Different inhibitory effect of etomidate and ketoconazole on the human adrenal steroid biosynthesis

Summary The narcotic agent etomidate and the antimycotic drug ketoconazole are known to block steroid biosynthesis in man. To study the different effects of these imidazole derivatives on human adrenal steroid biosynthesis we incubated slices of human adrenal glands with 3H-labeled precursors and increasing concentrations of etomidate or ketoconazole (0-2000 M). After extraction the labeled metabolites were separated by thin-layer chromatography and quantified by scintillation counting. Etomidate inhibited most potently 11-hydroxylase activity by suppressing the formation of corticosterone from 11-deoxycorticosterone to 1 % of control 50% inhibitory concentration (IC₅₀) 0.03 M] while ketoconazole suppressed 11-hy-droxylase to only 39% of control activity (IC₅₀ 15 M). Ketoconazole however, most potently blocked the conversion of 17-hydroxy-proges-terone to androstenedione by C17,20-desmolase to about 15% of control activity (IC₅₀ 1 M) while etomidate showed a much weaker effect on this enzyme with a suppression to 50% of C17,20-desmolase control activity at a concentration of 380 M. Both imidazole drugs showed a similar strong inhibitory effect on the activity of 17-hy-droxylase (IC₅₀ 6-18 M) and 16-hydroxylase (IC₅₀ 4–8 M) and did not affect 21-hydroxylase. These in vitro data indicate a predominant inhibitory effect of etomidate on corticosteroid biosynthesis by relative selective inhibition of 11-hydroxylase and of ketoconazole on the adrenal androgen biosynthesis by a predominant inhibition of C17,20-desmolase. This differential inhibitory effect of etomidate and ketoconazole on human steroid biosynthesis may be of clinical importance for a possible therapeutic use of these imidazole derivatives in endocrine disorders.Abbreviations IC₅₀ 50% inhibitory concentration Dedicated to Prof. Dr. G. Paumgartner on the occasion of his 60th birthday