Antifungal Climbazole alters androgenic pathways in mammalian cells

Among antifungal agents used in pharmaceuticals (e.g., antimycotic foot care) and personal care products, the synthetic azole climbazole (CBZ; 1-(4-Chlorophenoxy)-1-(imidazol-1-yl)-3,3-dimethylbutan-2-one) acts on the fungus Malassezia. Despite concerns surrounding its effects on health, based on reports of alterations to reproduction and steroidogenesis in fish, little is known about its mechanism of action as an endocrine disrupting chemical (EDC) in mammalian cells.<br/>
In this study, using OECD test guidelines, we investigated the effects of CBZ (i) in H295R cells, on the production of estradiol and testosterone, as well as intermediate metabolites in steroidogenesis pathway, and (ii) in HeLa9903 and AR-EcoScreen cell lines, on the transactivation of estrogen and androgen receptors.<br/>
Our results are the first evidence in H295R cells, that CBZ treatment (from 0.3 M) decreased secreted levels of testosterone and estradiol. This decreased secretion was associated with reduced 17-hydroxypregnenolone and 17-hydroxyprogesterone levels. The altered levels of these metabolites were not associated with decreased expression of cytochrome P450 17-hydroxylase/17,20-lyase (Cyp17). CBZ was also found to exert antagonistic effects toward androgen and estrogen  receptors. These results give additional insights into the toxicological mechanism of action of CBZ. Many azoles share structural similarities with CBZ, therefore, caution should be adopted with respect to their potential toxicological properties.