Effects of etomidate on cortisol biosynthesis in isolated guinea-pig adrenal cells: comparison with metyrapone.
The effects of the iv hypnotic etomidate on cortisol biosynthesis have been investigated in short term incubations of dispersed guinea-pig adrenal cells and were compared with those produced by metyrapone. Fifty percent inhibition of cortisol output was obtained at a final medium concentration of 3.5 10(-8) M (basal), 2.8 10(-8) M (ACTH-stimulated) for etomidate and of 5.10(-7) M (stimulated) for metyrapone. In the presence of etomidate, 11-deoxycortisol at 5.10(-8) M reached a peak value of 244 +/- 11% of control (mean +/- SE, n = 7). 17 alpha-Hydroxyprogesterone and progesterone were not significantly affected up to 10(-7) M, but at higher concentrations, all three precursors fell under their control values. Metyrapone induced a progressive rise of 11-deoxycortisol, from 10(-7) M upwards, to a maximum level at 10(-5) M (210 +/- 15% of control, mean +/- SE, n = 5). 17-Hydroxyprogesterone and progesterone concentrations were not significantly modified by metyrapone. The less active hypnotic L-enantiomer of etomidate had almost no inhibitory effect on cortisol production. The results obtained so far suggest that etomidate is a potent inhibitor of the mitochondrial cytochrome P-450 enzymes of the adrenal cortex, mainly the 11 beta-hydroxylase. At higher dose the cholesterol side-chain cleavage enzyme system seemed also to be affected.
De Coster
R
R
Beerens
D
D
Haelterman
C
C
Wouters
L
L
D019326:17-alpha-Hydroxyprogesterone; D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000096:biosynthesis; D000818:Animals; D003350:Cortodoxone / Q000096:biosynthesis; D005045:Etomidate / Q000494:pharmacology*; D006168:Guinea Pigs; D006854:Hydrocortisone / Q000096:biosynthesis*; D006908:Hydroxyprogesterones / Q000096:biosynthesis; D007093:Imidazoles / Q000494:pharmacology*; D008797:Metyrapone / Q000494:pharmacology*; D011374:Progesterone / Q000096:biosynthesis; D013997:Time Factors
D006908:Hydroxyprogesterones; D007093:Imidazoles; D011374:Progesterone; D019326:17-alpha-Hydroxyprogesterone; D000324:Adrenocorticotropic Hormone; D003350:Cortodoxone; D006854:Hydrocortisone; D005045:Etomidate; D008797:Metyrapone