The action of glucocorticoids at a tissue level is dependent on both the level of steroid in the circulation/interstitial space and intracellular metabolism of glucocorticoids by ‘pre-receptor’ enzymes. For glucocorticoids the best studied pre-receptor enzymes are the 11b-hydroxysteroid dehydrogenases (11b-HSDs) which interconvert cortisone and cortisol. 11b-HSD1 is an activator of glucocorticoids (converting inactive cortisone to active cortisol) whereas 11b-HSD2 is an inactivator. These enzymes also metabolise prednisone (inactive) and prednisolone (active) in a similar manner.
Much attention has focussed on the role of 11b-HSDs in normal physiology and clinical studies have evaluated the effect of drugs which inhibit these enzymes. Less attention has been paid to the role that these enzymes play in mediating the effects of therapeutic glucocorticoids. In a series of studies it has been shown that 11b-HSD activity is critical to the action of therapeutic glucocorticoids. In the absence of 11b-HSD1 many tissues are almost entirely protected against the action of commonly used glucocorticoids. Increased expression of 11b-HSD1 in specific cells and tissues during inflammation may be a key factor underpinning the effectiveness of current glucocorticoid therapy for inflammatory diseases.
These factors need to be considered in the evaluation of novel anti-inflammatory agents particularly when comparisons are made to current glucocorticoids. This knowledge also opens up the possibility of developing novel therapeutics with superior ability to selectively regulate glucocorticoid receptor action in target tissues.