EXPRESSION OF THE MDR1 P-GLYCOPROTEIN GENE - A MECHANISM OF ESCAPE FROM GLUCOCORTICOID-INDUCED APOPTOSIS

Glucocorticoid hormones cause apoptosis in the murine T-lymphoma cell line WEHI-7. Glucocorticoid receptors in these cells are cytoplasmic p roteins that translocate to the nucleus upon binding hormone. Thus, re gulation of cytoplasmic glucocorticoid concentrations controls the lev el of activated receptors and sensitivity to steroid-induced apoptosis . We found that expression of the mdr1 P-glycoprotein gene produces a reduced accumulation of dexamethasone in WEHI-7 cells. Concomitantly, there is a suppression of dexamethasone-induced changes in transcripti on and a decrease in steroid sensitivity. P-glycoproteins are known to cause an outward, ATP-dependent transport of a variety of unrelated h ydrophobic drugs across the plasma membrane. Our results indicate that glucocorticoid transport by P-glycoproteins depends upon the presence of an hydroxyl group at position 11 of corticosteroids and is enhance d by hydroxyl groups at the positions 16, 17, and 21. The antiprogesti n RU486, which contains a dimethyl aminophenyl substitution at the pos ition 11, is not transported by the mdr1 P-glycoprotein. We have found that RU486 is an inhibitor of P-glycoprotein function, indicating tha t steroid analogs could be useful chemosensitizers in patients undergo ing chemotherapy.