Prostaglandin biosynthesis in the human fetal adrenal gland: Regulation by glucocorticosteroids

M. D. Mitchell, B. R. Carr, J. I. Mason, E. R. Simpson

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Human fetal adrenal (HFA) tissue was maintained in organ culture to evaluate the biosynthesis of prostaglandins and hormonal regulation of prostaglandin formation by this tissue. The HFA tissue secreted substantial amounts of prostaglandin E2, prostaglandin F(2α), 13,14-dihydro-15-ketoprostaglandin F(2α), 6-ketoprostaglandin F(1α), and thromboxane B2; secretion of prostaglandin D2 could not be demonstrated. Prostaglandin biosynthesis in HFA tissue was inhibited in a time-dependent manner by corticotropin (ACTH; 0.4 μM); by the fourth day of culture, the extent of inhibition of biosynthesis of each prostaglandin was 60-90%. Progesterone (1 μM), cortisol (1 μM), and dexamethasone (1 μM) inhibited prostaglandin biosynthesis whereas estradiol (1 μM) did not. Of the compounds tested for inhibitory activity, dexamethasone was the most potent. An inhibitor of 11β-hydroxylase activity (metyrapone; 0.1 mM) effectively eliminated the inhibition of prostaglandin biosynthesis caused by corticotropin and progesterone. Metyrapone treatment alone caused a 3-fold increase in prostaglandin biosynthesis by fetal adrenal tissues. Similar stimulatory effects resulted from treatment with inhibitors of 3β-hydroxysteroid dehydrogenase (cyanoketone; 15 μM), steroid 17α-hydroxylase (SU 10603; 19 μM), and cholesterol side-chain cleavage (aminoglutethimide; 1 mM). Inhibition of prostaglandin biosynthesis by dexamethasone in the presence or absence of metyrapone was concentration dependent and 50% inhibition could be demonstrated at 1 nM. A competitive inhibitor of the binding of glucocorticosteroids to cytoplasmic receptors (cortisol 21-mesylate; 1 μM) significantly reduced the inhibition of prostaglandin biosynthesis effected by dexamethasone (10 nM). These findings suggest that prostaglandin biosynthesis in the HFA gland is regulated by endogenously synthesized glucocorticosteroids, the actions of which are mediated by a glucocorticosteroid receptor. Such glucocorticosteroids induce the synthesis of a substance that inhibits prostaglandin biosynthesis.

Original languageEnglish (US)
Pages (from-to)7547-7551
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number23 I
StatePublished - 1982

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