Zhou Tian, Hu Minlu, Pearlman Andrew, Rohan Lisa C
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States; Magee-Womens Research Institute, Pittsburgh, PA, United States.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States; Magee-Womens Research Institute, Pittsburgh, PA, United States.
Biochem Pharmacol. 2016 Sep 15;116:162-75. doi: 10.1016/j.bcp.2016.07.009. Epub 2016 Jul 21.
P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance protein 4 (MRP4) are three efflux transporters that play key roles in the pharmacokinetics of antiretroviral drugs used in the pre-exposure prophylaxis of HIV sexual transmission. In this study, we investigated the expression, regulation, and function of these transporters in cervicovaginal tissues of a mouse model. Expression and regulation were examined using real-time RT-PCR and immunohistochemical staining, in the mouse tissues harvested at estrus and diestrus stages under natural cycling or after hormone synchronization. The three transporters were expressed at moderate to high levels compared to the liver. Transporter proteins were localized in various cell types in different tissue segments. Estrous cycle and exogenous hormone treatment affected transporter mRNA and protein expression, in a tissue- and transporter-dependent manner. Depo-Provera-synchronized mice were dosed vaginally or intraperitoneally with (3)H-TFV, with or without MK571 co-administration, to delineate the function of cervicovaginal Mrp4. Co-administration of MK571 significantly increased the concentration of vaginally-administered TFV in endocervix and vagina. MK571 increased the concentration of intraperitoneally-administered TFV in the cervicovaginal lavage and vagina by several fold. Overall, P-gp, Bcrp, and Mrp4 were positively expressed in mouse cervicovaginal tissues, and their expression can be regulated by the estrous cycle or by exogenous hormones. In this model, the Mrp4 transporter impacted TFV distribution in cervicovaginal tissues.
P-糖蛋白（P-gp）、乳腺癌耐药蛋白（BCRP）和多药耐药蛋白4（MRP4）是三种外排转运蛋白，它们在用于预防HIV性传播的抗逆转录病毒药物的药代动力学中起关键作用。在本研究中，我们调查了这些转运蛋白在小鼠模型宫颈阴道组织中的表达、调节及其功能。使用实时RT-PCR和免疫组织化学染色，在自然周期或激素同步后处于发情期和动情后期的小鼠组织中检测表达和调节情况。与肝脏相比，这三种转运蛋白以中度至高水平表达。转运蛋白定位于不同组织段的各种细胞类型中。发情周期和外源激素处理以组织和转运蛋白依赖性方式影响转运蛋白mRNA和蛋白质表达。给醋酸甲羟孕酮同步化的小鼠经阴道或腹腔注射³H-替诺福韦（TFV），同时给予或不给予MK571，以描述宫颈阴道Mrp4的功能。MK571的共同给药显著增加了宫颈内和阴道中经阴道给药的TFV的浓度。MK571使腹腔注射的TFV在宫颈阴道灌洗液和阴道中的浓度增加了几倍。总体而言，P-gp、Bcrp和Mrp4在小鼠宫颈阴道组织中呈阳性表达，其表达可受发情周期或外源激素调节。在该模型中，Mrp4转运蛋白影响TFV在宫颈阴道组织中的分布。
