Identification of the fungicide epoxiconazole by virtual screening and biological assessment as inhibitor of human 11β-hydroxylase and aldosterone synthase

Akram, Muhammad and Patt, Melanie and Kaserer, Teresa and Temml, Veronika and Waratchareeyakul, Watcharee and Kratschmar, Denise V. and Haupenthal, Joerg and Hartmann, Rolf W. and Odermatt, Alex and Schuster, Daniela. (2019) Identification of the fungicide epoxiconazole by virtual screening and biological assessment as inhibitor of human 11β-hydroxylase and aldosterone synthase. Journal of Steroid Biochemistry and Molecular Biology, 192. p. 105358.

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Official URL: https://edoc.unibas.ch/71372/

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Humans are constantly exposed to a multitude of environmental chemicals that may disturb endocrine functions. It is crucial to identify such chemicals and uncover their mode-of-action to avoid adverse health effects. 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) catalyze the formation of cortisol and aldosterone, respectively, in the adrenal cortex. Disruption of their synthesis by exogenous chemicals can contribute to cardio-metabolic diseases, chronic kidney disease, osteoporosis, and immune-related disorders. This study applied in silico screening and in vitro evaluation for the discovery of xenobiotics inhibiting CYP11B1 and CYP11B2. Several databases comprising environmentally relevant pollutants, chemicals in body care products, food additives and drugs were virtually screened using CYP11B1 and CYP11B2 pharmacophore models. A first round of biological testing used hamster cells overexpressing human CYP11B1 or CYP11B2 to analyze 25 selected virtual hits. Three compounds inhibited CYP11B1 and CYP11B2 with IC; 50; values below 3 μM. The most potent inhibitor was epoxiconazole (IC; 50; value of 623 nM for CYP11B1 and 113 nM for CYP11B2, respectively); flurprimidol and ancymidol were moderate inhibitors. In a second round, these three compounds were tested in human adrenal H295R cells endogenously expressing CYP11B1 and CYP11B2, confirming the potent inhibition by epoxiconazole and the more moderate effects by flurprimidol and ancymidol. Thus, the in silico screening, prioritization of chemicals for initial biological tests and use of H295R cells to provide initial mechanistic information is a promising strategy to identify potential endocrine disruptors inhibiting corticosteroid synthesis. A critical assessment of human exposure levels and in vivo evaluation of potential corticosteroid disrupting effects by epoxiconazole is required.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
UniBasel Contributors:Odermatt, Alex and Patt, Melanie and Kratschmar, Denise
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:17 Aug 2020 14:02
Deposited On:17 Aug 2020 14:02

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