The multidrug transporter, a double-edged sword.

The elucidation of the means by which tumor cells develop resistance to the toxic effects of potent chemotherapeutic agents has revealed a great deal about mechanisms of drug uptake, metabolism, and extrusion, as well as providing basic insights into cellular processes such as regulation of gene expression and gene amplification. One perplexing problem facing the cell biologist and oncologist has been the tendency of cultured cells and tumors in patients to exhibit simultaneous resistance to multiple chemically unrelated chemotherapeutic agents that are of natural product origin. Recent work from several laboratories has shown that this multidrug resistance is due to a multidrug transport protein, known as P-glycoprotein or P170, which is encoded by the MDRl gene in the human (also reviewed in Refs. 1-4). This multidrug transporter directly uses the energy of ATP to extrude a large variety of drugs from cells. The identification of this transport protein in cells selected for multidrug resistance in tissue culture has made it possible to begin to examine the function of the multidrug transporter in normal tissues. As detailed in the fo1lowir.g review, this transporter, whose expression was identified as a mechanism of drug resistance in cancer cells, apparently may also function as a means of protecting animals against toxic substances present in their diets.