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Published on: November 15, 2013
Azole fungicides inhibit human and rat gonadal 3β-hydroxysteroid dehydrogenases: Structure-activity relationship and
Jianmin Sang1, Hong Wang1, Yang Yu1
1Department of Anaesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Abstract:
Azole fungicides are widely used in the agricultural industry to control fungal infections in crops. However, recent studies have shown that some azole fungicides inhibit the activity of 3β-hydroxysteroid dehydrogenases (3β-HSDs) in the gonads. Out of the 16 azole fungicides tested, 8 were found to inhibit human KGN cell 3β-HSD2 with IC50 values of less than 100 μM. The strongest inhibitor was difenoconazole, with an IC50 value of 1.88 μM. In contrast, only 3 of the azole fungicides inhibited rat testicular 3β-HSD1, which was less sensitive to inhibition. Azole fungicides potently inhibited progesterone secretion by KGN cells under basal and forskolin stimulated conditions at ≥ 5 μM. The inhibitory strength of azole fungicides was determined by their lipophilicity (LogP), molecular weight, pKa, and binding energy. A pharmacophore analysis revealed that the hydrogen bond acceptor-lipid group was a critical feature required for inhibition. Overall, these findings suggest that the use of azole fungicides have unintended consequences on reproductive health due to their inhibition of gonadal 3β-HSDs. Key words: Azole fungicides; steroid hormones; 3β-hydroxysteroid dehydrogenase; docking analysis; lipophilicity.
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