Food additive salicylates inhibit human and rat placental 3β-hydroxysteroid dehydrogenase: 3D-QSAR and in silico analysis

The use of salicylates as flavoring agents in food and beverages is common, but their potential to disrupt the endocrine system remains unclear. Human placental 3 beta-hydroxysteroid dehydrogenase 1 (h3 beta-HSD1) plays a role in progesterone synthesis and is the potential target. This study evaluated the inhibition of 13 salicylates on h3 beta HSD1, structure-activity relationship (SAR) and compared with rat placental homolog r3 beta-HSD4. Salicylates inhibited h3 beta-HSD1, depending on carbon chain number in the alcohol moiety and the IC50 values for hexyl, ethylhexyl, homomenthyl, and menthyl salicylates were 53.27, 15.78, 2.35, and 2.31 mu M, as mixed inhibitors, respectively, while methyl to benzyl salicylates were ineffective at 100 mu M. Interestingly, only hexyl salicylate inhibited r3 beta-HSD4 with IC50 of 31.05 mu M. Bivariate analysis revealed a negative correlation between IC50 and hydrophobicity (LogP), molecular weight, heavy atoms, and carbon number in the alcohol moiety against h3 beta HSD1. Docking analysis demonstrated that these salicylates bind to cofactor binding sites or between the steroid and cofactor binding sites. Additionally, 3D-QSAR showed distinct binding via hydrogen bond donors and hydrophobic regions. In conclusion, the inhibition of h3 beta-HSD1 by salicylates appears to be dependent on factors such as LogP, molecular weight, heavy atoms, and carbon-chain length and there is species-dependent inhibition sensitivity.