A family of drug transporters: the multidrug resistance-associated proteins

Borst, P.; Evers, R.; Kool, M.; Wijnholds, J.

doi:10.1093/jnci/92.16.1295

Cited by 1,751Drug Transport and Resistance MechanismsPharmacogenetics and Drug MetabolismAntibiotic Resistance in Bacteria

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

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Abstract

The human multidrug resistance-associated protein (MRP) family currently has seven members. The ability of several of these membrane proteins to transport a wide range of anticancer drugs out of cells and their presence in many tumors make them prime suspects in unexplained cases of drug resistance, although proof that they contribute to clinical drug resistance is still lacking. Recent studies have begun to clarify the function of the MRP family members. MRPs are organic anion transporters; i.e., they transport anionic drugs, exemplified by methotrexate, and neutral drugs conjugated to acidic ligands, such as glutathione (GSH), glucuronate, or sulfate. However, MRP1, MRP2, and MRP3 can also cause resistance to neutral organic drugs that are not known to be conjugated to acidic ligands by transporting these drugs together with free GSH. MRP1 can even confer resistance to arsenite and MRP2 to cisplatin, again probably by transporting these compounds in complexes with GSH. MRP4 overexpression is associated with high-level resistance to the nucleoside analogues 9-(2-phosphonylmethoxyethyl) adenine and azidothymidine, both of which are used as anti-human immunodeficiency virus drugs. MRPs may, therefore, also have a role in resistance against nucleoside analogues used in cancer chemotherapy. Mice without Mrp1, a high-affinity leukotriene C(4) transporter, have an altered response to inflammatory stimuli but are otherwise healthy and fertile. MRP2 is the major transporter responsible for the secretion of bilirubin glucuronides into bile, and humans without MRP2 develop a mild liver disease known as the Dubin-Johnson syndrome. The physiologic functions of the other MRPs are not known. Whether long-term inhibition of MRPs in humans can be tolerated (assuming that suitable inhibitors will be found) remains to be determined.

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From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [131]

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Authors: Borst, P., Evers, R., Kool, M., & Wijnholds, J.
Affiliations: The Netherlands Cancer Institute (NL)
Corresponding author: Borst, P.
ORCID: Borst, P.
Kool, M.
Wijnholds, J.
Venue: JNCI Journal of the National Cancer Institute
Publisher: Oxford University Press (OUP)
Published: 2000-08-16
Volume: 92
Issue: 16
Pages: 1295-1302
ISSN: 0027-8874 (ISSN-L)
1460-2105
DOI: 10.1093/jnci/92.16.1295
OpenAlex: W2110790042
Cited by: 1,751
References: 96
Citations by year: 2026: 9 · 2025: 26 · 2024: 24 · 2023: 38 · 2022: 38 · 2021: 52 · 2020: 44 · 2019: 32 · 2018: 48 · 2017: 58 · 2016: 66 · 2015: 63 · 2014: 81 · 2013: 74 · 2012: 57
FWCI: 11.10
Type: journal article
Language: en
Open access: closed
Locations: JNCI Journal of the National Cancer Institute (publishedVersion)
PubMed (publishedVersion)
Pure Amsterdam UMC (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Topics: Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
Keywords: multidrug resistance-associated protein, MRP1, MRP2, MRP3, MRP4, organic anion transporters, drug resistance, anticancer drug efflux, glutathione conjugates, methotrexate, cisplatin, arsenite, nucleoside analogues, HIV drugs, Dubin-Johnson syndrome, bile secretion
MeSH terms: Animals, Humans, Neoplasm Proteins, Neoplasms, Up-Regulation, Gene Expression Regulation, Neoplastic, Drug Resistance, Multiple, ATP-Binding Cassette Transporters, Drug Resistance, Neoplasm, ATP-Binding Cassette, Sub-Family C Proteins

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A family of drug transporters: the multidrug resistance-associated proteins

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