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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 ± 10−5 mol/l). In the absence of drug, the steroid precursors or ACTH provoked a cortisol secretion of > 14 times that secreted by cells incubated in their absence. ACTH‐stimulated Co secretion was inhibited by > 85% by all the drugs employed. In the presence of trilostane and megestrol acetate, Co secretion provoked by the Δ4 3‐keto steroids (Po, 17‐Po, 21‐DOC and 11‐DOC) was similar to the controls. However, with the Δ5, 3β‐hydroxy steroids, 17‐Pe and Pe, Co secretion was inhibited by > 57% in the presence of these drugs. In contrast, etomidate and metyrapone inhibited Co secretion by >60% when 11‐deoxycortisol was employed, indicative of a block at 11 β‐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 β‐hydroxylase. In contrast the transformation of 21‐deoxycortisol to Co, a step which proceeds directly via 21‐hydroxylase, was unaffected by the presence of any of the drugs. The site of action for etomidate was confirmed by a second method. Adrenal cells were incubated for 90 min with ACTH (1–24, 100 ng/l) and 14C‐pregnenolone in the presence and absence of either etomidate or trilostane. 11‐DOC and Co were extracted from the incubates and assayed by thin‐layer chromotography. The ratio of 11‐DOC to Co was 0.20, 0.27 and 1.64 for the control, trilostane and etomidate incubations respectively. We conclude that trilostane and megestrol acetate are 3a‐hydroxysteroid dehydrogenase, A5‐A4 isomerase inhibitors, whereas metyrapone and etomidate act at the level of 1 la‐hydroxylase.