Multidrug Resistance Protein MRP1, Glutathione, and Related Enzymes

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Abstract
Multidrug resistance (MDR), which is cross-resistance to structurally and functionally unrelated drugs such as anthracyclines, epipodophyllotoxins and vinca alkaloids, is a major cause of treatment failure in malignant disorders. Known mechanisms of MDR are overexpression of the ATP-dependent membrane proteins P-glycoprotein (P-gp) and multidrug resistance protein (MRP1), or an increased detoxification of compounds mediated by glutathione (GSH) or GSH related enzymes. MRP1 appeared to transport drugs conjugated to GSH and also unmodified cytostatic agents in presence of GSH. The relation between MRP1, GSH and enzymes involved in GSH metabolism or GSH dependent detoxification reactions recently has drawn a lot of attention. Coordinated induction of MRP1 and GSH related enzymes is reported in malignant cells after exposure to cytostatic agents. Besides MRP1, a number of MRP1 homologs are identified, named MRP2, MRP3, MRP4, MRP5 and MRP6. The relation between MDR and expression of these MRP1 homologs is currently under research. In human Acute Myeloid Leukemia (AML) the expression of MRP1 appears to be of potential importance. We demonstrated that AML blasts of patients express MRP1 protein and MRP1 and MRP2 mRNA. Furthermore a functional flow cytometric assay was developed to determine MRP functional activity. Since GSH and related enzymes have shown to play a critical role in MRP1 mediated transport of several anticancer drugs, both mechanisms should be studied in relation with each other. Further work on these interwoven mechanisms is needed to improve our understanding of MDR in leukemia.