{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T02:36:56Z","timestamp":1773283016378,"version":"3.50.1"},"reference-count":31,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2016,3,24]],"date-time":"2016-03-24T00:00:00Z","timestamp":1458777600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81271884"],"award-info":[{"award-number":["81271884"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background &amp; Aims<\/jats:title><jats:p>Multidrug resistance protein 4 (<jats:styled-content style=\"fixed-case\">MRP<\/jats:styled-content>4) has been associated with nucleos(t)ide analogue (<jats:styled-content style=\"fixed-case\">NA<\/jats:styled-content>) antiretroviral therapy failure, though is unclear if<jats:styled-content style=\"fixed-case\">MRP<\/jats:styled-content>4 is also correlated with the failure of anti\u2010hepatitis B virus (<jats:styled-content style=\"fixed-case\">HBV<\/jats:styled-content>) therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Multidrug resistance protein 4 expression in human peripheral blood mononuclear cells (<jats:styled-content style=\"fixed-case\">PBMC<\/jats:styled-content>s), liver tissues and human hepatoma cell lines was detected by real\u2010time polymerase chain reaction (<jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content>), western blotting and immunohistochemistry assays. Supernatant and intracellular<jats:styled-content style=\"fixed-case\">HBV DNA<\/jats:styled-content>levels of<jats:styled-content style=\"fixed-case\">MRP<\/jats:styled-content>4\u2010overexpressing or silenced HepG2.4D14 (wild\u2010type) and HepG2.A64 (entecavir\u2010resistant mutant) cells were measured by quantitative<jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content>.<jats:styled-content style=\"fixed-case\">NA<\/jats:styled-content>concentrations and<jats:styled-content style=\"fixed-case\">HBV<\/jats:styled-content>mutational analysis were assessed by liquid chromatography\/mass spectrometry assays and<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content>sequencing. Multivariate analysis was used to assess predictive factors for treatment failure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>High expression of<jats:styled-content style=\"fixed-case\">MRP<\/jats:styled-content>4 was found in hepatoma cell lines and<jats:styled-content style=\"fixed-case\">PBMC<\/jats:styled-content>s, and up\u2010 or down\u2010regulation of<jats:styled-content style=\"fixed-case\">MRP<\/jats:styled-content>4 expression altered the susceptibility of cells to<jats:styled-content style=\"fixed-case\">NA<\/jats:styled-content>s.<jats:styled-content style=\"fixed-case\">MRP<\/jats:styled-content>inhibitors increased<jats:styled-content style=\"fixed-case\">NA<\/jats:styled-content>intracellular accumulation and decreased extracellular levels. Moreover,<jats:styled-content style=\"fixed-case\">MRP<\/jats:styled-content>4 expression in<jats:styled-content style=\"fixed-case\">PBMC<\/jats:styled-content>s was correlated with that in paired liver tissues. Furthermore, multivariate analysis showed<jats:italic><jats:styled-content style=\"fixed-case\">MRP<\/jats:styled-content>4<\/jats:italic><jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>expression to be an independent predictor of<jats:styled-content style=\"fixed-case\">NA<\/jats:styled-content>treatment failure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Multidrug resistance protein 4 is a critical protein associated with the antiviral efficacy of<jats:styled-content style=\"fixed-case\">NA<\/jats:styled-content>s, and combination therapy of<jats:styled-content style=\"fixed-case\">NA<\/jats:styled-content>and<jats:styled-content style=\"fixed-case\">MRP<\/jats:styled-content>inhibitors could reduce the dosage for long\u2010term<jats:styled-content style=\"fixed-case\">NA<\/jats:styled-content>use. This is the first report to demonstrate that<jats:styled-content style=\"fixed-case\">MRP<\/jats:styled-content>4 expression is an important factor predicting treatment failure in chronic hepatitis B patients and will provide a potential therapeutic target against<jats:styled-content style=\"fixed-case\">HBV<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.13104","type":"journal-article","created":{"date-parts":[[2016,3,2]],"date-time":"2016-03-02T08:38:57Z","timestamp":1456907937000},"page":"1284-1294","source":"Crossref","is-referenced-by-count":14,"title":["Multidrug resistance protein 4 is a critical protein associated with the antiviral efficacy of nucleos(t)ide analogues"],"prefix":"10.1111","volume":"36","author":[{"given":"Wei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 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