Receptor Binding and Biological Activity of 18-Hydroxycortisol*

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Abstract
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 primary with 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 rat hepatoma cell, was detectable at 10-5 M, but was too low for adequate quantification. In a 2nd in vitro glucocorticoid bioassay, inhibition of cell growth of the L929 fibroblast, 18-hydroxycortisol also showed minimal activity. 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.