SUMMARY The major site of cortisol metabolism in man has been thought to be the liver. Studies in patients with either congenital or acquired deficiency of 11β‐hydroxysteroid dehydrogenase (an enzyme responsible for the interconversion of cortisol to cortisone) suggested that the kidney was an important site of cortisone production. In 88 patients with proven renal disease but normal liver function, arbitrarily divided into four groups on the basis of plasma creatinine, 0900 h plasma cortisone was significantly reduced in all groups when compared with 47 controls (e.g. 21 ± 3 nmol/1 (mean ± SEM) in patients with plasma creatinine >0.45 mmol/1 vs 62 ± 3 nmol/1 in controls, P < 0.001). 0900 h plasma cortisol was not significantly different. There was an inverse correlation between plasma creatinine and plasma cortisone ( r =−0.55, p < 0.01). Four anephric patients had a 0900 h plasma cortisone level of 6 ± 1 nmol/1. We conclude that the kidney is a major site for the conversion of cortisol to cortisone and hence cortisone production in man. The relevance of this to the pathophysiology of salt and water metabolism in renal disease remains to be elucidated.

In humans, glycyrrhetinic acid (GE), the active pharmacological ingredient of licorice, produces symptoms resembling those caused by excess mineralocorticoid secretion. We are proposing that 11 beta-dehydrogenase inhibition, and not intrinsic mineralocorticoid activity, is the primary mechanism of licorice induced pseudoaldosteronism. Glycyrrhizic acid (glycyrrhetinic acid glucuronide), when given orally to rats, partially inhibited renal 11 beta-dehydrogenase. In rats treated with dexamethasone before glycyrrhizic acid administration there was similar enzyme inhibition, suggesting that antimineralocorticoid effects of dexamethasone in licorice excess states are not mediated through a direct effect on 11 beta-dehydrogenase activity. Dispersed renal proximal tubular preparations, kidney homogenates, and microsomes readily converted corticosterone to 11-dehydrocorticosterone. GE and its synthetic analog carbenoxolone inhibited the conversion in these systems in a dose-dependent manner. Corticosteroid 11-oxoreductase, which was present in kidney homogenates at a level 10-20% that of 11 beta-dehydrogenase was not inhibited by any of the agents. With homogenate and microsomes, the Ki of GE was about 10(-9)-10(-8) M; with intact tubules, the Ki of GE was about 10(-5)-10(-6) M. It is suggested that a permeability barrier slows the entry of GE into the tubule cells. We conclude that the effects of licorice on corticosteroid metabolism in the kidney are based on its inhibition of 11 beta-dehydrogenase. Our data, supplemented by published evidence, is inconsistent with the conclusion that interaction with mineralocorticoid receptors accounts for the pharmacological effects of GE.

Stewart, P M; Whitworth, J A; Burt, D; Atherden, S M; Edwards, C R W Author Information

In vitro the mineralocorticoid receptor is non-specific and does not distinguish between aldosterone and cortisol. In vivo certain tissues with this receptor are aldosterone selective (eg, kidney and parotid) whereas others with the same receptor are not (eg, hippocampus and heart). Experiments in rats showed that 11 beta-hydroxysteroid dehydrogenase (which converts cortisol to cortisone in man and corticosterone to 11-dehydrocorticosterone in the rat) was much more highly concentrated in aldosterone-selective tissues than in non-selective tissues. The localisation in the selective tissues was such that the enzyme could act as a paracrine or possibly an autocrine mechanism protecting the receptor from exposure to corticosterone. Autoradiographic studies showed that protection is lost when the enzyme is inhibited; 3H-corticosterone and 3H-aldosterone were bound to similar sites. These findings seem to explain why sodium retention, hypokalaemia, and hypertension develop in subjects with congenital deficiency of 11 beta-OHSD and those in whom the enzyme has been inhibited by liquorice.

We report a newly diagnosed family in which a father and his two sons were found to be hypertensive and to have the rare familial condition dexamethasone-suppressible hyperaldosteronism (DSH). All three patients became normotensive on dexamethasone treatment alone and have been successfully maintained on low doses of the drug for 6 months since diagnosis. Each of the patients had extremely high plasma and urinary concentrations of the recently discovered steroid 18-hydroxycortisol, which were more than ten times higher than the upper normal limit. Plasma levels were readily suppressed by dexamethasone treatment. The hypothesis that 18-hydroxycortisol might derive from 18-hydroxylation of recirculating cortisol was tested by measuring plasma 18-hydroxycortisol levels during low-dose and high-dose hydrocortisone infusions, in a normal subject and in one of the patients with DSH. During the high-dose infusions (with plasma cortisol levels of 3000-5000 nmol/l) there was net production of 18-hydroxycortisol within 8 h, but this was not observed during the low-dose infusions (plasma cortisol levels 300-400 nmol/l). The origin of 18-hydroxycortisol remains uncertain: these findings do not support the recirculation theory, but lend weight to the alternative hypothesis that 18-hydroxycortisol is produced in transitional adrenocortical tissue. This steroid is of considerable value in the differential diagnosis of primary hyperaldosteronism and may also be important as a marker of transitional adrenal cell function.

University Department of Medicine, Western General Hospital, Crewe Road South, Edinburgh †Department of Biochemistry, Glasgow Royal Infirmary, Glasgow, Scotland

The sodium retention associated with liquorice ingestion has been thought to be due to a direct mineralocorticoid effect, despite the fact that it does not seem to occur in patients or animals with severe adrenal insufficiency. This study in seven normal subjects given liquorice showed that sodium retention is associated with a significant change in cortisol metabolism indicating inhibition of 11-beta-hydroxysteroid dehydrogenase (11 beta-OHSD). Congenital deficiency of this enzyme produces a syndrome of apparent mineralocorticoid excess. It is suggested that in both conditions there is a defect in the renal conversion of cortisol to cortisone by 11 beta-OHSD which results in high intrarenal cortisol levels, acting on type 1 mineralocorticoid receptors to cause sodium retention.