title: MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs.
abstract: Dideoxynucleosides, which are potent inhibitors of HIV reverse transcriptase and other viral DNA polymerases, are a common component of highly active anti-retroviral therapy (HAART) (ref. 1). Six reverse transcriptase inhibitors have been approved for human use: azidothymidine; 2'3'-dideoxycytidine; 2'3'-dideoxyinosine; 2', 3'-didehydro-3'deoxythymidine; 2',3'-dideoxy-3'-thiacytidine; and 4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-++ +metha nol. Although drug-resistant HIV strains resulting from genetic mutation have emerged in patients treated with HAART (ref. 1), some patients show signs of drug resistance in the absence of drug-resistant viruses. In our study of alternative or additional mechanisms of resistance operating during antiviral therapy, overexpression and amplification of the MRP4 gene correlated with ATP-dependent efflux of PMEA (9-(2-phosphonylmethoxyethyl)adenine) and azidothymidine monophosphate from cells and, thus, with resistance to these drugs. Overexpression of MRP4 mRNA and MRP4 protein severely impaired the antiviral efficacy of PMEA, azidothymidine and other nucleoside analogs. Increased resistance to PMEA and amplification of the MRP4 gene correlated with enhanced drug efflux; transfer of chromosome 13 containing the amplified MRP4 gene conferred resistance to PMEA. MRP4 is the first transporter, to our knowledge, directly linked to the efflux of nucleoside monophosphate analogs from mammalian cells.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. john.schuetz@stjude.org
authors.forename: J D
authors.initials: JD
authors.lastname: Schuetz
authors.forename: M C
authors.initials: MC
authors.lastname: Connelly
authors.forename: D
authors.initials: D
authors.lastname: Sun
authors.forename: S G
authors.initials: SG
authors.lastname: Paibir
authors.forename: P M
authors.initials: PM
authors.lastname: Flynn
authors.forename: R V
authors.initials: RV
authors.lastname: Srinivas
authors.forename: A
authors.initials: A
authors.lastname: Kumar
authors.forename: A
authors.initials: A
authors.lastname: Fridland
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004352:Drug Resistance, Microbial; D005784:Gene Amplification / Q000235:genetics; D018628:Gene Dosage; D015870:Gene Expression; D005799:Genes, Dominant / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects / Q000378:metabolism; D020128:Inhibitory Concentration 50; D026901:Membrane Transport Proteins; D009705:Nucleosides / Q000493:pharmacokinetics / Q000494:pharmacology*; D063065:Organophosphonates; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D015215:Zidovudine / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D009705:Nucleosides; D063065:Organophosphonates; D012333:RNA, Messenger; D018894:Reverse Transcriptase Inhibitors; C086860:glutathione transporter; D015215:Zidovudine; C053001:adefovir; D000225:Adenine