Expression of Genes for Drug Transporters in the Human Female Genital Tract and Modulatory Effect of Antiretroviral Drugs
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...
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| Veröffentlicht in: | PloS one 2015-06, Vol.10 (6), p.e0131405-e0131405 |
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| creator | Hijazi, Karolin Cuppone, Anna M Smith, Kieron Stincarelli, Maria A Ekeruche-Makinde, Julia De Falco, Giulia Hold, Georgina L Shattock, Robin Kelly, Charles G Pozzi, Gianni Iannelli, Francesco |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0131405 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0131405</identifier><identifier>PMID: 26102284</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acquired immune deficiency syndrome ; Adult ; AIDS ; Anti-HIV Agents - pharmacology ; Antiretroviral agents ; Antiretroviral drugs ; Biological Transport ; Biopharmaceuticals ; Biotechnology ; CD4 antigen ; Cell Line ; Cell Line, Tumor ; Cell lines ; Cervix Uteri - cytology ; Cervix Uteri - drug effects ; Cervix Uteri - metabolism ; Clinical trials ; Comparative analysis ; Darunavir - pharmacology ; Dentistry ; Developmental stages ; Disease transmission ; DNA polymerases ; Drug delivery ; Drug delivery systems ; Drug Resistance ; Drug screening ; Drug Synergism ; Drugs ; Efflux ; Epithelial cells ; Epithelium ; Ethics ; Female ; Gene expression ; Gene Expression Regulation - drug effects ; Genes ; Genital tract ; Glycoproteins ; Highly active antiretroviral therapy ; HIV ; Human immunodeficiency virus ; Humans ; Infections ; Infectious diseases ; Kinetics ; Laboratories ; Lymphocytes ; Lymphocytes T ; Material requirements planning ; Membrane Transport Proteins - biosynthesis ; Membrane Transport Proteins - genetics ; Microbicides ; Middle Aged ; Mucosa ; Nucleoside analogs ; Nucleotide analogs ; Organ Culture Techniques ; P-Glycoprotein ; Pharmaceuticals ; Protease inhibitors ; Proteases ; Proteinase inhibitors ; Pyrimidines - pharmacology ; RNA-directed DNA polymerase ; Substrates ; Tenofovir ; Tenofovir - pharmacology ; Transport ; Vagina ; Vagina - cytology ; Vagina - drug effects ; Vagina - metabolism</subject><ispartof>PloS one, 2015-06, Vol.10 (6), p.e0131405-e0131405</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Hijazi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Hijazi et al 2015 Hijazi et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-2a59225b25afa1a5271951ae2a31ccfbbdbb788b5b7a613e042d38e21c702f2f3</citedby><cites>FETCH-LOGICAL-c692t-2a59225b25afa1a5271951ae2a31ccfbbdbb788b5b7a613e042d38e21c702f2f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477895/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477895/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26102284$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Le Grand, Roger</contributor><creatorcontrib>Hijazi, Karolin</creatorcontrib><creatorcontrib>Cuppone, Anna M</creatorcontrib><creatorcontrib>Smith, Kieron</creatorcontrib><creatorcontrib>Stincarelli, Maria A</creatorcontrib><creatorcontrib>Ekeruche-Makinde, Julia</creatorcontrib><creatorcontrib>De Falco, Giulia</creatorcontrib><creatorcontrib>Hold, Georgina L</creatorcontrib><creatorcontrib>Shattock, Robin</creatorcontrib><creatorcontrib>Kelly, Charles G</creatorcontrib><creatorcontrib>Pozzi, Gianni</creatorcontrib><creatorcontrib>Iannelli, Francesco</creatorcontrib><title>Expression of Genes for Drug Transporters in the Human Female Genital Tract and Modulatory Effect of Antiretroviral Drugs</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Acquired immune deficiency syndrome</subject><subject>Adult</subject><subject>AIDS</subject><subject>Anti-HIV Agents - pharmacology</subject><subject>Antiretroviral agents</subject><subject>Antiretroviral drugs</subject><subject>Biological Transport</subject><subject>Biopharmaceuticals</subject><subject>Biotechnology</subject><subject>CD4 antigen</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cell lines</subject><subject>Cervix Uteri - cytology</subject><subject>Cervix Uteri - drug effects</subject><subject>Cervix Uteri - metabolism</subject><subject>Clinical trials</subject><subject>Comparative analysis</subject><subject>Darunavir - pharmacology</subject><subject>Dentistry</subject><subject>Developmental