Multiple SLC and ABC Transporters Contribute to the Placental Transfer of Entecavir
Multiple SLC and ABC Transporters Contribute to the Placental Transfer of Entecavir
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DOI：
10.1124/dmd.116.073304
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发表时间：
2017-03
影响因子：
3.9
通讯作者：
Zhiyuan Ma;Xi Yang;Ting Jiang;Mengru Bai;Cai-hong Zheng;S. Zeng;Dong-li Sun;Huidi Jiang
中科院分区：
文献类型：
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作者：
Zhiyuan Ma;Xi Yang;Ting Jiang;Mengru Bai;Cai-hong Zheng;S. Zeng;Dong-li Sun;Huidi Jiang
恩替卡韦（Entecavir，ETV）是一种抗B型肝炎病毒的核苷类似物，被推荐为治疗慢性B型肝炎的一线抗病毒药物。然而，关于在怀孕期间使用ETV的信息很少。为了更好地了解ETV在孕妇中的安全性，我们的目的是证明ETV是否可以透过胎盘屏障及其潜在机制。本研究表明，少量ETV可透过胎盘。在存在100 µM腺苷、胞苷和无Na+培养基的情况下，活化或非活化BeWo细胞（用或不用毛喉素处理）中的ETV蓄积急剧减少，表明核苷转运蛋白可能介导ETV的摄取。此外，ETV被证明是底物的浓缩核苷转运蛋白（CNT）2和CNT 3，有机阳离子转运蛋白（OCT）3，和乳腺癌耐药蛋白（BCRP）使用转染细胞表达各自的转运蛋白。ETV在原代人滋养层细胞中摄取的抑制进一步证实了平衡型核苷转运体（ENT）1/2、CNT 2/3、OCT 3和有机阳离子/肉毒碱转运体（OCTN）2可能参与了ETV在人胎盘中的转运。因此，ETV从母体循环到滋养层细胞的摄取可能由CNT 2/3、ENT 1/2和OCTN 2转运，而ETV从滋养层细胞到胎儿循环的流出由OCT 3介导，从滋养层细胞到母体循环的流出可能由BCRP、多药耐药相关蛋白2和P-糖蛋白介导。本研究所获得的信息可能为ETV在妊娠期的应用提供依据。
Entecavir (ETV), a nucleoside analog with high efficacy against hepatitis B virus, is recommended as a first-line antiviral drug for the treatment of chronic hepatitis B. However, scant information is available on the use of ETV in pregnancy. To better understand the safety of ETV in pregnant women, we aimed to demonstrate whether ETV could permeate placental barrier and the underlying mechanism. Our study showed that small amount of ETV could permeate across placenta in mice. ETV accumulation in activated or nonactivated BeWo cells (treated with or without forskolin) was sharply reduced in the presence of 100 µM of adenosine, cytidine, and in Na+ free medium, indicating that nucleoside transporters possibly mediate the uptake of ETV. Furthermore, ETV was proved to be a substrate of concentrative nucleoside transporter (CNT) 2 and CNT3, of organic cation transporter (OCT) 3, and of breast cancer resistance protein (BCRP) using transfected cells expressing respective transporters. The inhibition of ETV uptake in primary human trophoblast cells further confirmed that equilibrative nucleoside transporter (ENT) 1/2, CNT2/3, OCT3, and organic cation/carnitine transporter (OCTN) 2 might be involved in ETV transfer in human placenta. Therefore, ETV uptake from maternal circulation to trophoblast cells was possibly transported by CNT2/3, ENT1/2, and OCTN2, whereas ETV efflux from trophoblast cells to fetal circulation was mediated by OCT3, and efflux from trophoblast cells to maternal circulation might be mediated by BCRP, multidrug resistance-associated protein 2, and P-glycoprotein. The information obtained in the present study may provide a basis for the use of ETV in pregnancy.