The 11-ketosteroid 11-ketodexamethasone is a glucocorticoid receptor agonist.
Dexamethasone (Dex) is a potent and long-acting glucocorticoid in terms of anti-inflammatory activity without substantial sodium retaining effect. Here, we examine the ability of the 11beta-hydroxyglucocorticoids Dex and cortisol and their 11-keto forms 11-ketodexamethasone (11-ketoDex) and cortisone to bind to glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) and to mediate nuclear translocation and transactivation of a reporter-gene. Unlike cortisone, the 11-ketosteroid 11-ketoDex acts as a potent GR agonist, comparable to Dex and cortisol. Transactivation of MR by Dex or 11-ketoDex was weak or undetectable, despite efficient binding and induction of nuclear translocation. 11beta-HSD2 protects MR and GR from inappropriate occupation by cortisol; it is, however, unable to prevent activation of GR by 11-ketoDex. The finding that 11-ketoDex is a specific GR agonist may explain the potent glucocorticoid effect of Dex in tissues expressing 11beta-HSD2 including kidney and colon and also in certain tumor cells.
Rebuffat
Alexandre G
AG
Department of Clinical Research, University of Berne, Freiburgstrasse 15, 3010 Berne, Switzerland.
Tam
Steven
S
Nawrocki
Andrea R
AR
Baker
Michael E
ME
Frey
Brigitte M
BM
Frey
Felix J
FJ
Odermatt
Alex
A
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003907:Dexamethasone / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D007664:Ketosteroids / Q000494:pharmacology*; D007700:Kinetics; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism / Q000502:physiology; D015533:Transcriptional Activation
C484907:11-ketodexamethasone; D007664:Ketosteroids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D006854:Hydrocortisone