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8th Conference on Retroviruses and Opportunistic Infections
Chicago, IL - February 4 - 8, 2001
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Effect of multidrug-resistance associated protein 4 on antiviral nucleotide analogs
Conf Retroviruses Opportunistic Infect 2001 Feb 4-8; 8:280 (abstract no. S2)
Fridland A; Gilead Sciences, Boulder, CO.
We have identified and characterized a novel member of the ATP binding cassette superfamily of transport proteins (MRP) that interacts with nucleotide analogs. The MRPs are organic anion transporters that can mediate the cellular extrusion of many structurally unrelated drugs and are an important defense mechanism of cells against toxic agents. We found that overexpression and amplification of the MRP 4 gene in a subline (CEM-1) of the human T lymphoid cells, CEMs severely suppresses the antiviral activity of the NRTIs, adefovir (PMEA), AZT, D4T, and 3TC. MRP4 did not affect the antiviral activity of HIV protease inhibitors in the CEM-1 cells. This multinucleoside analog resistance phenotype is associated with an enhanced efflux for analog monophosphate and decreased accumulation of the active analog triphosphates in the overproducing MRP4 cells. Inhibitors of organic anion transport inhibit the efflux mediated MRP4. Dipyridamol, a non-specific transport inhibitor, reversed the enhanced drug efflux, induced the accumulation of analog triphosphate and potentiated the antiviral activity of the NRTIs in the MRP4 expressing cells. Results from another group (Wijnholds et al, PNAS 97, 7476) have shown that MRP5, another anion transporter like MRP4, also appears to be a nucleotide analog pump. The physiological functions of these two drug transporters are not known, but it is possible that the efflux pumps are involved in creating cellular sanctuaries, that limit the accessibility to antiviral drugs.
Keywords: AEGIS, Drug Resistance, Multiple, Carrier Proteins, Biological Transport, Ribosomal Proteins, Zidovudine, Antiviral Agents, Adenosine Triphosphate, Adenine, Reverse Transcriptase Inhibitors, Anti-HIV Agents, mitochondrial ribosomal protein 4, 9-(2-phosphonylmethoxyethyl)adenine, Human, analogs & derivatives, AIDS
2001-02-04
S2
Copyright © 2001 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.