17 Xenobiotic Metabolism by Cytochrome P450 …
353
Fig. 17.9 Possible pathways for the reaction BDE-47 with Compound I
further rearrange via ring closure to six possible epoxides. As the epoxidation step
generally requires low activation barriers (<5 kcal/mol), the precedent π-addition
is rate-determining in BDE-47 oxidation catalyzed by Compound I. Formation of
cyclohexanones and epoxides manifests the accomplishment of the monooxygenation functionality of Compound I and retrieves the resting state of P450 enzymes.
Since the formed BDE-47 epoxides are weakly bound with the porphyrin iron,
they are easily released out of the active site to the bulk polar environment. These
epoxides are prone to protonation in the non-enzymatic environment, which cleaves
the epoxy bond barrierless to two types of ring-opened hydroxyl-cyclohexadienyl
products, i.e., with –OH attached to Br-substituted and non-substituted phenyl carbons, respectively. These hydroxyl-cyclohexadienyl products are subjected to further
rearrangement, with a scheme shown in Fig. 17.10.
When –OH is attached to Br-substituted carbons (#1), the hydroxylcyclohexadienyls rearrange via shifting the Br atom to neighboring carbons, followed by a proton loss to yield HO-PBDEs. Hydroxyl-cyclohexadienyls with –OH
attached to non-substituted carbons (#2) would shift the H atom to proximate carbons, which subsequently deprotonate to form HO-BDE-47. Computational results
have demonstrated that the NIH shift of Br is more preferable than the H atom, which
leads to an alteration of the brominated pattern in HO-PBDEs. It is noteworthy that
attachment of –OH to the ether carbon (C 1 ) induces homolytic or heterotic fission
of the ether bond (#3), resulting exclusively in bromophenol products. Calculated
activation barriers reveal that heterotic fission of the ether bond is more feasible than
the homolysis reaction. The predicted products, e.g., 4-HO-BDE-42, 4
-HO-BDE49, 5-HO-BDE-47, and 2,4-dibromophenol, are in line with the metabolites detected
in in vitro experiment. Thus, DFT calculations are effective tools for elucidating
353
Fig. 17.9 Possible pathways for the reaction BDE-47 with Compound I
further rearrange via ring closure to six possible epoxides. As the epoxidation step
generally requires low activation barriers (<5 kcal/mol), the precedent π-addition
is rate-determining in BDE-47 oxidation catalyzed by Compound I. Formation of
cyclohexanones and epoxides manifests the accomplishment of the monooxygenation functionality of Compound I and retrieves the resting state of P450 enzymes.
Since the formed BDE-47 epoxides are weakly bound with the porphyrin iron,
they are easily released out of the active site to the bulk polar environment. These
epoxides are prone to protonation in the non-enzymatic environment, which cleaves
the epoxy bond barrierless to two types of ring-opened hydroxyl-cyclohexadienyl
products, i.e., with –OH attached to Br-substituted and non-substituted phenyl carbons, respectively. These hydroxyl-cyclohexadienyl products are subjected to further
rearrangement, with a scheme shown in Fig. 17.10.
When –OH is attached to Br-substituted carbons (#1), the hydroxylcyclohexadienyls rearrange via shifting the Br atom to neighboring carbons, followed by a proton loss to yield HO-PBDEs. Hydroxyl-cyclohexadienyls with –OH
attached to non-substituted carbons (#2) would shift the H atom to proximate carbons, which subsequently deprotonate to form HO-BDE-47. Computational results
have demonstrated that the NIH shift of Br is more preferable than the H atom, which
leads to an alteration of the brominated pattern in HO-PBDEs. It is noteworthy that
attachment of –OH to the ether carbon (C 1 ) induces homolytic or heterotic fission
of the ether bond (#3), resulting exclusively in bromophenol products. Calculated
activation barriers reveal that heterotic fission of the ether bond is more feasible than
the homolysis reaction. The predicted products, e.g., 4-HO-BDE-42, 4
-HO-BDE49, 5-HO-BDE-47, and 2,4-dibromophenol, are in line with the metabolites detected
in in vitro experiment. Thus, DFT calculations are effective tools for elucidating