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

There are two mouse P-glycoproteins that convey multidrug resistance, mdr1 (mdr1b and mdr3 (mdr1a), by serving as drug efflux transporters. These prot eins each exhibit tissue specific expression. There is relatively high expr ession of the mdr1 gene in the adrenals, the site of glucocorticoid and min eralocorticoid hormone synthesis. We previously demonstrated that mdr1 gene expression in murine thymoma cells correlated well with a decrease in thei r ability to accumulate the glucocorticoid dexamethasone and their increase d resistance to glucocorticoid-induced apoptosis. Additional evidence is pr esented that supports the proposition that the mdr1 P-glycoprotein can tran sport glucocorticoids. Specifically, introduction and expression of the mou se mdr1 gene in the human HEK 293T cell line conveys a multidrug resistance phenotype that. includes a reduced capacity to accumulate dexamethasone. M oreover, isolation of additional mdr1-expressing mouse lymphoid cells, with out using steroids in the selection, confirms the linkage between multidrug resistance conveyed by the mdr1 P-glycoprotein and resistance to dexametha sone. In contrast, two newly isolated lymphoid lines, selectively expressin g the mdr3 gene, were not found to have increased dexamethasone resistance or the capacity to accumulate significantly lower levels of hormone. The re sults support the concept that the mdr1 and mdr3 P-glycoproteins may serve alternative roles in the transport of endogenous substances such as steroid s. (C) 1999 Elsevier Science Inc.