17 Xenobiotic Metabolism by Cytochrome P450 …
357
Fig. 17.12 Feasible pathway for HO-PBDD evolution from HO-PBDE metabolism catalyzed by
Compound I
DFT studies have elucidated a feasible pathway (Fig. 17.12) for PBDD evolution
using 5
,6-di-HO-BDE as the example substrate. Compound I first oxidizes 5
,6-diHO-BDE to a diketone intermediate via two consecutive phenolic H-abstractions.
The diketone is electronically in resonance with a biradical structure with the radicals
resided on O 6 and C 6 . Aryl biradical coupling of the diketone intermediate generates
a PBDD ketone isomer, which undergoes keto–enol tautomerism non-enzymatically
to HO-PBDD. In the initial step, the phenolic H-abstraction is facilitated by hydrogen
bonding between the O atom of Compound I and the hydroxyl H atom of 5
,6-diHO-BDE. Calculated barriers indicate that phenolic H-abstractions, cyclization of
the diketone intermediate, and tautomerism of the PBDD isomer are quite facile
(<10 kcal/mol). However, PBDDs are observed as minor products in in vitro incubations of PBDEs, possibly due to a low efficient yield of di-HO-PBDEs or less
substrate accessibility to the active site.
17.3.2.3 Simulation of the Metabolism of Perfluorooctane Sulfonate
Precursors Catalyzed by P450 Enzymes
Perfluorooctane sulfonate (PFOS) pertains to one representative of persistent organic
pollutants, yet its exposure profile in biota remains implicit. As indicated by in vivo
and in vitro experiments, metabolism of PFOS precursors (PreFOS) is an important indirect exposure pathway for PFOS, whereas the underlying molecular mechanisms are largely unclarified. Fu et al. [50] investigated the metabolism of one
typical PreFOS, N-ethyl perfluorooctane sulfonamide (N-EtPFOSA) catalyzed by
Compound I. As shown in Fig. 17.13a, the metabolism of N-EtPFOSA proceeds
via N-deethylation, which comprises a precedent Cα-H hydroxylation (a) and subsequent ethanolamine decomposition. Initially, the Cα-H abstraction of N-EtPFOSA
catalyzed by Compound I produces a carbon-centered radical species, which combines with the rebounding hydroxyl to an ethanolamine intermediate. Subsequently,
357
Fig. 17.12 Feasible pathway for HO-PBDD evolution from HO-PBDE metabolism catalyzed by
Compound I
DFT studies have elucidated a feasible pathway (Fig. 17.12) for PBDD evolution
using 5
,6-di-HO-BDE as the example substrate. Compound I first oxidizes 5
,6-diHO-BDE to a diketone intermediate via two consecutive phenolic H-abstractions.
The diketone is electronically in resonance with a biradical structure with the radicals
resided on O 6 and C 6 . Aryl biradical coupling of the diketone intermediate generates
a PBDD ketone isomer, which undergoes keto–enol tautomerism non-enzymatically
to HO-PBDD. In the initial step, the phenolic H-abstraction is facilitated by hydrogen
bonding between the O atom of Compound I and the hydroxyl H atom of 5
,6-diHO-BDE. Calculated barriers indicate that phenolic H-abstractions, cyclization of
the diketone intermediate, and tautomerism of the PBDD isomer are quite facile
(<10 kcal/mol). However, PBDDs are observed as minor products in in vitro incubations of PBDEs, possibly due to a low efficient yield of di-HO-PBDEs or less
substrate accessibility to the active site.
17.3.2.3 Simulation of the Metabolism of Perfluorooctane Sulfonate
Precursors Catalyzed by P450 Enzymes
Perfluorooctane sulfonate (PFOS) pertains to one representative of persistent organic
pollutants, yet its exposure profile in biota remains implicit. As indicated by in vivo
and in vitro experiments, metabolism of PFOS precursors (PreFOS) is an important indirect exposure pathway for PFOS, whereas the underlying molecular mechanisms are largely unclarified. Fu et al. [50] investigated the metabolism of one
typical PreFOS, N-ethyl perfluorooctane sulfonamide (N-EtPFOSA) catalyzed by
Compound I. As shown in Fig. 17.13a, the metabolism of N-EtPFOSA proceeds
via N-deethylation, which comprises a precedent Cα-H hydroxylation (a) and subsequent ethanolamine decomposition. Initially, the Cα-H abstraction of N-EtPFOSA
catalyzed by Compound I produces a carbon-centered radical species, which combines with the rebounding hydroxyl to an ethanolamine intermediate. Subsequently,