Effect of the antiglucocorticoid RU486 on adrenal steroidogenic enzyme activity and steroidogenesis

B. D. Albertson, R. B. Hill, K. A. Sprague, K. E. Wood, L. K. Nieman, Donald (Lynn) Loriaux

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

RU486, a synthetic steroid receptor antagonist, has strong antiprogesterone and antiglucocorticoid properties. Chronic RU486 administration in two patients with ectopic secretion of adrenocorticotropin (ACTH) has been associated with decreasing plasma cortisol concentrations. One explanation of this finding is that RU486 may directly inhibit adrenal steroidogenesis. To test this hypothesis, we measured the effect of RU486 on specific steroidogenic enzymatic steps using an in vivo rat and an in vitro monkey model. Hypophysectomized-castrated-ACTH-replaced Sprague-Dawley rats were given RU486 i.p. at daily doses of 0, 0.0005, 0.005, 0.05, 0.5 and 5 mg/kg body weight per day for 7 days. The animals were sacrificed, and blood and adrenal glands collected. Adrenal cortical mitochondria and microsomes were purified from the rats and from the two untreated Cynomolgus macaque monkeys. Specific steroidogenic enzyme activities were measured in the rat by the incorporation of 14C-labeled steroid substrates into products. A similar protocol was used to assay the steroidogenesis in the monkey adrenal fractions in the presence and absence of added RU486. Although rat adrenal weights decreased significantly at the highest RU486 dose, plasma levels of corticosterone were similar in control and treated rats. Rat adrenal 3β- hydroxysteroid dehydrogenase/isomerase (3-HSD), 21-hydroxylase (21-OH) and 11-hydroxylase (11-OH) activities decreased with increasing RU486 doses, with 21-OH and 11-OH being most severely affected. Monkey adrenal 3-HSD, 21-OH, 11-OH, 17-hydroxylase and 17,20-desmolase similarly decreased in the presence of increasing in vitro concentrations of RU486. Taken together, these results suggest that RU486 directly inhibits adrenal steroidogenesis, with a locus of action at several key enzymatic steps in the glucocorticoid pathway. This steroidogenic blockade may account for the observed decreases in glucocorticoids during RU486 treatment.

Original languageEnglish (US)
Pages (from-to)195-200
Number of pages6
JournalEuropean Journal of Endocrinology
Volume130
Issue number2
StatePublished - 1994
Externally publishedYes

Fingerprint

Enzymes
3-Hydroxysteroid Dehydrogenases
Adrenocorticotropic Hormone
Haplorhini
Isomerases
Mixed Function Oxygenases
Glucocorticoids
Artificial Receptors
Steroid 17-alpha-Hydroxylase
Steroid 21-Hydroxylase
Macaca fascicularis
Steroid Receptors
Macaca
Adrenal Glands
Corticosterone
Microsomes
Sprague Dawley Rats
Hydrocortisone
Mitochondria
Steroids

ASJC Scopus subject areas

  • Endocrinology

Cite this

Albertson, B. D., Hill, R. B., Sprague, K. A., Wood, K. E., Nieman, L. K., & Loriaux, D. L. (1994). Effect of the antiglucocorticoid RU486 on adrenal steroidogenic enzyme activity and steroidogenesis. European Journal of Endocrinology, 130(2), 195-200.

Effect of the antiglucocorticoid RU486 on adrenal steroidogenic enzyme activity and steroidogenesis. / Albertson, B. D.; Hill, R. B.; Sprague, K. A.; Wood, K. E.; Nieman, L. K.; Loriaux, Donald (Lynn).

In: European Journal of Endocrinology, Vol. 130, No. 2, 1994, p. 195-200.

Research output: Contribution to journalArticle

Albertson, BD, Hill, RB, Sprague, KA, Wood, KE, Nieman, LK & Loriaux, DL 1994, 'Effect of the antiglucocorticoid RU486 on adrenal steroidogenic enzyme activity and steroidogenesis', European Journal of Endocrinology, vol. 130, no. 2, pp. 195-200.
Albertson, B. D. ; Hill, R. B. ; Sprague, K. A. ; Wood, K. E. ; Nieman, L. K. ; Loriaux, Donald (Lynn). / Effect of the antiglucocorticoid RU486 on adrenal steroidogenic enzyme activity and steroidogenesis. In: European Journal of Endocrinology. 1994 ; Vol. 130, No. 2. pp. 195-200.
@article{445b6f7d062d4f4e95985e9ac416b127,
title = "Effect of the antiglucocorticoid RU486 on adrenal steroidogenic enzyme activity and steroidogenesis",
abstract = "RU486, a synthetic steroid receptor antagonist, has strong antiprogesterone and antiglucocorticoid properties. Chronic RU486 administration in two patients with ectopic secretion of adrenocorticotropin (ACTH) has been associated with decreasing plasma cortisol concentrations. One explanation of this finding is that RU486 may directly inhibit adrenal steroidogenesis. To test this hypothesis, we measured the effect of RU486 on specific steroidogenic enzymatic steps using an in vivo rat and an in vitro monkey model. Hypophysectomized-castrated-ACTH-replaced Sprague-Dawley rats were given RU486 i.p. at daily doses of 0, 0.0005, 0.005, 0.05, 0.5 and 5 mg/kg body weight per day for 7 days. The animals were sacrificed, and blood and adrenal glands collected. Adrenal cortical mitochondria and microsomes were purified from the rats and from the two untreated Cynomolgus macaque monkeys. Specific steroidogenic enzyme activities were measured in the rat by the incorporation of 14C-labeled steroid substrates into products. A similar protocol was used to assay the steroidogenesis in the monkey adrenal fractions in the presence and absence of added RU486. Although rat adrenal weights decreased significantly at the highest RU486 dose, plasma levels of corticosterone were similar in control and treated rats. Rat adrenal 3β- hydroxysteroid dehydrogenase/isomerase (3-HSD), 21-hydroxylase (21-OH) and 11-hydroxylase (11-OH) activities decreased with increasing RU486 doses, with 21-OH and 11-OH being most severely affected. Monkey adrenal 3-HSD, 21-OH, 11-OH, 17-hydroxylase and 17,20-desmolase similarly decreased in the presence of increasing in vitro concentrations of RU486. Taken together, these results suggest that RU486 directly inhibits adrenal steroidogenesis, with a locus of action at several key enzymatic steps in the glucocorticoid pathway. This steroidogenic blockade may account for the observed decreases in glucocorticoids during RU486 treatment.",
author = "Albertson, {B. D.} and Hill, {R. B.} and Sprague, {K. A.} and Wood, {K. E.} and Nieman, {L. K.} and Loriaux, {Donald (Lynn)}",
year = "1994",
language = "English (US)",
volume = "130",
pages = "195--200",
journal = "European Journal of Endocrinology",
issn = "0804-4643",
publisher = "BioScientifica Ltd.",
number = "2",

