Regulation of mdr RNA levels in response to cytotoxic drugs in rodent cells

Abstract

The mdr gene, which encodes an energy-dependent multidrug efflux pump termed P-glycoprotein, is expressed in some normal human and rodent tissues, including the adrenal gland, kidney, liver, colon, small intestine, and brain and testis capillary endothelial cells. Because of the important role played by the multidrug transporter in determining sensitivity of normal tissues and resistance of cancers to chemotherapeutic drugs, we and others have been determining the environmental factors which regulate expression of the mdr gene. In previous studies, expression of the human MDR1 gene has been shown to be regulated by heat shock, arsenite, and cadmium in a kidney carcinoma cell line, and mdr RNA is dramatically elevated in rat liver after partial hepatectomy or treatment of the animals with cytotoxic agents. We have now investigated the genetic response of the mdr gene to acute cytotoxic insults in rodent and human tissue culture cells. Following exposure to several drugs, most of which are known to be substrates for the multidrug transporter, mdr RNA levels were found to increase substantially in the rodent cells, but not the human cells. Furthermore, RNA levels for topoisomerase II, an intracellular target for these drugs, decreased in the rodent cells. These results suggest a complex pattern of regulation of mdr RNA levels, depending on animal species and cell type, and possible coordinate regulation with topoisomerase II RNA levels.