe uptake of [3H]E217βG was observed. In vivo, the biliary excretionof intravenously administered [3H]E217βG was severely impaired inEHBR while the biliary excretion of [3H]E217βG in SD rats wasreduced by administering a cholestatic dose (10 μmol/kg) unlabeledE217βG, but not by PSC-833 (3 mg/kg). Conclusions. The transport of E217βG across the bile canalicularmembrane is predominantly mediated by cMOAT/MRP2.