By screening databases of human expressed sequence tags, we have identified three new homologues of MRP1, the gene encoding the multidrug resistance-associated protein, and cMOAT (or MRP2), the canalicular multispecific organic anion transporter gene. We call these new genes MRP3, MRP4, and MRP5. MRP3, like cMOAT, is mainly expressed in the liver. MRP4 is expressed only at very low levels in a few tissues, and MRP5, like MRP1, is expressed in almost every tissue tested. To assess a possible role of these new MRP homologues in multidrug or cisplatin resistance, a large set of resistant cell lines was examined for the (over)expression of MRP1, cMOAT, MRP3, MRP4, and MRP5. We find that even in cells selected for a low level of resistance, several MRP-related genes can be up-regulated simultaneously. However, MRP4 is not overexpressed in any of the cell lines we analyzed; MRP3 and MRP5 are only overexpressed in a few cell lines, and the RNA levels do not seem to correlate with resistance to either doxorubicin or cisplatin. cMOAT is substantially overexpressed in several cell lines, and cMOAT RNA levels correlate with cisplatin but not doxorubicin resistance in a subset of resistant cell lines. Our results emphasize the need for gene-specific blocks in gene expression to define which transporter contributes to resistance in each resistant cell line.
This work was supported by a grant from the Dutch Cancer Society (to F. B. and P. B.).