Is 11β-hydroxysteroid dehydrogenase type 1 a good therapeutic target for blockade of glucocorticoid actions?

In 1950, the Noble Prize in Physiology or Medicine was awarded to two chemists and a physician for the discovery and use of cortisone, a classic prohormone devoid of inherent glucocorticoid activity (1). This steroid was active because of its transformation, by reduction of the 11-keto into an 11-hydroxyl group, to cortisol, the natural human glucocorticoid. Since then, we have learned a great deal about cortisone and cortisol and the enzymes that catalyze their inter-conversion to each other in glucocorticoid and mineralocorticoid target tissues. In general, two enzymes catalyze these reactions. 11β-Hydroxysteroid dehydrogenase (11β-HSD) type 1 is responsible for potentiating the actions of glucocorticoids in many target tissues by converting cortisone to cortisol. In contrast, 11β-HSD type 2 works in the opposite direction and is responsible for converting cortisol into cortisone. This enzyme protects the mineralocorticoid receptor (MR) from the effects of cortisol, which has a high binding affinity for this receptor and inherent mineralocorticoid activity. In this issue of PNAS, Sandeep et al. (2) suggest that use of a 11-β-HSD type 1 enzyme inhibitor could be useful in the treatment of cognitive dysfunction in elderly men and patients with type 2 diabetes mellitus. The results are promising for a broad spectrum of potential therapeutic applications of such inhibitors but raise several questions as to whether such agents will ever reach clinical practice. These questions have to do with tissue specificity, dose optimization, and chronicity of therapy.

Glucocorticoids are ubiquitous, highly pervasive nuclear hormones (3, 4). They exert their actions in almost all tissues, influencing the expression of a large proportion of the human genome. Binding of the glucocorticoid to its receptor is followed by a multistep process, ultimately changing the transcription rates of target genes. A large number of molecules participate directly or indirectly in the glucocorticoid signaling …