DIFFERENT INHIBITORY EFFECT OF ETOMIDATE AND KETOCONAZOLE ON THE HUMAN ADRENAL-STEROID BIOSYNTHESIS

The narcotic agent etomidate and the antimycotic drug ketoconazole are known to block steroid biosynthesis in man. To study the different ef fects of these imidazole derivatives on human adrenal steroid biosynth esis we incubated slices of human adrenal glands with H-3-labeled prec ursors and increasing concentrations of etomidate or ketoconazole (0-2 000 muM). After extraction the labeled metabolites were separated by t hin-layer chromatography and quantified by scintillation counting. Eto midate inhibited most potently 11beta-hydroxylase activity by-suppress ing the formation of corticosterone from 11-deoxycorticosterone to 1% of control [50% inhibitory concentration (IC50) 0.03 muM] while ketoco nazole suppressed 11beta-hydroxylase to only 39% of control activity ( IC50 15 muM). Ketoconazole however, most potently blocked the conversi on of 17alpha-hydroxy-progesterone to androstenedione by C17,20-desmol ase to about 15% of control activity (IC50 1 muM) while etomidate show ed a much weaker effect on this enzyme with a suppression to 50% of C1 7,20-desmolase control activity at a concentration of 380 muM. Both im idazole drugs showed a similar strong inhibitory effect on the activit y of 17alpha-hydroxylase (IC50 6-18 muM) and 16alpha-hydroxylase (IC50 4-8 muM) and did not affect 21-hydroxylase. These in vitro data indic ate a predominant inhibitory effect of etomidate on corticosteroid bio synthesis by relative selective inhibition of 11beta-hydroxylase and o f ketoconazole on the adrenal androgen biosynthesis by a predominant i nhibition of C17,20-desmolase. This differential inhibitory effect of etomidate and ketoconazole on human steroid biosynthesis may be of cli nical importance for a possible therapeutic use of these imidazole der ivatives in endocrine disorders.