Δ(1,9(11))-11-deoxycortisol: An improved glucocorticoid antagonist

G. P. Chrousos, K. M. Barnes, M. A. Sauer, Donald (Lynn) Loriaux, G. B. Cutler

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Previous studies in the rat have demonstrated that 11-deoxycortisol [compound S (pregn-4-ene-17α,21-diol-3,20-dione)], a competitive glucocorticoid antagonist in vitro, fails to behave as an antagonist in growth and adrenal suppression bioassays in nonadrenalectomized animals. This is probably explained by conversion of 11-deoxycortisol to cortisol by the adrenal glands. Δ(1,9(11))-11-deoxycortisol (pregn-1,4,9(11))-triene-17α,21-diol-3,20 dione) has been shown to resist 11-hydroxylation because of the double bond at the 9-11 position and, hence, should be a more effective antiglucocorticoid in vivo. This hypothesis was tested by comparing the in vivo antiglucocorticoid activity of Δ(1,9(11))-11-deoxycortisol with that of 11-deoxycortisol. The affinity of both compounds for the rat thymus glucocorticoid receptor was similar (equilibrium dissociation constant, 3 x 10 -7 M). Both compounds antagonized dexamethasone-induced liver glycogen accumulation in nonadrenalectomized rats, Δ(1,9(11))-11-deoxycortisol being 3-fold more potent than 11-deoxycortisol. Neither compound showed agonist activity in this bioassay. Δ(1,9(11))-11-Deoxycortisol showed partial agonist-antagonist activity in 1-week growth suppression and thymus suppression assays, while 11-deoxycortisol behaved as a glucocorticoid agonist. Both compounds failed to antagonize dexamethasone and acted as agonists of equal potency in a 1-week adrenal suppression assay. Δ 1,911-11-Deoxycortisol, administered to adrenalectomized rats, lost all its agonist activity in the gorwth suppression assay and exhibited only antagonist activity. These observations suggest that adrenal 11-hydroxylation of both 11-deoxycortisol and Δ(1,9(11))-11-deoxycortisol produces metabolites with agonist activity. Δ 1,911-11-Deoxycortisol retains antagonist activity, probably because conversion to the agonist metabolite is less complete and its intrinsic antagonist activity is greater. These observations support the hypothesis that analogs of 11-deoxycortisol with increased resistance to 11-hydroxylation will have increased antiglucocorticoid activity in intact (nonadrenalectomized) animals.

Original languageEnglish (US)
Pages (from-to)472-477
Number of pages6
JournalEndocrinology
Volume107
Issue number2
StatePublished - 1980
Externally publishedYes

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Cortodoxone
Glucocorticoids
Hydroxylation
Biological Assay
Thymus Gland
Dexamethasone
Liver Glycogen
Glucocorticoid Receptors
Adrenal Glands
Growth

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Chrousos, G. P., Barnes, K. M., Sauer, M. A., Loriaux, D. L., & Cutler, G. B. (1980). Δ(1,9(11))-11-deoxycortisol: An improved glucocorticoid antagonist. Endocrinology, 107(2), 472-477.

Δ(1,9(11))-11-deoxycortisol : An improved glucocorticoid antagonist. / Chrousos, G. P.; Barnes, K. M.; Sauer, M. A.; Loriaux, Donald (Lynn); Cutler, G. B.

In: Endocrinology, Vol. 107, No. 2, 1980, p. 472-477.

Research output: Contribution to journalArticle

Chrousos, GP, Barnes, KM, Sauer, MA, Loriaux, DL & Cutler, GB 1980, 'Δ(1,9(11))-11-deoxycortisol: An improved glucocorticoid antagonist', Endocrinology, vol. 107, no. 2, pp. 472-477.
Chrousos GP, Barnes KM, Sauer MA, Loriaux DL, Cutler GB. Δ(1,9(11))-11-deoxycortisol: An improved glucocorticoid antagonist. Endocrinology. 1980;107(2):472-477.
Chrousos, G. P. ; Barnes, K. M. ; Sauer, M. A. ; Loriaux, Donald (Lynn) ; Cutler, G. B. / Δ(1,9(11))-11-deoxycortisol : An improved glucocorticoid antagonist. In: Endocrinology. 1980 ; Vol. 107, No. 2. pp. 472-477.
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