title: Effects of two oral antimycotics, ketoconazole and fluconazole, upon steroidogenesis in rat adrenal cells in vitro.
abstract: Rat adrenal cells were incubated with various concentrations of two orally active azole antimycotics in order to evaluate the effects on steroidogenesis. The first compound was ketoconazole, a well-known inhibitor not only of fungal cytochrome P-450 but at higher concentrations also of mammalian cytochrome P-450 dependent enzymes. The second was fluconazole, a newly developed oral antimycotic with a triazole structure, which likewise inhibits fungal cytochrome P-450. The influence of both drugs on mammalian cytochrome P-450 dependent enzymes was investigated in this study. Ketoconazole inhibited ACTH-stimulated corticosterone (IC50 = 0.9 microM) and aldosterone secretion (IC50 = 1.4 microM) and enhanced 11-deoxycorticosterone output at low concentrations but reduced it at higher concentrations. Radiotracer experiments with [3H]pregnenolone or [3H]11-deoxycorticosterone as exogenous substrates revealed a 50% inhibition of the oxidative substrate metabolism at about 1 microM ketoconazole. These effects could also be observed with fluconazole but occurred at concentrations approximately two orders of magnitude higher as compared to ketoconazole. We conclude that fluconazole has a much higher selectivity for fungal cytochrome P-450 than ketoconazole. The order of sensitivity of the cytochrome P-450 dependent enzymes of rat adrenal steroidogenesis to ketoconazole was the 11 beta/18-hydroxylase, the cholesterol side chain cleavage enzyme and the 21-hydroxylase with decreasing sensitivities.
authors.affiliation: Freie Universität Berlin, Institut für Toxikologie und Embryonalpharmakologie, F.R.G.
authors.forename: C
authors.initials: C
authors.lastname: Eckhoff
authors.forename: W
authors.initials: W
authors.lastname: Oelkers
authors.forename: V
authors.initials: V
authors.lastname: Bähr
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects* / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015725:Fluconazole; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D011284:Pregnenolone / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013256:Steroids / Q000096:biosynthesis*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D013256:Steroids; D014230:Triazoles; D011284:Pregnenolone; D015725:Fluconazole; D000324:Adrenocorticotropic Hormone; D007654:Ketoconazole