Organic anion transporter 4-mediated transport of olmesartan at basal plasma membrane of human placental barrier
Organic anion transporter 4-mediated transport of olmesartan at basal plasma membrane of human placental barrier
复制标题
有机阴离子转运蛋白 4 介导的奥美沙坦在人胎盘屏障基底质膜上的转运
DOI：
10.1002/jps.24434
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Nakashima E.
中科院分区：
文献类型：
--
作者：
Noguchi S;Nishimura T;Fujibayashi A;Maruyama T;Tomi M;Nakashima E.
奥美沙坦是一种血管紧张素II受体1型拮抗剂，其调节胎儿转移的机制是危及生命的不良胎儿效应的重要潜在决定因素。本研究的目的是研究奥美沙坦通过形成胎盘屏障的人合体滋养层基底质膜（BM）的转运机制。硫酸脱氢表雄酮（DHEAS）、雌酮3-硫酸酯和溴磺酞可有效抑制人胎盘BM囊泡对奥美沙坦的摄取，这些物质均为位于合体滋养层BM的有机阴离子转运蛋白（OAT）4的典型底物，在无氯化物的情况下可增加奥美沙坦的摄取。在四环素诱导型OAT 4表达细胞中，四环素处理增加了[3 H]奥美沙坦摄取。奥美沙坦通过OAT 4的摄取呈浓度依赖性，aKm为20 μM，在无氯化物存在下增加。还观察到[3 H]奥美沙坦通过OAT 4流出，并被细胞外氯化物和DHEAS反式刺激。因此，OAT 4介导奥美沙坦的双向转运，并似乎调节奥美沙坦在合体滋养层BM的胎儿转移。奥美沙坦通过OAT 4从合体滋养层流出转运至胎儿循环可能在存在内向生理氯化物梯度和细胞外DHEAS的情况下得到促进。© 2015 Wiley Periodicals，Inc.和American Pharmacologist Association J Pharm Sci 104：3128-3135，2015
Mechanisms regulating fetal transfer of olmesartan, an angiotensin-II receptor type 1 antagonist, are important as potential determinants of life-threatening adverse fetal effects. The purpose of this study was to examine the olmesartan transport mechanism through the basal plasma membrane (BM) of human syncytiotrophoblasts forming the placental barrier. Uptake of olmesartan by human placental BM vesicles was potently inhibited by dehydroepiandrosterone sulfate (DHEAS), estrone 3-sulfate, and bromosulfophthalein, which are all typical substrates of organic anion transporter (OAT) 4 localized at the BM of syncytiotrophoblasts, and was increased in the absence of chloride. In tetracycline-inducible OAT4-expressing cells, [3H]olmesartan uptake was increased by tetracycline treatment. Olmesartan uptake via OAT4 was concentration dependent with aKmof 20 μM, and was increased in the absence of chloride. [3H]Olmesartan efflux via OAT4 was also observed and wastrans-stimulated by extracellular chloride and DHEAS. Thus, OAT4 mediates bidirectional transport of olmesartan and appears to regulate fetal transfer of olmesartan at the BM of syncytiotrophoblasts. Efflux transport of olmesartan via OAT4 from syncytiotrophoblasts to the fetal circulation might be facilitated in the presence of an inwardly directed physiological chloride gradient and extracellular DHEAS. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3128–3135, 2015