Elsevier

Biochemical Pharmacology

Volume 52, Issue 7, 11 October 1996, Pages 967-977
Biochemical Pharmacology

Commentary
Multidrug resistance mediated by the multidrug resistance protein (MRP) gene,☆☆

https://doi.org/10.1016/0006-2952(96)00450-9Get rights and content

Abstract

Inherent or acquired resistance to multiple natural product drugs is a major obstacle to the success of chemotherapy. Two proteins have been shown to cause this type of multidrug resistance in human tumour cells, the 170 kDa P-glycoprotein and the 190 kDa multidrug resistance protein (MRP). Overexpression of these N-glycosylated phosphoproteins in mammalian cells is associated with reduced drug accumulation. Both MRP and p-glycoprotein belong to the ATP-binding cassette superfamily of transmembrane transport proteins, but they share only 15% amino acid identity. Furthermore, their predicted membrane topologies differ considerably, with MRP containing three multispanning transmembrane domains compared with the two that are present in P-glycoprotein. The drug cross-resistance profiles of cells that overexpress MRP or P-glycoprotein are similar but not identical. For example, lower levels of taxol resistance are associated with overexpression of MRP than with overexpression of P-glycoprotein. There also appear to be fundamental differences in the mechanisms by which the two proteins transport chemotherapeutic drugs. P-glycoprotein-enriched membrane vesicles have been shown to directly transport several chemotherapeutic drugs, whereas vincristine transport by MRP-enriched membrane vesicles is demonstrable only in the presence of reduced glutathione. Several potential physiologic substrates of MRP including leukotriene C4 and 17β-estradiol-17-(β-d-glucuronide) have been identified. In contrast, these conjugated organic anions are transported poorly, if at all, by P-glycoprotein. Finally, agents that reverse P-glycoprotein-associated resistance are usually much less effective in MRP-associated resistance. Antisense oligonucleotide-mediated suppression of MRP synthesis offers a highly specific alternative approach to circumventing resistance mediated by this novel drug resistance protein.

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    Supported by La Ligue Nationale Contre le Cancer.

    ☆☆

    This work was supported by grants from the National Cancer Institute of Canada (No. 3839) with funds from the Canadian Cancer Society and from the Medical Research Council of Canada (MT 10519).

    Present address: Laboratoire de Pharmacologie et Toxicologie Fondamentales, Toulouse 31, France

    Stauffer Research Professor of Queen's University.

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