11-BETA-HYDROXYSTEROID DEHYDROGENASES - KEY ENZYMES IN DETERMINING TISSUE-SPECIFIC GLUCOCORTICOID EFFECTS

Recent studies have demonstrated that the interconversion of active an d inactive glucocorticoids plays a key role in determining the specifi city of the mineralocorticoid receptor and controlling local tissue gl ucocorticoid receptor activation. Two distinct isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) have been identifie d. 11 beta-HSD1 is NADPH-dependent and at its major site of action (th e liver) is a reductase, converting cortisone to cortisol (11-dehydroc orticosterone to corticosterone in the rat). 11 beta-HSD2 is NAD-depen dent, is present in tissues such as the kidney and placenta, and conve rts cortisol to cortisone (corticosterone to 11-dehydrocorticosterone in the rat). Congenital or acquired deficiency of 11 beta-HSD2 produce s the syndrome of apparent mineralocorticoid excess (SAME) in which co rtisol gains access to the unprotected nonspecific mineralocorticoid r eceptor. The congenital deficiency is associated with mutations in the gene encoding the kidney isoform of 11 beta-HSD2; the acquired form r esults from inhibition of the enzyme by licorice, carbenoxolone, ACTH- dependent steroids in the ectopic ACTH syndrome, and possibly circulat ing inhibitors of the enzyme. This paper focuses on recent evidence, w hich suggests that low levels of placental 11 beta-HSD2 result in incr eased exposure of the fetus to maternal glucocorticoid and low birth w eight. In animal studies using the rat we have shown that birth weight is correlated positively and placental weight negatively with the lev el of placental 11 beta-HSD. Thus animals with low birth weight and la rge placentae were those likely to be exposed to the highest level of maternal glucocorticoid. In man a similar relationship was found with birth weight being significantly correlated either with placental 11 b eta-HSD activity or with the extent of cortisol inactivation by isolat ed perfused placental cotyledons. Administration of dexamethasone (whi ch is poorly metabolized by placental 11 beta-HSD2) to pregnant rats r esulted in decreased birth weight and the development of hypertension in the pups when adult. The same results were obtained when pregnant r ats were given carbenoxolone, an inhibitor of placental 11 beta-HSD2. Low protein diet during pregnancy in the rat resulted in low birth wei ght of the pups, increased placental weight but decreased placental 11 beta-HSD activity, and adult hypertension. Thus increased glucocortic oid exposure of the fetus secondary to a failure of the normal inactiv ation of maternal glucocorticoid by the placenta may be an important m echanism linking changes in the in utero environment and common adult diseases.