Expression of Genes for Drug Transporters in the Human Female Genital Tract and Modulatory Effect of Antiretroviral Drugs.
Expression of Genes for Drug Transporters in the Human Female Genital Tract and Modulatory Effect of Antiretroviral Drugs.
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DOI：
10.1371/journal.pone.0131405
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Iannelli F
中科院分区：
文献类型：
--
作者：
Hijazi K;Cuppone AM;Smith K;Stincarelli MA;Ekeruche-Makinde J;De Falco G;Hold GL;Shattock R;Kelly CG;Pozzi G;Iannelli F
基于抗逆转录病毒的杀微生物剂是预防HIV-1传播的战略之一。将抗逆转录病毒药物以保护性浓度递送到上皮下CD 4 + T细胞可能是由宫颈阴道上皮中表达的药物转运蛋白决定的。为了确定药物转运蛋白在局部应用的基于抗逆转录病毒的杀微生物剂的粘膜处置中的作用，这些必须在基于上皮细胞系的生物制药测定中进行测试，以考虑相关药物转运蛋白的作用。我们的特点是基因表达的流入和流出药物转运蛋白在一组宫颈阴道细胞系，并比较这在宫颈阴道组织中的表达。我们还研究了达匹韦林，地瑞那韦和替诺福韦，目前在杀微生物剂开发的高级阶段，对药物转运蛋白在细胞系中的表达的影响。外排ABC转运蛋白在宫颈组织中的表达在HeLa、Ect 1/E6 E7和End 1/E6 E7细胞系中表现最好。OCT和ENT内流转运蛋白在宫颈细胞中的表达与Hela细胞中的表达相匹配，而SLCO内流转运蛋白在阴道细胞中的表达在VK 2/E6 E7细胞系中最好地反映。用地瑞那韦和达匹韦林刺激可上调MRP转运蛋白，包括参与替诺福韦转运的MRP 5。达匹韦林还显著下调宫颈细胞系中替诺福韦底物MRP 4。地瑞那韦和达匹韦林治疗对BCRP、MRP 2和P-糖蛋白的表达无显著影响，这些蛋白与不同ARV药物的外排有关。在大多数细胞系中，地瑞那韦强烈诱导参与核苷酸/核苷类似物逆转录酶抑制剂细胞摄取的CNT 3和参与蛋白酶抑制剂细胞摄取的SLCO药物转运蛋白的表达。这项研究提供了深入了解宫颈阴道细胞系的适用性评估抗逆转录病毒药物的运输动力学研究。地瑞那韦和达匹韦林对参与替诺福韦转运的药物转运蛋白表达的调节作用表明，将这些药物组合以改善单个药物在靶组织中的保留的可能性。
Anti-retroviral (ARV) –based microbicides are one of the strategies pursued to prevent HIV-1 transmission. Delivery of ARV drugs to subepithelial CD4+ T cells at concentrations for protection is likely determined by drug transporters expressed in the cervicovaginal epithelium. To define the role of drug transporters in mucosal disposition of topically applied ARV-based microbicides, these must be tested in epithelial cell line-based biopharmaceutical assays factoring the effect of relevant drug transporters. We have characterised gene expression of influx and efflux drug transporters in a panel of cervicovaginal cell lines and compared this to expression in cervicovaginal tissue. We also investigated the effect of dapivirine, darunavir and tenofovir, currently at advanced stages of microbicides development, on expression of drug transporters in cell lines. Expression of efflux ABC transporters in cervical tissue was best represented in HeLa, Ect1/E6E7 and End1/E6E7 cell lines. Expression of influx OCT and ENT transporters in ectocervix matched expression in Hela while expression of influx SLCO transporters in vagina was best reflected in VK2/E6E7 cell line. Stimulation with darunavir and dapivirine upregulated MRP transporters, including MRP5 involved in transport of tenofovir. Dapivirine also significantly downregulated tenofovir substrate MRP4 in cervical cell lines. Treatment with darunavir and dapivirine showed no significant effect on expression of BCRP, MRP2 and P-glycoprotein implicated in efflux of different ARV drugs. Darunavir strongly induced expression in most cell lines of CNT3 involved in cell uptake of nucleotide/nucleoside analogue reverse transcriptase inhibitors and SLCO drug transporters involved in cell uptake of protease inhibitors. This study provides insight into the suitability of cervicovaginal cell lines for assessment of ARV drugs in transport kinetics studies. The modulatory effect of darunavir and dapivirine on expression of drug transporters involved in transport of tenofovir points to the possibility of combining these drugs to improve retention of individual drugs at target tissues.
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影响因子：
2
作者：
Fujimoto H;Higuchi M;Watanabe H;Koh Y;Ghosh AK;Mitsuya H;Tanoue N;Hamada A;Saito H
通讯作者：
Saito H
影响因子：
32.4
作者：
Hladik, Florian;Sakchalathorn, Polachai;Ballweber, Lamar;Lentz, Gretchen;Fialkow, Michael;Eschenbach, David;McElrath, M. Juliana
通讯作者：
McElrath, M. Juliana
影响因子：
3.7
作者：
Gunawardana M;Mullen M;Moss JA;Pyles RB;Nusbaum RJ;Patel J;Vincent KL;Wang C;Guo C;Yuan YC;Warden CD;Baum MM
通讯作者：
Baum MM
影响因子：
1.8
作者：
Annaert, P.;Ye, Z. W.;Augustijns, P.
通讯作者：
Augustijns, P.
影响因子：
4.9
作者：
Grammen, Carolien;Baes, Myriam;Brouwers, Joachim
通讯作者：
Brouwers, Joachim