MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs.

Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.

MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs.

Nat Med. 1999 Sep;5(9):1048-51. Unique Identifier : AIDSLINE MED/99401086
Schuetz JD; Connelly MC; Sun D; Paibir SG; Flynn PM; Srinivas RV; Kumar A; Fridland A; Department of Pharmaceutical Sciences, St. Jude Children's; Research Hospital, Memphis, Tennessee 38105, USA.; john.schuetz@stjude.org

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.

Keywords: JOURNAL ARTICLE Adenine/ANALOGS & DERIVATIVES/PHARMACOLOGY/PHARMACOKINETICS Anti-HIV Agents/*PHARMACOLOGY/PHARMACOKINETICS Carrier Proteins/GENETICS/*METABOLISM Cell Line Drug Resistance, Microbial Gene Amplification/GENETICS Gene Dosage Gene Expression Genes, Dominant/GENETICS Human Hybrid Cells/DRUG EFFECTS/METABOLISM HIV-1/*DRUG EFFECTS Inhibitory Concentration 50 Nucleosides/*PHARMACOLOGY/PHARMACOKINETICS Phenotype Reverse Transcriptase Inhibitors/PHARMACOLOGY/PHARMACOKINETICS RNA, Messenger/ANALYSIS/GENETICS Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. T-Lymphocytes/*DRUG EFFECTS/METABOLISM Zidovudine/PHARMACOLOGY/PHARMACOKINETICS
991230
A99C1012

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