Transformation pathways of isomeric perfluorooctanesulfonate precursors catalyzed by the active species of P450 enzymes: in silico investigation.

As evidenced from various in vitro and in vivo studies, metabolism of perfluorooctanesulfonate (PFOS) precursors by cytochrome P450 enzymes (CYPs) acts as an important indirect pathway for mammal PFOS exposure. Nevertheless, the mechanism of this transformation remains largely unclarified. In this study, in silico investigations adopting density functional theory (DFT) were performed to reveal the biotransformation of a typical PFOS precursor, N-ethyl perfluorooctane sulfonamide (N-EtPFOSA), catalyzed by the active species of CYPs (Compound I). Results unveil that in the enzymatic environment, N-EtPFOSA is hydroxylated feasibly (reaction energy barriers ΔE = 11.4-14.5 kcal/mol) with a H atom transfer (HAT) from the ethyl Cα to Compound I. The HAT derived Cα radical then barrierlessly combines with the OH radical to produce a ferric-ethanolamine intermediate. Subsequently, the ethanolamine intermediate decomposes via N-dealkylation to perfluorooctane sulfonamide (PFOSA) and acetaldehyde products nonenzymatically with the assistance of water molecules. The rate-limiting O-addition (ΔE = 21.2-34.0 kcal/mol) of Compound I to PFOSA initiated a novel deamination pathway that comprises O-S bond formation and S-N bond cleavage. The resulting hydroxylamine is then hydrolyzed to PFOS. In addition, the results reveal that both the N-dealkylation and deamination pathways are isomeric-specific, which is consistent with experimental observations. Accordingly, DFT calculations may help uncover possible toxicological effects by predicting the biotransformation mechanisms and products of xenobiotics by CYPs.