Gallates (Wenzhou Medical University)

Gallates are extensively utilized as additives in food, pharmaceuticals, and cosmetics. Despite their widespread use, their impact on the endocrine system remains poorly understood. This study investigates the potential interaction of gallates with 3β-hydroxysteroid dehydrogenase (3β-HSD), a critical enzyme in placental progesterone synthesis. The inhibitory effects and structure-activity relationship (SAR) and 3D-QSAR of nine gallates on human (h3β-HSD1) and rat (r3β-HSD4) placental enzymes were evaluated. Results revealed that the inhibitory potency of gallates on h3β-HSD1 was dependent on the carbon-chain length in the alcohol moiety. Propyl, butyl, hexyl, octyl, and dodecyl gallates exhibited mixed inhibition with IC₅₀ values of 75.16, 64.59, 25.44, 19.56, and 5.99 μM, respectively, while gallic acid, methyl, ethyl, and cetyl gallates showed no significant inhibition at 100 μM. Similarly, r3β-HSD4 displayed a comparable inhibition pattern but was more sensitive, with IC₅₀ values of 49.60, 31.86, 25.14, 10.79, and 5.91 μM for the same gallates, respectively. Bivariate correlation analysis demonstrated a negative correlation between IC₅₀ values and hydrophobicity, molecular weight, heavy atom number, carbon number, rotatable bonds, fraction of sp3-hybridized carbon atoms, and volume, while a positive correlation was observed with the lowest binding energy. Molecular docking analysis indicated that these gallates bind to cofactor binding sites or between the steroid and cofactor binding sites. Additionally, 3D-QSAR modeling highlighted the influence of hydrogen bond acceptors and hydrophobic regions on the inhibitory activity of these compounds. The suppression of progesterone production by these gallates in intact JAr cells is influenced not only by their inhibitory potency on h3β-HSD1 but also by their aqueous solubility. These findings provide valuable insights into the endocrine-disrupting potential of gallates and their interaction with 3β-HSDs.