Suppression of human and rat 17β-hydroxysteroid dehydrogenase 1 by isothiazolinone-based disinfectants: Insights into mechanism and implications for hormonal homeostasis

Isothiazolinone disinfectants constitute a class of broad-spectrum antimicrobial agents due to the pandemic of COVID-19. The aim of this study was to assess the impacts of six distinct isothiazolinone disinfectants on the activity of 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1) in humans and rats, as well as on BeWo cells. We identified IC 50 with 4,5-dichloro-2-octyl-1,2-thiazol-3-one exhibiting the most potent inhibition (8.09 μM for human 17β-HSD1) and 5-chloro-2-methyl-1,2-thiazol-3-one showing the weak inhibition (81.94 μM for human 17β-HSD1) and these chemicals can potently inhibit estradiol production at ≥ 1 μM. Additionally, 4,5-dichloro-2-octyl-1,2-thiazol-3-one and 2-octyl-1,2-thiazol-3-one inhibited rat 17β-HSD1 at IC 50 concentrations of 20.53 and 32.47 μM, respectively. Through mode action analyses, these compounds were found to exert mixed inhibition. Computational docking simulations revealed that isothiazolinone disinfectants interact with the NADPH binding domains of the two enzymes. Bivariate correlation analysis confirmed negative relationships between physicochemical properties such as LogP and heavy atoms, and half maximum inhibition concentrations of these chemicals. 3D-QSAR analysis revealed the presence of hydrophobic and hydrogen bond regions and both positively contribute to the binding. In conclusion, isothiazolinone disinfectants repress human and rat 17β-HSD1, depending on their hydrophobicity and hydrogen bonds.