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 proteins that translocate to the nucleus upon binding hormone. Thus, regulation of cytoplasmic glucocorticoid concentrations controls the level 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 transcription and a decrease in steroid sensitivity. P-glycoproteins are known to cause an outward, ATP-dependent transport of a variety of unrelated hydrophobic 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 enhanced by hydroxyl groups at the positions 16, 17, and 21. The antiprogestin RU486, which contains a dimethyl aminophenyl substitution at the position 11, is not transported by the mdr1 P-glycoprotein. We have found that RU486 is an inhibitor of P-glycoprotein function, indicating that steroid analogs could be useful chemosensitizers in patients undergoing chemotherapy.
Gruol
D J
DJ
Regulatory Biology Laboratory, Salk Institute for Biological Studies, San Diego, CA 92186-5800, USA.
Bourgeois
S
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005938:Glucocorticoids / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015735:Mifepristone / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone