TYPE-2 11-BETA-HYDROXYSTEROID DEHYDROGENASE IN FETAL AND ADULT LIFE

Two isoforms of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) cat alyse the interconversion of active cortisol to inactive cortisone; 11 beta-HSD1 is a low affinity, NADP(H)-dependent dehydrogenase/oxo-redu ctase, and 11 beta-HSD2, a high affinity, NAD-dependent dehydrogenase. Because of the importance of 11 beta-HSD in regulating corticosteroid hormone action, we have analysed the distribution of the 11 beta-HSD isoforms in human adult and foetal tissues (including placenta), and, in addition have performed a series of substrate specificity studies o n the novel, kidney 11 beta-HSD2 isoform. Using an RT-PCR approach, we failed to detect 11 beta-HSD1 mRNA in any human mid-gestational foeta l tissues. In contrast 11 beta-HSD2 mRNA was present in foetal lung, a drenal, colon and kidney. In adult tissues 11 beta-HSD2 gene expressio n was confined to the mineralocorticoid target tissues, kidney and col on, whilst 11 beta-HSD1 was expressed predominantly in glucocorticoid target tissues, liver, lung, pituitary and cerebellum. In human kidney homogenates, 11-hydroxylated progesterone derivatives, glycyrrhetinic acid, corticosterone and the ''end products'' cortisone and 11-dehydr ocorticosterone were potent inhibitors of the NAD-dependent conversion of cortisol to cortisone. Finally high levels of 11 beta-HSD2 mRNA an d activity were observed in term placentae, which correlated positivel y with foetal weight. The tissue-specific distribution of the 11 beta- HSD isoforms is in keeping with their differential roles, 11 beta-HSD1 regulating glucocorticoid hormone action and 11 beta-HSD2 mineralocor ticoid hormone action. The correlation of 11 beta-HSD2 activity in the placenta with foetal weight suggests, in addition, a crucial role for this enzyme in foetal development, possibly in mediating ontogeny of the foetal hypothalamo-pituitary-adrenal axis.