Sertraline Alters Multidrug Resistance Phosphoglycoprotein Activity in the Mouse Placenta and Fetal Blood-Brain Barrier
Sertraline Alters Multidrug Resistance Phosphoglycoprotein Activity in the Mouse Placenta and Fetal Blood-Brain Barrier
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DOI：
10.1177/1933719111424438
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发表时间：
2012-04-01
影响因子：
2.9
通讯作者：
Matthews, Stephen G.
中科院分区：
文献类型：
--
作者：
Bhuiyan, Manzerul;Petropoulos, Sophie;Matthews, Stephen G.
磷酸糖蛋白（P-gp）在胎盘合体滋养层中高表达，可防止异生物质进入胎儿。在肿瘤细胞中，P-gp 介导的底物流出受到选择性血清素再摄取抑制剂 (SSRI) 的抑制。然而，关于 SSRIs 对胎盘或胎儿组织中 P-gp 功能的影响尚不清楚。我们假设 SSRI 舍曲林会减少胎盘和胎儿血脑屏障 (BBB) 处 P-gp 介导的药物流出，增加 P-gp 底物从母亲到胎儿和胎儿大脑的转移。与我们的假设相反，这项研究提出了新的发现，即舍曲林（暴露 4 小时）增加胎盘 P-gp 介导的外排 (P < .001)，导致药物向胎儿的转移减少。同时，舍曲林减少胎儿 (P < .001) 和母体 (P < .05) BBB P-gp 介导的外流，导致药物从循环系统转移到胎儿和母体大脑中。这表明舍曲林对 P-gp 的调节具有组织特异性。这些发现对于妊娠期间母亲药物治疗期间的胎儿保护具有重要的临床意义。
Phosphoglycoprotein (P-gp) is highly expressed in the placental syncytiotrophoblast and prevents xenobiotics from entering the fetus. In tumor cells, P-gp-mediated substrate efflux is inhibited by selective serotonin reuptake inhibitors (SSRIs). However, nothing is known regarding the effects of SSRIs on P-gp function in the placenta or fetal tissues. We hypothesized that the SSRI sertraline would decrease P-gp-mediated drug efflux at the placenta and fetal blood-brain barrier (BBB)-increasing P-gp substrate transfer from the mother to the fetus and fetal brain. In contrast to our hypothesis, this study presents the novel findings that sertraline (4 hours exposure) increases placental P-gp-mediated efflux (P < .001), resulting in decreased drug transfer to the fetus. Meanwhile, sertraline decreases fetal (P < .001) and maternal (P < .05) BBB P-gp-mediated efflux, resulting in increased drug transfer into the fetal and maternal brain from the circulation. This suggests that P-gp regulation by sertraline is tissue specific. These findings have important clinical implications with respect to fetal protection during maternal drug therapy in pregnancy.