title: Multidrug resistance protein 4 is a critical protein associated with the antiviral efficacy of nucleos(t)ide analogues.
abstract: Multidrug resistance protein 4 (MRP4) has been associated with nucleos(t)ide analogue (NA) antiretroviral therapy failure, though is unclear if MRP4 is also correlated with the failure of anti-hepatitis B virus (HBV) therapy.
  
  
  
  Multidrug resistance protein 4 expression in human peripheral blood mononuclear cells (PBMCs), liver tissues and human hepatoma cell lines was detected by real-time polymerase chain reaction (PCR), western blotting and immunohistochemistry assays. Supernatant and intracellular HBV DNA levels of MRP4-overexpressing or silenced HepG2.4D14 (wild-type) and HepG2.A64 (entecavir-resistant mutant) cells were measured by quantitative PCR. NA concentrations and HBV mutational analysis were assessed by liquid chromatography/mass spectrometry assays and DNA sequencing. Multivariate analysis was used to assess predictive factors for treatment failure.
  
  
  
  High expression of MRP4 was found in hepatoma cell lines and PBMCs, and up- or down-regulation of MRP4 expression altered the susceptibility of cells to NAs. MRP inhibitors increased NA intracellular accumulation and decreased extracellular levels. Moreover, MRP4 expression in PBMCs was correlated with that in paired liver tissues. Furthermore, multivariate analysis showed MRP4 mRNA expression to be an independent predictor of NA treatment failure.
  
  
  
  Multidrug resistance protein 4 is a critical protein associated with the antiviral efficacy of NAs, and combination therapy of NA and MRP inhibitors could reduce the dosage for long-term NA use. This is the first report to demonstrate that MRP4 expression is an important factor predicting treatment failure in chronic hepatitis B patients and will provide a potential therapeutic target against HBV.
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hongxuan
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Chunli
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yutian
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Baoju
authors.initials: B
authors.lastname: Wang
authors.affiliation: Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China.
authors.forename: Dongping
authors.initials: D
authors.lastname: Xu
authors.affiliation: Institute of Virology, University Hospital of Essen, Essen, Germany.
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zheng
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D017211:Treatment Failure; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000225:Adenine; D000998:Antiviral Agents; D006147:Guanine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014700:Verapamil; C073492:ABCC4 protein, human; C413685:entecavir
keywords: antiviral efficacy; multidrug resistance protein 4; nucleos(t)ide analogue; treatment failure