stages</subject><subject>Disease transmission</subject><subject>DNA polymerases</subject><subject>Drug delivery</subject><subject>Drug delivery systems</subject><subject>Drug Resistance</subject><subject>Drug screening</subject><subject>Drug Synergism</subject><subject>Drugs</subject><subject>Efflux</subject><subject>Epithelial cells</subject><subject>Epithelium</subject><subject>Ethics</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Genes</subject><subject>Genital tract</subject><subject>Glycoproteins</subject><subject>Highly active antiretroviral therapy</subject><subject>HIV</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Kinetics</subject><subject>Laboratories</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Material requirements planning</subject><subject>Membrane Transport Proteins - biosynthesis</subject><subject>Membrane Transport Proteins - genetics</subject><subject>Microbicides</subject><subject>Middle Aged</subject><subject>Mucosa</subject><subject>Nucleoside analogs</subject><subject>Nucleotide analogs</subject><subject>Organ Culture Techniques</subject><subject>P-Glycoprotein</subject><subject>Pharmaceuticals</subject><subject>Protease inhibitors</subject><subject>Proteases</subject><subject>Proteinase inhibitors</subject><subject>Pyrimidines - pharmacology</subject><subject>RNA-directed DNA polymerase</subject><subject>Substrates</subject><subject>Tenofovir</subject><subject>Tenofovir - pharmacology</subject><subject>Transport</subject><subject>Vagina</subject><subject>Vagina - cytology</subject><subject>Vagina - drug effects</subject><subject>Vagina - metabolism</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk01v1DAQhiMEoqXwDxBEQkJw2MV24nxckFZl265UVAkKV2uSjHe9SuzFdqruv8dp02qDekA-2Bo_8449H1H0lpI5TXL6ZWt6q6Gd74zGOaEJTQl_Fh3TMmGzjJHk-cH5KHrl3JYQnhRZ9jI6YhkljBXpcbRf3u4sOqeMjo2Mz1Gji6Wx8Tfbr-NrC9rtjPVoXax07DcYX_Qd6PgMO2hx4JWHdgBrH4Nu4u-m6Vvwxu7jpZQYrEF2ob2y6K25UTbQg7Z7Hb2Q0Dp8M-4n0a-z5fXpxezy6nx1uric1VnJ_IwBLxnjFeMggQJnOS05BWSQ0LqWVdVUVV4UFa9yyGiCJGVNUiCjdU6YZDI5id7f6-5a48SYNSdoVpKMZ0E6EKt7ojGwFTurOrB7YUCJO4OxawHWq7pFwXKeFTLNioawtKqglIQkHIGmiDmhRdD6Okbrqw6bGrUPP56ITm-02oi1uRFpmudFOTzm0yhgzZ8enRedcjW2LWg0_d27KSs4Swf0wz_o078bqXUomFBamhC3HkTFIqUBYzyngZo_QYXVYKfq0GJSBfvE4fPEITAeb_0aeufE6ueP_2evfk_ZjwfsBqH1G2fa3ocOdVMwvQdra5yzKB-TTIkYJuQhG2KYEDFOSHB7d1igR6eHkUj-ApnPC1U</recordid><startdate>20150623</startdate><enddate>20150623</enddate><creator>Hijazi, Karolin</creator><creator>Cuppone, Anna M</creator><creator>Smith, Kieron</creator><creator>Stincarelli, Maria A</creator><creator>Ekeruche-Makinde, Julia</creator><creator>De Falco, Giulia</creator><creator>Hold, Georgina L</creator><creator>Shattock, Robin</creator><creator>Kelly, Charles G</creator><creator>Pozzi, Gianni</creator><creator>Iannelli, Francesco</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150623</creationdate><title>Expression of Genes for Drug Transporters in the Human Female Genital Tract and Modulatory Effect of Antiretroviral Drugs</title><author>Hijazi, Karolin ; Cuppone, Anna M ; Smith, Kieron ; Stincarelli, Maria A ; Ekeruche-Makinde, Julia ; De Falco, Giulia ; Hold, Georgina L ; Shattock, Robin ; Kelly, Charles G ; Pozzi, Gianni ; Iannelli, Francesco</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-2a59225b25afa1a5271951ae2a31ccfbbdbb788b5b7a613e042d38e21c702f2f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Acquired immune deficiency syndrome</topic><topic>Adult</topic><topic>AIDS</topic><topic>Anti-HIV Agents - pharmacology</topic><topic>Antiretroviral agents</topic><topic>Antiretroviral drugs</topic><topic>Biological Transport</topic><topic>Biopharmaceuticals</topic><topic>Biotechnology</topic><topic>CD4 antigen</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Cell lines</topic><topic>Cervix Uteri - cytology</topic><topic>Cervix Uteri - drug effects</topic><topic>Cervix Uteri - metabolism</topic><topic>Clinical trials</topic><topic>Comparative analysis</topic><topic>Darunavir - pharmacology</topic><topic>Dentistry</topic><topic>Developmental stages</topic><topic>Disease transmission</topic><topic>DNA polymerases</topic><topic>Drug delivery</topic><topic>Drug delivery systems</topic><topic>Drug Resistance</topic><topic>Drug screening</topic><topic>Drug Synergism</topic><topic>Drugs</topic><topic>Efflux</topic><topic>Epithelial