Enhanced inhibition of human and rat aromatase activity by benzene ring substitutions in bisphenol A: QSAR structure-activity relationship and in silico docking analysis.
Level 5 - mechanism / opinion, no new human data
In vitro biochemical and in silico modeling study without human clinical data
PubMed 38128231 · doi:10.1016/j.jhazmat.2023.133252
What was done
The authors evaluated the inhibitory effects of 11 bisphenol A (BPA) analogues on human and rat placental aromatase (CYP19A1). They determined enzyme inhibition mechanisms, measured estradiol production in human BeWo choriocarcinoma cells, and conducted molecular docking at the CYP19A1 active site. They also performed quantitative structure-activity relationship (QSAR) correlations evaluating lipophilicity (LogP) and water solubility (LogS), pharmacophore modeling, and computerized pharmacokinetic analysis.
What was found
Human CYP19A1 inhibitory potency varied widely across analogues, ranging from bisphenol H (IC50 = 0.93 µM) to tetramethyl BPA and tetrabromobisphenol S (ineffective at 100 µM), compared to BPA (IC50 = 73.48 µM). Most analogues acted as mixed or competitive inhibitors and reduced estradiol production in BeWo cells. Docking revealed that analogues bind the steroid active site or between the steroid pocket and heme, forming a hydrogen bond with Met374. Pharmacophore analysis identified 4 hydrophobic regions, all occupied by bisphenol H. IC50 values correlated with LogP and LogS. Bisphenol H, tetrabromobisphenol A, and tetrachlorobisphenol A demonstrated low solubility, which the authors noted may explain their weaker inhibition of estradiol production in BeWo cells.
Why it matters
Chemical alternatives marketed to replace BPA may pose greater endocrine-disrupting risks than the parent compound. Identifying how benzene ring substitutions and lipophilicity enhance aromatase inhibition helps inform chemical toxicity screening and the design of safer plasticizers.
Limits
The study is entirely in vitro and in silico, precluding direct conclusions about in vivo human exposure, placental transfer, or systemic endocrine disruption. Specific quantitative values for rat aromatase inhibition, replicate numbers, and exact correlation statistics were not reported in the abstract.
Cited by
- supports Bisphenol A (BPA) inhibits the enzyme aromatase, which converts testosterone into estrogen.