Predicting metabolism of environmental contaminants and potential toxicities of relevant metabolites remains a vital and difficult task in risk assessment. Herein, we employed in silico simulations to probe the metabolism of selective contaminants (PBDEs, methoxylated PBDEs (CH3O-PBDEs) and PFOS precursors) catalyzed by cytochrome P450 enzymes (CYPs), using the active center model (Compound I) to mimic CYPs. Results show that Compound I preferably oxidizes CH3O-PBDEs by inserting a hydroxyl to the methyl group. The derived hydroxylated products are then decomposed with water assistance, leading to HO-PBDEs which may imply one natural origin of HO-PBDEs in the environment. The reaction of PBDEs with Compound I starts with π-addition (preferably on non-brominated carbons) and epoxidation to epoxides. These epoxides are prone to degradation via protonation, yielding various HO-PBDEs that are potential endocrine disrupting chemicals. The study as well uncovers a novel protonation pathway that leads to ether bond cleavage and bromophenol formation. In addition, using HO-PBDEs as substrates, we elucidated a unique phenolic H-abstraction and HO rebound pathway that well explains the observation of diHO-PBDEs in in vitro studies. Particularly, diHO-PBDEs with heterophenyl −OH substituents ortho- and meta- to the ether bond can produce dioxin metabolites via aryl biradical coupling of diketone intermediates that are produced from dehydrogenation of diHO-PBDEs by Compound I. As a main PFOS precursor, N-ethyl perfluorooctane sulfonamide is metabolized by Compound I via ethyl Cα-hydroxylation to an ethanolamine intermediate. Subsequently, the ethanolamine decomposes nonenzymatically via N-dealkylation to PFOSA and acetaldehyde. Furthermore, our study predicted a novel deamination pathway that comprises O–S bond formation and S–N bond cleavage. The resulting hydroxylamine is then hydrolyzed to PFOS, indicating indirect PFOS exposure via precursors metabolism. The predicted products are consistent with the available in vitro observations. Accordingly, in silico simulations may help uncover possible toxicological effects by predicting the metabolic mechanisms of xenobiotics by CYPs.

In silico investigation on the metabolic mechanisms of selective environmental contaminants catalyzed by the active species of P450 enzymes

256th National Meeting (2018)

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