{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T03:24:05Z","timestamp":1789788245281,"version":"4.0.1"},"reference-count":45,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2017,4,1]],"date-time":"2017-04-01T00:00:00Z","timestamp":1491004800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100004704","name":"National Research Council of Thailand","doi-asserted-by":"publisher","award":["172138"],"award-info":[{"award-number":["172138"]}],"id":[{"id":"10.13039\/501100004704","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2017,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Tenofovir disoproxil fumarate (TDF), a nucleotide reverse transcriptase inhibitor, after conversion to tenofovir (TFV), is mainly eliminated by glomerular filtration and active tubular secretion. The major adverse effect of tenofovir is nephrotoxicity; however, the exact mechanism remains poorly understood. In this study, the ATP-binding cassette subfamily C member 11 (ABCC11; multidrug resistance protein 8 [MRP8]) transporter, which is abundant in proximal tubular cells, was demonstrated to act as an efflux transporter of tenofovir. Real-time PCR (RT-PCR) and indirect immunofluorescence assays were used to determine MRP8 overexpression in a continuous cell line. Tenofovir accumulations were assessed by cytotoxicity, cellular transport, and vesicular uptake assays. Substrate specificity was confirmed using MK-571, an MRP-specific inhibitor, and methotrexate, which served as a known substrate. Intracellular and intravesicular concentrations of tenofovir were determined by liquid chromatography-tandem mass spectrometry (LC-MS\/MS). The 50% cytotoxic concentration (CC\n            <jats:sub>50<\/jats:sub>\n            ) of TDF in MRP8-overexpressing cells was 4.78 times higher than that of parental cells. Transport assays also showed that the intracellular accumulation of tenofovir in MRP8-overexpressing cells was 55 times lower than that in parental cells and was partly reversed by MK-571. Similarly, an \u201cinside-out\u201d vesicular uptake assay, using Sf9 inverted membrane vesicles to allow measuring of accumulation of the substrates into the vesicles, demonstrated a higher intravesicular concentration of tenofovir in MRP8-overexpressing vesicles than in Sf9 insect control vesicles. These effects were effectively reversed by increasing concentrations of the specific inhibitor MK-571. In conclusion, tenofovir is a new substrate of the MRP8 transporter. An alteration in the activity of this efflux pump may increase the intracellular accumulation of tenofovir in proximal renal tubular cells.\n          <\/jats:p>","DOI":"10.1128\/aac.01725-16","type":"journal-article","created":{"date-parts":[[2017,2,7]],"date-time":"2017-02-07T01:50:11Z","timestamp":1486432211000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["Tenofovir Disoproxil Fumarate Is a New Substrate of ATP-Binding Cassette Subfamily C Member 11"],"prefix":"10.1128","volume":"61","author":[{"given":"Wisith","family":"Tun-Yhong","sequence":"first","affiliation":[{"name":"Pharmacy Program in Biopharmaceutical Sciences, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chatchai","family":"Chinpaisal","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perayot","family":"Pamonsinlapatham","sequence":"additional","affiliation":[{"name":"Department of Health and Related Informatics, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sindchai","family":"Kaewkitichai","sequence":"additional","affiliation":[{"name":"Pharmacy Program in Biopharmaceutical Sciences, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/354908"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/378068"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.3.716-723.2002"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-012-2269-7"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-014-1712-z"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.104.007138"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF03401856"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(01)00572-8"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.5865"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M005463200"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M104833200"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V133595"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00251-06"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2009.05.029"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2013.05.008"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.34.877"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2006.12.034"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1086\/428840"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02797469"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1016256325921"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2121-14-55"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2006.01.009"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2005.09.001"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1053\/hupa.2002.124012"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1517\/14740338.6.2.155"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2011.01.022"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0b013e31815e7478"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1086\/508546"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0147724"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04930-14"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir215"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis772"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1086\/598507"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1080\/00498250701883514"},{"key":"e_1_3_2_36_2","first-page":"237","article-title":"Chemotherapy-induced resistance by ATP-binding cassette transporter genes","volume":"1775","author":"Gillet JP","year":"2007","unstructured":"Gillet JP EfferthTRemacleJ. 2007. 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