The 11-ketosteroid 11-ketodexamethasone is a glucocorticoid receptor agonist

• Published in: Molecular and cellular endocrinology Vol. 214; no. 1; pp. 27 - 37
• Main Authors: Rebuffat, Alexandre G, Tam, Steven, Nawrocki, Andrea R, Baker, Michael E, Frey, Brigitte M, Frey, Felix J, Odermatt, Alex
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 12.02.2004
• Subjects: 11β-Hydroxysteroid dehydrogenase; Active Transport, Cell Nucleus - drug effects; Animals; Binding Sites; Cell Line; Cortisol; Dexamethasone; Dexamethasone - analogs & derivatives; Dexamethasone - pharmacology; Glucocorticoid receptor; Humans; Hydrocortisone - pharmacology; Ketosteroids - pharmacology; Kinetics; Mineralocorticoid receptor; Protein Binding; Receptors, Glucocorticoid - agonists; Receptors, Glucocorticoid - metabolism; Receptors, Glucocorticoid - physiology; Transcriptional Activation; Cortisol; Dexamethasone; Mineralocorticoid receptor; Glucocorticoid receptor; 11β-Hydroxysteroid dehydrogenase
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2003.11.027

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 11β-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. 11β-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 11β-HSD2 including kidney and colon and also in certain tumor cells.