The 11β‐Hydroxysteroid Dehydrogenase System, A Determinant of Glucocorticoid and Mineralocorticoid Action

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Abstract
11β‐Hydroxysteroid dehydrogenases (11β‐HSD) catalyse the interconversion of active glucocorticoids (cortisol, corticosterone) and their inert 11‐keto derivatives (cortisone, 11‐dehydrocorticosterone). The type‐2 isozyme (11β‐HSD‐2) is a high‐affinity dehydrogenase that catalyses the rapid inactivation of glucocorticoids, thus ensuring selective access of aldosterone to otherwise non‐selective mineralocorticoid receptors in the distal nephron. Mutations of the gene encoding 11β‐HSD‐2 are responsible for the syndrome of apparent mineralocorticoid excess, in which cortisol illicitly occupies mineralocorticoid receptors, causing hypertension and hypokalaemia. 11β‐HSD‐2 is also highly expressed in the placenta and mid‐gestation fetus, where it may protect developing tissues from the often deleterious actions of glucocorticoids upon fetal growth and organ maturation. β‐HSD‐1 is probably an 11β‐reductase in vivo. Its function is obscure, but may amplify glucocorticoid action during the diurnal nadir, drawing upon the substantial circulating levels of 11‐keto steroids. Both isozymes are regulated during ontogeny and by a series of hormonal and other factors. 11β‐HSD provide an important control of glucocorticoid action at a cellular level, and may represent new targets for therapeutic intervention.