Division of Research, Department of Obstetrics and Gynecology, University of Kansas School of Medicine, Kansas City, KS, 66208, USA.
Division of Research, Department of Obstetrics and Gynecology, University of Kansas School of Medicine, Kansas City, KS, 66208, USA; Center for Perinatal Research, University of Kansas School of Medicine, Kansas City, KS, 66208, USA.
Placenta. 2018 Sep;69:32-39. doi: 10.1016/j.placenta.2018.07.005. Epub 2018 Jul 10.
The objectives of this study were to determine how HCV infection affects placental drug transporters, and to determine the role of drug transporters on the cellular accumulation of direct-acting antiviral drugs in human trophoblasts.
Eighty-four ABC and SLC transporter genes were first screened in normal and HCV infected pregnant women using PCR profiler array. The changes in expression were confirmed by qPCR and Western blot. The impact of selected drug transporters on the cellular accumulation of radiolabeled antiviral drugs sofosbuvir, entecavir, and tenofovir was measured in primary human trophoblasts (PHT) and BeWo b30 cells in the presence or absence of transporter-specific inhibitors. PHT were then treated with CL097, ssRNA40, and imquimod to determine the impact of Toll-like receptor (TLR) 7/8 activation on drug transporter expression.
The expression of the ABC efflux transporters ABCB1/P-gp and ABCG2/BCRP was increased in placenta of women with HCV, while the nucleoside transporters SLC29A1/ENT1 and SLC29A2/ENT2 remained unchanged. The accumulation of sofosbuvir and tenofovir was unaffected by inhibition of these transporters in trophoblast cells. Entecavir accumulation was decreased by the inhibition of ENT2. P-gp and BCRP inhibition enhanced entecavir accumulation in BeWo b30, but not PHT. Overall, there was little effect of TLR7/8 activation on these drug transporters, and the accumulation of entecavir in PHT.
The data suggest that expression of placental drug transporters and selection of antiviral drug may impact fetal drug exposure in pregnancies complicated by HCV infections.
本研究旨在确定 HCV 感染如何影响胎盘药物转运体，并确定药物转运体在人滋养细胞中直接作用抗病毒药物细胞内积累中的作用。
首先使用 PCR 谱阵列在正常和 HCV 感染的孕妇中筛选 84 种 ABC 和 SLC 转运体基因。通过 qPCR 和 Western blot 验证表达变化。在存在或不存在转运体特异性抑制剂的情况下，在原代人滋养细胞（PHT）和 BeWo b30 细胞中测量选定药物转运体对放射性标记抗病毒药物索非布韦、恩替卡韦和替诺福韦的细胞内积累的影响。然后用 CL097、ssRNA40 和咪喹莫特处理 PHT，以确定 Toll 样受体（TLR）7/8 激活对药物转运体表达的影响。
在 HCV 感染的妇女胎盘组织中，ABC 外排转运体 ABCB1/P-gp 和 ABCG2/BCRP 的表达增加，而核苷转运体 SLC29A1/ENT1 和 SLC29A2/ENT2 保持不变。索非布韦和替诺福韦的积累不受滋养细胞中这些转运体的抑制影响。ENT2 的抑制使恩替卡韦的积累减少。P-gp 和 BCRP 抑制增强了 BeWo b30 中恩替卡韦的积累，但在 PHT 中没有。总体而言，TLR7/8 激活对这些药物转运体和 PHT 中恩替卡韦的积累影响不大。
数据表明，胎盘药物转运体的表达和抗病毒药物的选择可能会影响 HCV 感染合并妊娠中胎儿的药物暴露。
