Document Detail

Fluconazole inhibits human adrenocortical steroidogenesis in vitro.
MedLine Citation:
PMID:  23038793     Owner:  NLM     Status:  MEDLINE    
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.
R van der Pas; L J Hofland; J Hofland; A E Taylor; W Arlt; J Steenbergen; P M van Koetsveld; W W de Herder; F H de Jong; R A Feelders
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Publication Detail:
Type:  Journal Article     Date:  2012-10-04
Journal Detail:
Title:  The Journal of endocrinology     Volume:  215     ISSN:  1479-6805     ISO Abbreviation:  J. Endocrinol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-12     Completed Date:  2013-01-16     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0375363     Medline TA:  J Endocrinol     Country:  England    
Other Details:
Languages:  eng     Pagination:  403-12     Citation Subset:  IM    
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MeSH Terms
17-alpha-Hydroxyprogesterone / metabolism
Adrenal Cortex / drug effects*,  metabolism*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cells, Cultured
Cortodoxone / metabolism
Desoxycorticosterone / metabolism
Fluconazole / pharmacology*
Hydrocortisone / metabolism
Ketoconazole / adverse effects,  pharmacology
Pregnenolone / metabolism
Progesterone / metabolism
Grant Support
G0801473//Medical Research Council
Reg. No./Substance:
40GP35YQ49/Desoxycorticosterone; 4G7DS2Q64Y/Progesterone; 68-96-2/17-alpha-Hydroxyprogesterone; 73R90F7MQ8/Pregnenolone; 8VZV102JFY/Fluconazole; R9400W927I/Ketoconazole; WDT5SLP0HQ/Cortodoxone; WI4X0X7BPJ/Hydrocortisone

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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