Previous studies have demonstrated that 11-deoxycortisol (pregn-4-ene-17α, 21-diol-3, 20-dione) competes with glucocorticoids for binding to the glucocorticoid receptor and is a competitive antagonist of glucocorticoid action in vitro. 11-Deoxycortisol, however, has been reported to be ineffective as a glucocorticoid antagonist in vivo. The present study was undertaken to examine this discrepancy between the in vivo and in vitro antiglucocorticoid activities of 11-deoxycortisol. In adrenalectomized rats, 11-deoxycortisol antagonized dexamethasone (9a-fluoro-16a-methyl-pregna-l, 4-diene-llβ-17α, 21-triol-3, 20-dione)-induced liver glycogen accumulation and growth suppression at plasma levels comparable to those at which antiglucocorticoid activity has been reported in vitro and was itself devoid of agonist activity. In intact rats, on the other hand, 11-deoxycortisol showed agonist activity in growth suppression and adrenal suppression assays, and failed to antagonize dexamethasone activity. Plasma cortisol, measured by RIA after administration of 11-deoxycortisol, was significantly greater in intact compared to adrenalectomized rats. These observations suggest that adrenal 11-hydroxylation of 11-deoxycortisol may account for its lack of effectiveness as a glucocorticoid antagonist in intact animals. Thus, analogs of 11-deoxycortisol that cannot undergo 11-hydroxylation should be promising compounds to examine in seeking a clinically effective glucocorticoid antagonist.
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