Profound differences in the transport of steroids by two mouse P-glycoproteins

There are two mouse P-glycoproteins that convey multidrug resistance, mdr1 (mdr1b) and mdr3 (mdr1a), by serving as drug efflux transporters. These proteins each exhibit tissue-specific expression. There is relatively high expression of the mdr1 gene in the adrenals, the site of glucocorticoid and mineralocorticoid hormone synthesis. We previously demonstrated that mdr1 gene expression in murine thymoma cells correlated well with a decrease in their ability to accumulate the glucocorticoid dexamethasone and their increased resistance to glucocorticoid-induced apoptosis. Additional evidence is presented that supports the proposition that the mdr1 P-glycoprotein can transport glucocorticoids. Specifically, introduction and expression of the mouse mdr1 gene in the human HEK 293T cell line conveys a multidrug resistance phenotype that includes a reduced capacity to accumulate dexamethasone. Moreover, isolation of additional mdr1-expressing mouse lymphoid cells, without using steroids in the selection, confirms the linkage between multidrug resistance conveyed by the mdr1 P-glycoprotein and resistance to dexamethasone. In contrast, two newly isolated lymphoid lines, selectively expressing the mdr3 gene, were not found to have increased dexamethasone resistance or the capacity to accumulate significantly lower levels of hormone. The results support the concept that the mdr1 and mdr3 P-glycoproteins may serve alternative roles in the transport of endogenous substances such as steroids.