Bisphenol A Analogues Inhibit Human and Rat 11-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.