cells</topic><topic>Epithelium</topic><topic>Ethics</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Genes</topic><topic>Genital tract</topic><topic>Glycoproteins</topic><topic>Highly active antiretroviral therapy</topic><topic>HIV</topic><topic>Human immunodeficiency virus</topic><topic>Humans</topic><topic>Infections</topic><topic>Infectious diseases</topic><topic>Kinetics</topic><topic>Laboratories</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Material requirements planning</topic><topic>Membrane Transport Proteins - biosynthesis</topic><topic>Membrane Transport Proteins - genetics</topic><topic>Microbicides</topic><topic>Middle Aged</topic><topic>Mucosa</topic><topic>Nucleoside analogs</topic><topic>Nucleotide analogs</topic><topic>Organ Culture Techniques</topic><topic>P-Glycoprotein</topic><topic>Pharmaceuticals</topic><topic>Protease inhibitors</topic><topic>Proteases</topic><topic>Proteinase inhibitors</topic><topic>Pyrimidines - pharmacology</topic><topic>RNA-directed DNA polymerase</topic><topic>Substrates</topic><topic>Tenofovir</topic><topic>Tenofovir - pharmacology</topic><topic>Transport</topic><topic>Vagina</topic><topic>Vagina - cytology</topic><topic>Vagina - drug effects</topic><topic>Vagina - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hijazi, Karolin</creatorcontrib><creatorcontrib>Cuppone, Anna M</creatorcontrib><creatorcontrib>Smith, Kieron</creatorcontrib><creatorcontrib>Stincarelli, Maria A</creatorcontrib><creatorcontrib>Ekeruche-Makinde, Julia</creatorcontrib><creatorcontrib>De Falco, Giulia</creatorcontrib><creatorcontrib>Hold, Georgina L</creatorcontrib><creatorcontrib>Shattock, Robin</creatorcontrib><creatorcontrib>Kelly, Charles G</creatorcontrib><creatorcontrib>Pozzi, Gianni</creatorcontrib><creatorcontrib>Iannelli, Francesco</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hijazi, Karolin</au><au>Cuppone, Anna M</au><au>Smith, Kieron</au><au>Stincarelli, Maria A</au><au>Ekeruche-Makinde, Julia</au><au>De Falco, Giulia</au><au>Hold, Georgina L</au><au>Shattock, Robin</au><au>Kelly, Charles G</au><au>Pozzi, Gianni</au><au>Iannelli, Francesco</au><au>Le Grand, Roger</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Expression of Genes for Drug Transporters in the Human Female Genital Tract and Modulatory Effect of Antiretroviral Drugs</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-06-23</date><risdate>2015</risdate><volume>10</volume><issue>6</issue><spage>e0131405</spage><epage>e0131405</epage><pages>e0131405-e0131405</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26102284</pmid><doi>10.1371/journal.pone.0131405</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-06, Vol.10 (6), p.e0131405-e0131405 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1690656225 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acquired immune deficiency syndrome Adult AIDS Anti-HIV Agents - pharmacology Antiretroviral agents Antiretroviral drugs Biological Transport Biopharmaceuticals Biotechnology CD4 antigen Cell Line Cell Line, Tumor Cell lines Cervix Uteri - cytology Cervix Uteri - drug effects Cervix Uteri - metabolism Clinical trials Comparative analysis Darunavir - pharmacology Dentistry Developmental stages Disease transmission DNA polymerases Drug delivery Drug delivery systems Drug Resistance Drug screening Drug Synergism Drugs Efflux Epithelial cells Epithelium Ethics Female Gene expression Gene Expression Regulation - drug effects Genes Genital tract Glycoproteins Highly active antiretroviral therapy HIV Human immunodeficiency virus Humans Infections Infectious diseases Kinetics Laboratories Lymphocytes Lymphocytes T Material requirements planning Membrane Transport Proteins - biosynthesis Membrane Transport Proteins - genetics Microbicides Middle Aged Mucosa Nucleoside analogs Nucleotide analogs Organ Culture Techniques P-Glycoprotein Pharmaceuticals Protease inhibitors Proteases Proteinase inhibitors Pyrimidines - pharmacology RNA-directed DNA polymerase Substrates Tenofovir Tenofovir - pharmacology Transport Vagina Vagina - cytology Vagina - drug effects Vagina - metabolism |
| title | Expression of Genes for Drug Transporters in the Human Female Genital Tract and Modulatory Effect of Antiretroviral Drugs |
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