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Biochem Pharmacol. 1996 Oct 11;52(7):967-77.

Multidrug resistance mediated by the multidrug resistance protein (MRP) gene.

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1
CJF INSERM 9503, Centre Claudius R├ęgaud, Toulouse, France.

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 17 beta-estradiol-17-(beta-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.

PMID:
8831715
DOI:
10.1016/0006-2952(96)00450-9
[Indexed for MEDLINE]

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