18-Ethynyl-deoxycorticosterone inhibition of steroid production is different in freshly isolated compared to cultured calf zona glomerulosa cells.
The inhibiting effects of 18-ethynyl-deoxycorticosterone (18-E-DOC) as a mechanism-based inhibitor on the late-steps of the aldosterone biosynthetic pathway were examined in calf adrenal zona glomerulosa cells in primary culture and in freshly isolated calf zona glomerulosa cells. 18-E-DOC inhibited the stimulated secretion of aldosterone and 18-hydroxycorticosterone in a similar dose-response and time fashion. No significant differences were found between the inhibition in cultured and freshly isolated cells (Ki of 0.25 vs 0.26 microM) Corticosterone secretion stimulated by ACTH or angiotensin II was also cultured in freshly isolated zona glomerulosa and fasciculata cells, but was not inhibited in cultured calf adrenal cells. Cortisol secretion stimulated by ACTH was not inhibited by 18-E-DOC in cultured zona fasciculata adrenal cells, but was inhibited in freshly isolated zona fasciculata cells with a Ki of 48 microM. The secretion of 18-hydroxyDOC or 19-hydroxyDOC stimulated by ACTH was not inhibited by 18-E-DOC. The bovine adrenal has been reported to have cytochrome P-450 11 beta-hydroxylases that can perform the various hydroxylations required for the synthesis of cortisol and aldosterone in the different areas of the adrenal. In other species a distinct 11 beta-hydroxylase which participates in the biosynthesis of aldosterone and is located in the zona glomerulosa has been described. These studies with the mechanism-based inhibitor, 18-E-DOC, suggest that the bovine adrenal functions in a manner very similar to that of other species and raises the possibility that a distinct 11 beta-hydroxylase with aldosterone synthase activity might be present, but has not been cloned as yet.
Gomez-Sanchez
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CE
Department of Internal Medicine, University of Missouri-Columbia, Harry S. Truman Memorial Veterans Hospital.
Chiou
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S
Yamakita
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N
D000305:Adrenal Cortex Hormones / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007700:Kinetics; D011188:Potassium / Q000494:pharmacology; D015383:Zona Fasciculata / Q000187:drug effects / Q000378:metabolism; D015384:Zona Glomerulosa / Q000187:drug effects / Q000378:metabolism*
D000305:Adrenal Cortex Hormones; D000804:Angiotensin II; D003900:Desoxycorticosterone; C071418:18-ethynyldeoxycorticosterone; D000324:Adrenocorticotropic Hormone; D011188:Potassium