Biotransformation of Bisphenol by Human Cytochrome P450 2C9 Enzymes: A Density Functional Theory Study

• DOI: 10.1021/acs.inorgchem.2c03984
• Publication Date: 2023-01-18T09:14:57Z
• Authors: Artur Hermano Sam...; Rolly Yadav; Thirakorn Mokkawes; Asheesh Kumar; Munir S. Skaf; Chivukula V. Sastri; Devesh Kumar; Sam P. de Visser
• Keywords: Hydroxylation; Reactivity; Hydrogen atom abstraction

Bisphenol A (BPA, 2,2-bis-(4-hydroxyphenyl)propane) is used as a precursor in the synthesis of polycarbonate and epoxy plastics; however, its availability environment causing toxicity an endocrine-disrupting chemical. Metabolism BPA their analogues (substitutes) generally performed by liver cytochrome P450 enzymes often leads to mixture products, some those are toxic. To understand product distributions activation BPA, we have computational study into mechanisms reactivities using large model structures human isozyme (P450 2C9) with bound. Density functional theory (DFT) calculations on compound I were investigated, leading number possible products. The substrate-binding pocket tight, consequence, aliphatic hydroxylation not feasible methyl substituents cannot reach well due constraints pocket. Instead, find low-energy pathways that initiated phenol hydrogen atom abstraction followed OH rebound phenolic ortho- or para-position. barriers para-rebound lower energy than for ortho-rebound, consequently, our 2C9 predicts dominant hydroxycumyl alcohol reactions proceed through two-state reactivity competing doublet quartet spin state surfaces. show fast efficient substrate surface rate-determining electrophilic addition step, while has multiple high-energy can also lead various side products including C4-aromatic hydroxylation. This work shows formation more low state, physicochemical properties govern barrier heights step reaction. Finally, importance second-coordination sphere highlighted determines guides bifurcation pathways.