352
Z. Fu and J. Chen
17.3.2 Case Studies Simulating Xenobiotic Chemical
Metabolism by P450 Enzymes
17.3.2.1 Metabolism of PBDEs by P450 Enzymes: DFT Studies Using
the Active Species of P450s
Existing computational case studies on P450 metabolism focused primarily on conventional chemical substrates (e.g., alkanes, alkenes, and benzene), endogenous hormones, pharmaceuticals, etc. By contrast, the metabolic profile of vast majority of
environmental pollutants catalyzed by P450 enzymes is yet to be detailed. Flame
retardants are typical pollutants that attract worldwide attention, especially polybrominated diphenyl ethers (PBDEs), demonstrated to be of environmental persistence (P), bioaccumulation potential (B), and toxicity potential (T) by numerous
studies. As the primary metabolite of PBDEs, HO-PBDEs have been reported to
possess enhanced endocrine disrupting potency and mitochondrial toxicity compared with PBDEs. Recent in vitro studies indicated that apart from HO-PBDEs,
metabolism of PBDEs by P450 enzymes would lead to dihydroxylated and even to
the notorious polybrominated dibenzo-p-dioxins (PBDDs) as products [38, 39], for
which the underlying molecular mechanisms are unclear. In this section, DFT studies
predicting the mechanisms for PBDEs metabolism by P450 enzymes are reviewed
[40–42].
Based on the metabolic mechanisms for halogenated benzenes [35], Wang et al.
[40] proposed oxidation of PBDEs by Compound I that would proceed via the pathways shown in Fig. 17.9, using 2,2
,4,4
-tetraBDE (BDE-47) as the model compound. The preceding π-addition of Compound I (a) to the non-Br-substituted phenyl
carbons of BDE-47 leads to tetrahedral adducts that are subjected to further rearrangements (b). Otherwise, reaction with the Br-bonded phenyl carbons drives the
NIH shift of Br to cyclohexanones that undergo reduction (d) in the non-enzymatic
medium. For the rearrangements of tetrahedral adducts, three pathways are possible, which involve the NIH shift to cyclohexanones, ring closure to epoxides, and
proton shuttle to phenol products. The epoxides are then rearranged (c) via protonassisted ring-opening, giving rise to multiple products including HO-PBDEs and
bromophenols.
According to the computational study by Wang et al. [40], π-addition of Compound I to Br-substituted phenyl carbons (C 2 and C 4 ) was more energy-demanding
than non-substituted carbons (C 3 , C 5 , C 6 ), except for the C 1 site that possessed an
increased barrier compared with non-substituted carbons due to large steric hindrances. The π-addition of Compound I to non-substituted carbons is endothermic
with the resultant tetrahedral intermediate lying higher on the potential energy surface than the reactant. However, π-addition of Compound I to Br-substituted carbons
is strongly exothermic and yields cyclohexanones via NIH shift of the Br atoms,
a reaction analogous to the dehalogenation of hexachlorobenzene. Particularly, πaddition to the C 2 position leads to the expelling of a bromide ion due to the steric
effects. The tetrahedral adducts formed from π-additions at the C 1 , C 3 , C 5 , C 6 sites
Z. Fu and J. Chen
17.3.2 Case Studies Simulating Xenobiotic Chemical
Metabolism by P450 Enzymes
17.3.2.1 Metabolism of PBDEs by P450 Enzymes: DFT Studies Using
the Active Species of P450s
Existing computational case studies on P450 metabolism focused primarily on conventional chemical substrates (e.g., alkanes, alkenes, and benzene), endogenous hormones, pharmaceuticals, etc. By contrast, the metabolic profile of vast majority of
environmental pollutants catalyzed by P450 enzymes is yet to be detailed. Flame
retardants are typical pollutants that attract worldwide attention, especially polybrominated diphenyl ethers (PBDEs), demonstrated to be of environmental persistence (P), bioaccumulation potential (B), and toxicity potential (T) by numerous
studies. As the primary metabolite of PBDEs, HO-PBDEs have been reported to
possess enhanced endocrine disrupting potency and mitochondrial toxicity compared with PBDEs. Recent in vitro studies indicated that apart from HO-PBDEs,
metabolism of PBDEs by P450 enzymes would lead to dihydroxylated and even to
the notorious polybrominated dibenzo-p-dioxins (PBDDs) as products [38, 39], for
which the underlying molecular mechanisms are unclear. In this section, DFT studies
predicting the mechanisms for PBDEs metabolism by P450 enzymes are reviewed
[40–42].
Based on the metabolic mechanisms for halogenated benzenes [35], Wang et al.
[40] proposed oxidation of PBDEs by Compound I that would proceed via the pathways shown in Fig. 17.9, using 2,2
,4,4
-tetraBDE (BDE-47) as the model compound. The preceding π-addition of Compound I (a) to the non-Br-substituted phenyl
carbons of BDE-47 leads to tetrahedral adducts that are subjected to further rearrangements (b). Otherwise, reaction with the Br-bonded phenyl carbons drives the
NIH shift of Br to cyclohexanones that undergo reduction (d) in the non-enzymatic
medium. For the rearrangements of tetrahedral adducts, three pathways are possible, which involve the NIH shift to cyclohexanones, ring closure to epoxides, and
proton shuttle to phenol products. The epoxides are then rearranged (c) via protonassisted ring-opening, giving rise to multiple products including HO-PBDEs and
bromophenols.
According to the computational study by Wang et al. [40], π-addition of Compound I to Br-substituted phenyl carbons (C 2 and C 4 ) was more energy-demanding
than non-substituted carbons (C 3 , C 5 , C 6 ), except for the C 1 site that possessed an
increased barrier compared with non-substituted carbons due to large steric hindrances. The π-addition of Compound I to non-substituted carbons is endothermic
with the resultant tetrahedral intermediate lying higher on the potential energy surface than the reactant. However, π-addition of Compound I to Br-substituted carbons
is strongly exothermic and yields cyclohexanones via NIH shift of the Br atoms,
a reaction analogous to the dehalogenation of hexachlorobenzene. Particularly, πaddition to the C 2 position leads to the expelling of a bromide ion due to the steric
effects. The tetrahedral adducts formed from π-additions at the C 1 , C 3 , C 5 , C 6 sites