The influence of ketoconazole on human adrenal steroidogenesis: incubation studies with tissue slices.

OBJECTIVE

The influence of ketoconazole on the various enzymes of human adrenal steroid biosynthesis was examined in vitro.

MEASUREMENTS

After incubation of human adrenal tissue slices with labelled precursors and ketoconazole (0-2000 microM), radioactive metabolites were separated by thin-layer chromatography and quantified by liquid scintillation counting. Enzyme activity was assessed by measuring conversion of tritium-labelled precursors to products.

RESULTS

In vitro, ketoconazole showed a significant inhibition on the following adrenal enzyme systems (with decreasing activity): C17,20-desmolase (IC50 2 microM), 16 alpha-hydroxylase (IC50 9 microM), 17 alpha-hydroxylase (IC50 18 microM), 18-hydroxylase (IC50 28 microM), and 11 beta-hydroxylase (IC50 35 microM). In the tested concentrations ketoconazole had no inhibitory effect on the 21-hydroxylase, the 3 beta-hydroxysteroid dehydrogenase and the 20-hydroxysteroid dehydrogenase component of the C17,20-desmolase enzyme system.

CONCLUSIONS

The data are in accordance with clinical findings where a strong suppression of serum androgen levels by relatively selective inhibition of C17, 20-desmolase has been assumed. The predominant blocking effect of ketoconazole on adrenal as well as on gonadal androgen biosynthesis might be of clinical benefit in the management of hyperandrogenic states.