title: Fluconazole inhibits human adrenocortical steroidogenesis in vitro.
abstract: The antifungal agent ketoconazole is often used to suppress cortisol production in patients with Cushing's syndrome (CS). However, ketoconazole has serious side effects and is hepatotoxic. Here, the in vitro effects of ketoconazole and fluconazole, which might be less toxic, on human adrenocortical steroidogenesis were compared. The effects on steroidogenesis were examined in primary cultures of nine human adrenocortical tissues and two human adrenocortical carcinoma cell lines. Moreover, the effects on mRNA expression levels of steroidogenic enzymes and cell growth were assessed. Ketoconazole significantly inhibited 11-deoxycortisol (H295R cells; maximum inhibition 99%; EC(50) 0.73 μM) and cortisol production (HAC15 cells; 81%; EC(50) 0.26 μM and primary cultures (mean EC(50) 0.75 μM)). In cultures of normal adrenal cells, ketoconazole increased pregnenolone, progesterone, and deoxycorticosterone levels, while concentrations of 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, DHEA, and androstenedione decreased. Fluconazole also inhibited 11-deoxycortisol production in H295R cells (47%; only at 1 mM) and cortisol production in HAC15 cells (maximum inhibition 55%; EC(50) 35 μM) and primary cultures (mean EC(50) 67.7 μM). In the cultures of normal adrenals, fluconazole suppressed corticosterone, 17-hydroxypregnenolone, and androstenedione levels, whereas concentrations of progesterone, deoxycorticosterone, and 11-deoxycortisol increased. Fluconazole (1 mM) slightly increased STAR mRNA expression in both cell lines. Neither compound affected mRNA levels of other steroidogenic enzymes or cell number. In conclusion, by inhibiting 11β-hydroxylase and 17-hydroxylase activity, pharmacological concentrations of fluconazole dose dependently inhibit cortisol production in human adrenocortical cells in vitro. Although fluconazole seems less potent than ketoconazole, it might become an alternative for ketoconazole to control hypercortisolism in CS. Furthermore, patients receiving fluconazole because of mycosis might be at risk for developing adrenocortical insufficiency.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands. r.vanderpas@erasmusmc.nl
authors.forename: R
authors.initials: R
authors.lastname: van der Pas
authors.forename: L J
authors.initials: LJ
authors.lastname: Hofland
authors.forename: J
authors.initials: J
authors.lastname: Hofland
authors.forename: A E
authors.initials: AE
authors.lastname: Taylor
authors.forename: W
authors.initials: W
authors.lastname: Arlt
authors.forename: J
authors.initials: J
authors.lastname: Steenbergen
authors.forename: P M
authors.initials: PM
authors.lastname: van Koetsveld
authors.forename: W W
authors.initials: WW
authors.lastname: de Herder
authors.forename: F H
authors.initials: FH
authors.lastname: de Jong
authors.forename: R A
authors.initials: RA
authors.lastname: Feelders
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000378:metabolism; D000302:Adrenal Cortex / Q000187:drug effects* / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003350:Cortodoxone / Q000378:metabolism; D003900:Desoxycorticosterone / Q000378:metabolism; D015725:Fluconazole / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007654:Ketoconazole / Q000009:adverse effects / Q000494:pharmacology; D011284:Pregnenolone / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism
chemical_list: D003900:Desoxycorticosterone; D011374:Progesterone; D019326:17-alpha-Hydroxyprogesterone; D011284:Pregnenolone; D015725:Fluconazole; D007654:Ketoconazole; D003350:Cortodoxone; D006854:Hydrocortisone