Cortisol metabolism and the role of II beta-hydroxysteroid dehydrogenase

Two isoforms of the enzyme 11 beta -hydroxysteroid dehydrogenase (11 beta - HSD) interconvert the active glucocorticoid, cortisol, and inactive cortiso ne. 11 beta -HSDI is believed to act in vivo predominantly as an oxo-reduct ase using NADP(H) as a cofactor to generate cortisol. In contrast, 11 beta -HSD2 acts exclusively as an MAD-dependent dehydrogenase inactivating corti sol to cortisone, thereby protecting the mineralocorticoid receptor from oc cupation by cortisol. In peripheral tissues, both enzymes serve to control the availability of cortisol to bind to the corticosteroid receptors. Defec tive expression of 11 beta -HSD2 is implicated in patients with hypertensio n and intra-uterine growth retardation, while 11 beta -HSDI appears to be i ntricately involved in the conditions of apparent cortisone reductase defic iency, insulin resistance and visceral obesity. The ability of peripheral tissues to regulate corticosteroid concentrations through 11 beta -HSD isozymes is established as an important mechanism in the pathogenesis of diverse human diseases. Modulation of enzyme activity m ay offer a novel therapeutic approach to treating human disease while circu mventing the consequences of systemic glucocorticoid excess or deficiency.