Binding and Metabolism of Brominated Flame Retardant β-1,2-Dibromo-4-(1,2-dibromoethyl)cyclohexane in Human Microsomal P450 Enzymes: Insights from Computational Studies

Abstract

The emerging brominated flame retardant, 1,2-dibromo-4-(1,2-dibromoethyl)­cyclohexane (TBECH), has recently attracted strong interest due to its extensive detection in the environment and potential toxicological effects on humans. Previous in vitro experiments have shown that the technical mixture of TBECH and the pure β-isomer (β-TBECH) can be metabolized by cytochrome P450 enzymes (CYPs) into multiple metabolites, but the specific CYP isoforms involved in TBECH metabolism and the relevant metabolic regioselectivity remain unknown. Here, we, for the first time, investigated the binding patterns and affinities of β-TBECH in human CYPs 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4, through molecular dynamics (MD) simulations. The binding affinities of β-TBECH in CYPs, which are estimated by the calculated binding free energies, follow the order of 2A6 > 2C9 > 2B6 > 2E1 > 3A4 ≈ 2C19 ≈ 1A2 > 2D6. Although all CYPs are important β-TBECH receptors, only 2A6, 2C19, 2E1, and 3A4 are responsible for metabolizing β-TBECH. Specially, 2A6 and 2E1 may selectively hydroxylate the C1 and C7 sites of β-TBECH, while 2C19 and 3A4 show metabolic preference for C7- and C8-hydroxylations, respectively. The three hydroxylation routes proposed by the further density functional theory (DFT) calculations generate C1-, C7-, and C8-hydroxylated metabolites, while the latter two may further undergo debromination to yield the respective ketone and aldehyde as additional metabolites. The results provide meaningful insight into the binding and metabolism of β-TBECH by human CYPs, which is helpful for understanding the metabolic fate and toxicity mechanism of this chemical.

Computational Study of the Peroxygenase Mechanism Catalyzed by Hemoglobin Dehaloperoxidase Involved in the Degradation of Chlorophenols

“…We have summarized some relevant calculation results in Table . The energy barriers of the H-abstraction from phenolic hydroxyl are usually quite low, less than 5 kcal/mol ,− while those from C–H are larger than 13 kcal/mol. − According to our calculations, the energy barriers of H1-abstraction catalyzed by DHP B are 9.1 and 8.7 kcal/mol at doublet and quartet states, respectively, which are slightly higher than those of other P450 enzymes. By comparing the structures of reactants with those in other P450s, we found that in the optimized structures of 2 R and 4 R, His55 forms a strong hydrogen bond with the OH group of the substrate.…”

“…Our calculation results showed that it is the electron transfer that makes the proton transfer to be quite easy. 69 13.6/16.7 0.9/0.9 TPHP 70 1.3(doublet) triclosan 54 2.5/3.2 BPA 71 0.3/0.3 griseophenone B 72 3.4/2.9 TBECH 73 17.7/18.5 dieldrin 74 14.2/16.3 (R)-2-methylbutyrate 75 19.6/20.9 After H1-proton transfer, there are two reaction pathways starting from IM1b, as shown in Scheme 5. One is the electrophilic addition of FeO to the substrate radical as suggested in the previous study.…”

Computational Insight into Biotransformation Profiles of Organophosphorus Flame Retardants to Their Diester Metabolites by Cytochrome P450

“…In the past two decades, molecular modeling techniques, such as molecular dynamics (MD) simulations and quantum chemical calculations, have been extensively used to shed light on the binding and metabolism of xenobiotics in various biomacromolecules including CYPs [38][39][40][41][42][43]. In this work, five OPFRs detected widely in the environment, including TDCIPP, tris(1-chloro-2-propyl) phosphate (TCIPP), tris(2-chloroethyl) phosphate (TCEP), triethyl phosphate (TEP), and EHDPHP (Figure S1 in the Supplementary Materials), were employed to investigate the reaction mechanism leading to their diester metabolites through the density functional theory (DFT) calculations.…”