Mechanism of action of adrenocorticosteroids – from: Bertram G. Katzung, Basic & Clinical Pharmacology (Mc Graw-Hill Medical, 2007) –
“Most of the known effects of the glucocorticoids are mediated by widely distributed glucocorticoid receptors. These proteins are members of the superfamily of nuclear receptors that includes steroid, sterol (vitamin D), thyroid, retinoic acid, and many other receptors with unknown or nonexistent ligands (orphan receptors). All these receptors interact with the promoters of and regulate the transcription of target genes . In the absence of the hormonal ligand, glucocorticoid receptors are primarily cytoplasmic, in oligomeric complexes with heat shock proteins (Hsp). The most important of these are two molecules of Hsp90, although other proteins are certainly involved. Free hormone from the plasma and interstitial fluid enters the cell and binds to the receptor, inducing conformational changes that allow it to dissociate from the heat shock proteins. The ligand-bound receptor complex then is actively transported into the nucleus, where it interacts with DNA and nuclear proteins. As a homodimer, it binds to glucocorticoid receptor elements (GRE) in the promoters of responsive genes. The GRE is composed of two palindromic sequences that bind to the hormone receptor dimer.
In addition to binding to GREs, the ligand-bound receptor also forms complexes with and influences the function of other transcription factors, such as AP1 and NF-kB, which act on non-GRE-containing promoters, to contribute to the regulation of transcription of their responsive genes. These transcription factors have broad actions on the regulation of growth factors, proinflammatory cytokines, etc, and to a great extent mediate the anti-growth, anti-inflammatory, and immunosuppressive effects of glucocorticoids.
Prompt effects such as initial feedback suppression of pituitary ACTH occur in minutes and are too rapid to be explained on the basis of gene transcription and protein synthesis. It is not known how these effects are mediated. Among the proposed mechanisms are direct effects on cell membrane receptors for the hormone or nongenomic effects of the classic hormone-bound glucocorticoid receptor. The putative membrane receptors might be entirely different from the known intracellular receptors.”
Comparative steroid potencies (From Wikipedia):
|Name||Glucocorticoid potency||Mineralocorticoid potency||Duration of action (t1/2 in hours)|
|Cortisone acetate||0.8||0.8||oral 8, intramuscular 18+|
|Beclometasone||8 puffs 4 times a day
equals 14 mg oral
prednisone once a day
|Deoxycorticosterone acetate (DOCA)||0||20||–|
Source of animation: La transduction du signal des hormones stéroïdes.