Biliary Excretion of 17β-Estradiol 17β-d-Glucuronide Is Predominantly Mediated by cMOAT/MRP2
Biliary Excretion of 17β-Estradiol 17β-d-Glucuronide Is Predominantly Mediated by cMOAT/MRP2
复制标题
DOI：
10.1023/a:1026412915168
复制
发表时间：
2000-05
影响因子：
3.7
通讯作者：
A. Morikawa;Y. Goto;H. Suzuki;T. Hirohashi;Y. Sugiyama
中科院分区：
文献类型：
--
作者：
A. Morikawa;Y. Goto;H. Suzuki;T. Hirohashi;Y. Sugiyama
目的。17β-estradiol17β0-d-葡糖苷（E217βG）是雌二醇的一种胆汁代谢产物，其胆汁排泄的机制仍有争议。本研究的目的是研究E217βG在胆小管膜上的转运。我们用Sprague-Dawley （SD）大鼠和卫材高胆红素血症大鼠（EHBR）制备的分离管状膜泡（CMVs）检测了[3H]E217βG的摄取情况，这些大鼠的管状多特异性有机阴离子转运体/多药耐药相关蛋白2 （cMOAT/MRP2）功能存在遗传缺陷。同时，对静脉给药[3H] e217 β g的胆内排泄进行了检测。在SD大鼠而非EHBR制备的cmv中，观察到标记的atp依赖性摄取[3H]E217βG。此外，E217βG竞争性地抑制atp依赖性摄取[3H]2,4-二硝基苯- s -谷胱甘肽（DNP-SG）。此外，维拉帕米（100 μM）和PSC-833 （5 μM）对[3H]E217βG的摄取无明显抑制作用。在体内，静脉给药[3H]E217βG严重损害了hbr大鼠的胆道排泄，而给药10 μmol/kg的无标记de217 β g可减少SD大鼠[3H]E217βG的胆道排泄，而PSC-833 （3 mg/kg）则无此作用。E217βG在胆管膜上的转运主要由cMOAT/MRP2介导。
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 vivobiliary 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.