}

TY - JOUR

T1 - Effect of the antiglucocorticoid RU486 on adrenal steroidogenic enzyme activity and steroidogenesis

AU - Albertson, B. D.

AU - Hill, R. B.

AU - Sprague, K. A.

AU - Wood, K. E.

AU - Nieman, L. K.

AU - Loriaux, Donald (Lynn)

PY - 1994

Y1 - 1994

N2 - RU486, a synthetic steroid receptor antagonist, has strong antiprogesterone and antiglucocorticoid properties. Chronic RU486 administration in two patients with ectopic secretion of adrenocorticotropin (ACTH) has been associated with decreasing plasma cortisol concentrations. One explanation of this finding is that RU486 may directly inhibit adrenal steroidogenesis. To test this hypothesis, we measured the effect of RU486 on specific steroidogenic enzymatic steps using an in vivo rat and an in vitro monkey model. Hypophysectomized-castrated-ACTH-replaced Sprague-Dawley rats were given RU486 i.p. at daily doses of 0, 0.0005, 0.005, 0.05, 0.5 and 5 mg/kg body weight per day for 7 days. The animals were sacrificed, and blood and adrenal glands collected. Adrenal cortical mitochondria and microsomes were purified from the rats and from the two untreated Cynomolgus macaque monkeys. Specific steroidogenic enzyme activities were measured in the rat by the incorporation of 14C-labeled steroid substrates into products. A similar protocol was used to assay the steroidogenesis in the monkey adrenal fractions in the presence and absence of added RU486. Although rat adrenal weights decreased significantly at the highest RU486 dose, plasma levels of corticosterone were similar in control and treated rats. Rat adrenal 3β- hydroxysteroid dehydrogenase/isomerase (3-HSD), 21-hydroxylase (21-OH) and 11-hydroxylase (11-OH) activities decreased with increasing RU486 doses, with 21-OH and 11-OH being most severely affected. Monkey adrenal 3-HSD, 21-OH, 11-OH, 17-hydroxylase and 17,20-desmolase similarly decreased in the presence of increasing in vitro concentrations of RU486. Taken together, these results suggest that RU486 directly inhibits adrenal steroidogenesis, with a locus of action at several key enzymatic steps in the glucocorticoid pathway. This steroidogenic blockade may account for the observed decreases in glucocorticoids during RU486 treatment.

AB - RU486, a synthetic steroid receptor antagonist, has strong antiprogesterone and antiglucocorticoid properties. Chronic RU486 administration in two patients with ectopic secretion of adrenocorticotropin (ACTH) has been associated with decreasing plasma cortisol concentrations. One explanation of this finding is that RU486 may directly inhibit adrenal steroidogenesis. To test this hypothesis, we measured the effect of RU486 on specific steroidogenic enzymatic steps using an in vivo rat and an in vitro monkey model. Hypophysectomized-castrated-ACTH-replaced Sprague-Dawley rats were given RU486 i.p. at daily doses of 0, 0.0005, 0.005, 0.05, 0.5 and 5 mg/kg body weight per day for 7 days. The animals were sacrificed, and blood and adrenal glands collected. Adrenal cortical mitochondria and microsomes were purified from the rats and from the two untreated Cynomolgus macaque monkeys. Specific steroidogenic enzyme activities were measured in the rat by the incorporation of 14C-labeled steroid substrates into products. A similar protocol was used to assay the steroidogenesis in the monkey adrenal fractions in the presence and absence of added RU486. Although rat adrenal weights decreased significantly at the highest RU486 dose, plasma levels of corticosterone were similar in control and treated rats. Rat adrenal 3β- hydroxysteroid dehydrogenase/isomerase (3-HSD), 21-hydroxylase (21-OH) and 11-hydroxylase (11-OH) activities decreased with increasing RU486 doses, with 21-OH and 11-OH being most severely affected. Monkey adrenal 3-HSD, 21-OH, 11-OH, 17-hydroxylase and 17,20-desmolase similarly decreased in the presence of increasing in vitro concentrations of RU486. Taken together, these results suggest that RU486 directly inhibits adrenal steroidogenesis, with a locus of action at several key enzymatic steps in the glucocorticoid pathway. This steroidogenic blockade may account for the observed decreases in glucocorticoids during RU486 treatment.

UR - http://www.scopus.com/inward/record.url?scp=0028325281&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028325281&partnerID=8YFLogxK

M3 - Article

C2 - 8130896

AN - SCOPUS:0028325281

VL - 130

SP - 195

EP - 200

JO - European Journal of Endocrinology

JF - European Journal of Endocrinology

SN - 0804-4643

IS - 2

ER -