Receptor binding and biological activity of 18-hydroxycortisol.

Recently, 18-hydroxycortisol (11 beta,17 alpha,18,21-tetrahydroxy-4-pregnene-3,20-dione) was isolated and identified from extracts of urine and adrenal incubates of patients with primary aldosteronism. The receptor-binding activity to the renal gluco- and mineralocorticoid receptors and its biological activity as a glucocorticoid and mineralocorticoid were investigated using synthetic 18-hydroxycortisol. The ability of 18-hydroxycortisol to compete with [3H]aldosterone for renal binding to the receptor was 0.13% that of unlabeled aldosterone. The addition of a specific glucocorticoid, RU-26988 (11 beta,17-dihydroxy-21-methyl-17 alpha-pregna-1,4,6-triene-20-yn-3-one) decreased the competing ability to 0.02%, indicating significant binding to the glucocorticoid receptor. The ability to compete with [3H]dexamethasone for the renal cytoplasmic glucocorticoid receptor was 0.1% that of unlabeled dexamethasone. The mineralocorticoid activity of 18-hydroxycortisol was undetectable. Its glucocorticoid activity using an in vitro bioassay based on the induction of tyrosine aminotransferase in the HTC cell was detectable at 10(-5) M, but was too low for adequate quantification. In a second in vitro glucocorticoid bioassay, inhibition of cell growth of the L929 fibroblast, 18-hydroxycortisol also showed minimal activity. In summary, it is unlikely that 18-hydroxycortisol plays a role in the metabolic syndrome in those patients who produce it in excess due to its inactivity as a gluco- or mineralocorticoid.