title: Dissimilar expression of multidrug resistance mdr1 and bcrp by the replication of hepatitis C virus: role of the nonstructural 5A protein.
abstract: Multidrug resistance associated with the overexpression of ATP-dependent binding cassette (ABC) proteins is widely accepted as an important cause of treatment failure in patients with neoplastic or infectious diseases. Some of them play also a pivotal role in detoxification processes. Herein, we investigated the effect of hepatitis C virus (HCV) replication and nonstructural 5A (NS5A) protein on the expression and functional activity of two ABC transport proteins: MDR1 and BCRP. RT-quantitative real-time polymerase chain reaction (qPCR) was carried out for mdr1 and bcrp mRNAs in both Huh7 cells expressing NS5A and Huh7.5 cells containing either full-length- or subgenomic-HCV replicon systems. The functional activity of these pumps was studied by performing a dye efflux assay with DiOC2 and Rhodamine 123. A dose-dependent down-regulation of mdr1 expression was documented in Huh7 cells expressing the NS5A protein, as well as in both replicon systems. In contrast, a significant increase of bcrp expression in both systems was recorded, which were in full agreement with the dye efflux assay results. These results warrant further in vivo studies in HCV patients with cholestasis and/or patients that are refractive to the pharmacotherapy due to the activity of these pumps.
authors.affiliation: Facultad de Medicina, Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPAM), UBA-CONICET, UBA, Buenos Aires, Argentina.
authors.forename: C
authors.initials: C
authors.lastname: W Rivero
authors.forename: N
authors.initials: N
authors.lastname: Rosso
authors.forename: E
authors.initials: E
authors.lastname: Gentile
authors.forename: M
authors.initials: M
authors.lastname: Cuestas
authors.forename: C
authors.initials: C
authors.lastname: Tiribelli
authors.forename: J R
authors.initials: JR
authors.lastname: Oubiña
authors.forename: V L
authors.initials: VL
authors.lastname: Mathet
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D002232:Carbocyanines / Q000378:metabolism; D002460:Cell Line; D015870:Gene Expression; D020869:Gene Expression Profiling; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D051562:Proto-Oncogene Proteins c-bcr / Q000096:biosynthesis*; D060888:Real-Time Polymerase Chain Reaction; D020112:Rhodamine 123 / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication; D012324:RNA-Dependent RNA Polymerase
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002232:Carbocyanines; D051562:Proto-Oncogene Proteins c-bcr; D020112:Rhodamine 123; D017361:Viral Nonstructural Proteins; C513055:ABCB1 protein, human; C081554:3,3'-diethyloxacarbocyanine; C496613:BCR protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase