Bisphenol A Analogues Inhibit Human and Rat 11β-Hydroxysteroid Dehydrogenase 1 Depending on Its Lipophilicity

Bisphenol A (BPA) analogues substituted on the benzene ring are widely used in a variety of industrial and consumer materials. However, their effects on the glucocorticoid-metabolizing enzyme 11 beta-hydroxysteroid dehydrogenase 1 (11 beta-HSD1) remain unclear. The inhibitory effects of 6 BPA analogues on the inhibition of human and rat 11 beta-HSD1 were investigated. The potencies of inhibition on human 11 beta-HSD1 were bisphenol H (IC50, 0.75 mu M) > bisphenol G (IC50, 5.06 mu M) > diallyl bisphenol A (IC50, 13.36 mu M) > dimethyl bisphenol A (IC50, 30.18 mu M) > bisphenol A dimethyl ether (IC50, 33.08 mu M) > tetramethyl bisphenol A (>100 mu M). The inhibitory strength of these chemicals on rat 11 beta-HSD1 was much weaker than that on the human enzyme, ranging from 74.22 to 205.7 mu M. All BPA analogues are mixed/competitive inhibitors of both human and rat enzymes. Molecular docking studies predict that bisphenol H and bisphenol G both bind to the active site of human 11 beta-HSD1, forming a hydrogen bond with catalytic residue Ser170. The bivariate correlation of IC50 values with LogP (lipophilicity), molecular weight, heavy atoms, and molecular volume revealed a significant inverse regression and the correlation of IC50 values with DG (low binding energy) revealed a positive regression. In conclusion, the lipophilicity, molecular weight, heavy atoms, molecular volume, and binding affinity of a BPA analogue determine the inhibitory strength of human and rat 11 beta-HSD isoforms.

Automated summary

This study investigated the inhibitory effects of six BPA analogues on the glucocorticoid-metabolizing enzyme 11 beta-hydroxysteroid dehydrogenase 1 (11 beta-HSD1). The results showed that these compounds had stronger inhibitory effects on human 11 beta-HSD1 than on rat 11 beta-HSD1. Molecular docking studies predicted that bisphenol H and bisphenol G bound to the active site of human 11 beta-HSD1 and formed a hydrogen bond with catalytic residue Ser170. The inhibitory strength of BPA analogues on both human and rat enzymes depended on their lipophilicity, molecular weight, heavy atoms, molecular volume, and binding affinity.