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The action of phorbol ester on steroidogenesis in cultured human fetal adrenal cells.

Abstract
The potent mitogen and tumor promoter, phorbol 12-myristate 13-acetate (PMA), has a primary action via activation of calcium-dependent protein kinase C. The treatment of monolayer cultures of human fetal adrenal neocortex (HFA) cells with PMA (50-250 nM) stimulated basal dehydroepiandrosterone sulfate (DS) secretion 2-3 fold. ACTH-treated HFA cells secreted amounts of DS and cortisol (F) 10-50 fold greater than basal secretions. PMA (250 nM) addition with ACTH to HFA cells decreased DS and F secretions at least 75% on days 2 and 3 of treatment. Treatment of HFA cells with 4 alpha-phorbol, which does not activate calcium-dependent protein kinase C, did not inhibit steroidogenesis. The attenuated rates of steroidogenesis after PMA treatment correlated with the decreased amounts of steroid 11 beta, 17 alpha- and 21-hydroxylase cholesterol side-chain cleavage steroid dehydrogenase and sulfotransferase activities. The decrease of steroid 17 alpha-hydroxylase activity correlated with the decreased amount of cytochrome P-450(17) alpha as determined after protein immunoblotting of NaDodSO4 cell lysates. After PMA treatment the ACTH-promoted increases of hydroxysteroid sulfotransferase and dehydrogenase activities of HFA cells were suppressed. PMA (50 nM) inhibited cAMP accumulation in ACTH-treated HFA cells, while 4 alpha-phorbol had no effect. Importantly, dibutyryl cAMP (0.2 mM) treatment of HFA cells did not reverse phorbol ester-promoted attenuation of steroidogenesis. We conclude that, in the presence of ACTH, phorbol ester chronically inhibits both cAMP synthesis and cAMP-dependent protein kinase action with resultant decreased steroidogenic enzyme synthesis and steroid production. This may be a consequence of activation, migration and a slow degradation of protein kinase C activity. These multifaceted actions of phorbol ester and associated protein kinase C activation may have critical effects on the ontogeny of fetal adrenal function.
AuthorsJ I Mason, B R Carr, W E Rainey
JournalEndocrine research (Endocr Res) Vol. 12 Issue 4 Pg. 447-67 ( 1986) ISSN: 0743-5800 [Print] England
PMID3030721 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Diglycerides
  • Phorbol Esters
  • Phorbols
  • Dehydroepiandrosterone
  • Dehydroepiandrosterone Sulfate
  • Bucladesine
  • Adrenocorticotropic Hormone
  • Cyclic AMP
  • Steroid Hydroxylases
  • Protein Kinase C
  • Tetradecanoylphorbol Acetate
  • Hydrocortisone
  • phorbol
Topics
  • Adrenal Cortex (embryology)
  • Adrenocorticotropic Hormone (pharmacology)
  • Bucladesine (pharmacology)
  • Cells, Cultured
  • Cyclic AMP (metabolism)
  • Dehydroepiandrosterone (analogs & derivatives, metabolism)
  • Dehydroepiandrosterone Sulfate
  • Diglycerides (metabolism)
  • Humans
  • Hydrocortisone (metabolism)
  • Phorbol Esters (pharmacology)
  • Phorbols (pharmacology)
  • Protein Kinase C (metabolism)
  • Steroid Hydroxylases (metabolism)
  • Tetradecanoylphorbol Acetate (pharmacology)

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