New insights into the biology and pharmacology of the multidrug resistanceprotein (MRP) from gene knockout models

Growing interest in the MRP (multidrug resistance protein) gene stems from its importance in multidrug resistance to chemotherapy, its possible use in gene therapy, and its relationship with the glutathione system. The recent generation of mrp gene knockout models in vitro and in vivo is providing i nformation on the mechanism of action and the physiological function(s) of mrp. The importance of mrp in protection of normal tissues from the toxicit y of the anticancer agent etoposide has been established. A total block of mrp has been found to be compatible with life, suggesting that MRP inhibito rs can be safely used for treating cancer patients. In some sub-classes of leukocytes, mrp contributes to the transport of leukotriene C-4, an endogen ous glutathione S-conjugate. However, the baseline expression of mrp does n ot appear to contribute to the export of glutathione-S-conjugates of alkyla ting agents, and thus does not exert a protective role against their toxici ty. Besides being capable of exporting certain glutathione-S-conjugates, mr p also catalyzes the co-transport of GSH and drug and, presumably, a presen tly unknown endogenous metabolite(s). (C) 1999 Elsevier Science Inc.