Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties.
BACKGROUND
Glucocorticoids (GCs) are commonly used for long-term medication in immunosuppressive and anti-inflammatory therapy. However, the data describing gluco- and mineralo-corticoid (MC) properties of widely applied synthetic GCs are often based on diverse clinical observations and on a variety of in vitro tests under various conditions, which makes a quantitative comparison questionable.


METHODS
We compared MC and GC properties of different steroids, often used in clinical practice, in the same in vitro test system (luciferase transactivation assay in CV-1 cells transfected with either hMR or hGRalpha expression vectors) complemented by a system to test the steroid binding affinities at the hMR (protein expression in T7-coupled rabbit reticulocyte lysate).


CONCLUSIONS
While the potency of a GC is increased by an 11-hydroxy group, both its potency and its selectivity are increased by the Delta1-dehydro-configuration and a hydrophobic residue in position 16 (16-methylene, 16alpha-methyl or 16beta-methyl group). Almost ideal GCs in terms of missing MC effects, as defined by our in vitro assay, are therefore prednylidene, budesonide, beclomethasone and betamethasone.The MC potency of a steroid is increased by a 9alpha- or a 6alpha-fluoro substituent. A hydrophilic substituent in position 16 (like 16-hydroxylation in triamcinolone) decreases both MC and GC properties. As no substituent that leads to an isolated reduction of GC activity could be characterized in our experiments, 9alpha-fluorocortisol, the most frequently used steroid for MC substitution, seems to be the best choice of available steroids for this purpose.
Grossmann
Claudia
C
Department of Endocrinology, Diabetes and Nutrition, Charite-Universitatsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
Scholz
Tim
T
Rochel
Marina
M
Bumke-Vogt
Christiane
C
Oelkers
Wolfgang
W
Pfeiffer
Andreas F H
AF
Diederich
Sven
S
Bahr
Volker
V
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003907:Dexamethasone / Q000737:chemistry / Q000494:pharmacology; D005938:Glucocorticoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000737:chemistry / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D011239:Prednisolone / Q000737:chemistry / Q000494:pharmacology*; D011245:Pregnadienes / Q000737:chemistry / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D011245:Pregnadienes; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D003907:Dexamethasone; D011239:Prednisolone; D006854:Hydrocortisone