A Family of Drug Transporters: the Multidrug Resistance-Associated Proteins

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,...

Full description

Saved in:
Bibliographic Details
Published in:JNCI : Journal of the National Cancer Institute 2000-08, Vol.92 (16), p.1295-1302
Main Authors: Borst, Piet, Evers, Raymond, Kool, Marcel, Wijnholds, Jan
Format: Article
Language:English
Subjects:
AIDS/HIV
Animals
Antineoplastic agents
ATP-Binding Cassette Transporters - metabolism
Biological and medical sciences
Cancer
Drug resistance
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
General aspects
Humans
Medical sciences
Membranes
Multidrug Resistance-Associated Proteins
Neoplasm Proteins - metabolism
Neoplasms - drug therapy
Neoplasms - metabolism
Pharmacology. Drug treatments
Proteins
Tumors
Up-Regulation
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 C4 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.
ISSN:0027-8874
1460-2105
DOI:10.1093/jnci/92.16.1295