On the site of action of the anti-adrenal steroidogenic effect of etomidate and megestrol acetate.

The sites of action of the anti-steroidogenic action of etomidate and megestrol acetate have been established with a novel in vitro approach based upon the inhibition of cortisol (Co) secretion by dispersed guinea-pig adrenal cells. The cells were challenged with the Co precursor steroids (all at 10(-5) mol/l) pregnenolone (Pe), 17-hydroxy-pregnenolone (17-Pe), progesterone (Po), 17-hydroxyprogesterone (17-Po), 21-deoxycortisol (21-DOC) and 11-deoxycortisol (11-DOC), or 1-24 adrenocorticotrophin (ACTH, 100 ng/l) in the presence or absence of either etomidate, megestrol acetate, metyrapone or trilostane (all at 5 X 10(-5) mol/l). In the absence of drug, the steroid precursors or ACTH provoked a cortisol secretion of greater than 14 times that secreted by cells incubated in their absence. ACTH-stimulated Co secretion was inhibited by greater than 85% by all the drugs employed. In the presence of trilostane and megestrol acetate, Co secretion provoked by the delta 4 3-keto steroids (Po, 17-Po, 21-DOC and 11-DOC) was similar to the controls. However, with the delta 5, 3 beta-hydroxy steroids, 17-Pe and Pe, Co secretion was inhibited by greater than 57% in the presence of these drugs. In contrast, etomidate and metyrapone inhibited Co secretion by greater than 60% when 11-deoxycortisol was employed, indicative of a block at 11 beta-hydroxylase, the final step in the cortisol biosynthetic pathway. Similar results were seen with Pe, 17-Pe, Po and 17-Po, all of which are converted to cortisol via a biosynthetic route which includes catalysis by 11 beta-hydroxylase.(ABSTRACT TRUNCATED AT 250 WORDS)