Transcriptional activity of potent glucocorticoids: relevance of glucocorticoid receptor isoforms and drug metabolites.
As compared to standard glucocorticoids (GC), prednicarbate (PC) is favorable in the treatment of eczema due to its high benefit/risk ratio. The remarkable anti-inflammatory effects of PC are in strong contrast to its reported low glucocorticoid receptor (GR) binding affinity. In transfected COS-7 cells we related the transcriptional potencies of PC, its metabolites and conventional GC to their receptor binding properties. Moreover, the expression pattern of the human GR isoform hGRalpha and its mutual dominant negative inhibitor hGRbeta in skin cells have been investigated as well as the influence of hGRbeta on receptor binding and transactivation. hGRalpha mRNA and protein was largely overexpressed in skin cells. hGRbeta showed no influence on hGRalpha binding and transactivation. Concentration response curves indicated the greater transactivation potency of betamethasone 17-valerate followed by dexamethasone and prednisolone 17-ethylcarbonate. Native PC appeared almost as potent as dexamethasone. With both a strong correlation was observed between transactivation and GR binding.
Spika
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I
Institut für Pharmazie, Abteilung für Pharmakologie und Toxikologie, Freie Universität Berlin, Berlin, Germany.
Hammer
S
S
Kleuser
B
B
Korting
H C
HC
Schäfer-Korting
M
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D001624:Betamethasone Valerate / Q000378:metabolism; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003907:Dexamethasone / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D015735:Mifepristone / Q000378:metabolism; D011239:Prednisolone / Q000031:analogs & derivatives* / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis; D015533:Transcriptional Activation; D014162:Transfection
D000893:Anti-Inflammatory Agents; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta; C480529:prednisolone 21-ethylcarbonate; C085709:prednisolone 17-ethylcarbonate; D015735:Mifepristone; D003907:Dexamethasone; D001624:Betamethasone Valerate; D011239:Prednisolone; C035287:prednicarbate