title: Expression, regulation, and function of drug transporters in cervicovaginal tissues of a mouse model used for microbicide testing.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States; Magee-Womens Research Institute, Pittsburgh, PA, United States.
authors.forename: Tian
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States; Magee-Womens Research Institute, Pittsburgh, PA, United States.
authors.forename: Minlu
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States; Magee-Womens Research Institute, Pittsburgh, PA, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Pearlman
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States; Magee-Womens Research Institute, Pittsburgh, PA, United States. Electronic address: lrohan@mwri.magee.edu.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Rohan
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D002460:Cell Line; D002584:Cervix Uteri / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004031:Diestrus / Q000187:drug effects / Q000378:metabolism; D004971:Estrus / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D011817:Rabbits; D012102:Reproductive Control Agents / Q000494:pharmacology; D013045:Species Specificity; D000068698:Tenofovir / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution / Q000187:drug effects; D014621:Vagina / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014622:Vaginal Creams, Foams, and Jellies / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D019380:Anti-HIV Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; D012102:Reproductive Control Agents; D000068698:Tenofovir; D014622:Vaginal Creams, Foams, and Jellies; C489540:Abcc4 protein, mouse; C501412:Abcg2 protein, mouse; C059141:verlukast; C507084:Abcb1b protein, mouse
keywords: Cervix; HIV prevention; Microbicide; Tenofovir; Transporter; Vagina