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Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs
Open accessAbstract
Two prominent members of the ATP-binding cassette superfamily of transmembrane proteins, multidrug resistance 1 (MDR1) P-glycoprotein and multidrug resistance protein 1 (MRP1), can mediate the cellular extrusion of xenobiotics and (anticancer) drugs from normal and tumor cells. The MRP subfamily consists of at least six members, and here we report the functional characterization of human MRP5. We found resistance against the thiopurine anticancer drugs, 6-mercaptopurine (6-MP) and thioguanine, and the anti-HIV drug 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in MRP5- transfected cells. This resistance is due to an increased extrusion of PMEA and 6-thioinosine monophosphate from the cells that overproduce MRP5. In polarized Madin–Darby canine kidney II (MDCKII) cells transfected with an MRP5 cDNA construct, MRP5 is routed to the basolateral membrane and these cells transport S -(2,4-dinitrophenyl)glutathione and glutathione preferentially toward the basal compartment. Inhibitors of organic anion transport inhibit transport mediated by MRP5. We speculate that MRP5 might play a role in some cases of unexplained resistance to thiopurines in acute lymphoblastic leukemia and/or to antiretroviral nucleoside analogs in HIV-infected patients.
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Citations
Cited by
Multidrug resistance in cancer: role of ATP–dependent transporters
Gottesman, M. M., Fojo, T., & Bates, S. E. (2002) · Nature Reviews Cancer · doi:10.1038/nrc706 · Cited by 5,536
Mechanisms of Cancer Drug Resistance
Gottesman, M. M. (2002) · Annual Review of Medicine · doi:10.1146/annurev.med.53.082901.103929 · Cited by 2,643
A family of drug transporters: the multidrug resistance-associated proteins
Borst, P., Evers, R., Kool, M., & Wijnholds, J. (2000) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/92.16.1295 · Cited by 1,751
Self-citationThe Human ATP-Binding Cassette (ABC) Transporter Superfamily
Dean, M., Rzhetsky, A., & Allikmets, R. (2001) · Genome Research · doi:10.1101/gr.184901 · Cited by 1,748
P-glycoprotein: from genomics to mechanism
Ambudkar, S. V., Kimchi-Sarfaty, C., Sauna, Z. E., & Gottesman, M. M. (2003) · Oncogene · doi:10.1038/sj.onc.1206948 · Cited by 1,074
Metadata
- Authors
- Wijnholds, J., Mol, C. A. A. M., van Deemter, L., de Haas, M., Scheffer, G. L., Baas, F., Beijnen, J. H., Scheper, R. J., Hatse, S., De Clercq, E., Balzarini, J., & Borst, P.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2000-06-06
- Volume
- 97
- Issue
- 13
- Pages
- 7476-7481
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2105599787
- Cited by
- 478
- References
- 0
- FWCI
- 15.66
- Type
- journal article
- Language
- en
- Open access
- green
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- Wijnholds, J., Mol, C. A. A. M., van Deemter, L., de Haas, M., Scheffer, G. L., Baas, F., Beijnen, J. H., Scheper, R. J., Hatse, S., De Clercq, E., Balzarini, J., & Borst, P. (2000). Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.120159197
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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