11-BETA-HYDROXYSTEROID DEHYDROGENASE EXPRESSION AND ACTIVITY IN THE HUMAN ADRENAL-CORTEX

Although oxidation of cortisol or corticosterone by 11 beta-hydroxyste roid dehydrogenase (11 beta-HSD) represents the physiological mechanis m conferring specificity for aldosterone on the mineralocorticoid rece ptor in mineralocorticoid target tissues, little attention has been pa id until now to the expression and activity of this enzyme in human ad renals. We have shown that human adrenal cortex expresses 11 beta-HSD type 2 (11 beta-HSD2) gene, and found a marked 11 beta-HSD2 activity i n microsomal preparations obtained from slices of decapsulated normal human adrenal cortices. Under basal conditions, adrenal slices secrete d, in addition to cortisol and corticosterone (B), sizeable amounts of cortisone and 11-dehydrocorticosterone (DH-B), the inactive forms to which the former glucocorticoids are converted by 11 beta-HSD. Additio n of the 11 beta-HSD inhibitor glycyrrhetinic acid elicited a moderate rise in the production of cortisol and B and suppressed that of corti sone and DH-B. ACTH and angiotensin II evoked a marked rise in the sec retion of cortisol and B, but unexpectedly depressed the release of co rtisone and DH-B. ACTH also lowered the capacity of adrenal slices to convert [H-3]cortisol to [H-3]cortisone. This last effect of ACTH was concentration-dependently abolished by both aminoglutethimide and cyan oketone, which blocks early steps of steroid synthesis, but not by met yrapone, an inhibitor of 11 beta-hydroxylase. Collectively, these find ings indicate that the human adrenal cortex possesses an active 11 bet a-HSD2 engaged in the inactivation of newly formed gluco corticoids. T he activity of this enzyme is negatively modulated by the main agonist s of glucocorticoid secretion through an indirect mechanism, probably involving the rise in the intra-adrenal concentration of non-11 beta-h ydroxylated steroid hormones.