17 Xenobiotic Metabolism by Cytochrome P450 …
359
Results revealed that the H-shift pathway leading to the hydroxylamine derivative
has a higher barrier than the one generating the epoxide analogue. Therefore, the
deamination of PFOSA to PFOS proceeds via an epoxidation mechanism, wherein
the initial O-addition (N-oxidation) step is rate-determining. By contrasting the activation barrier for N-dealkylation of N-EtPFOSA to that for deamination of PFOSA,
it can be concluded that transformation of PFOSA to PFOS is the rate-limiting step
in the whole process of PreFOS biotransformation, which supports the in vitro observation [51].
17.3.2.4 Metabolism of Halogenated Alkanes and Alkenes Catalyzed
by P450 Active Species
Halogenated alkyl moieties are frequently found in insecticides, pesticides, disinfection by-products, etc. By using DFT calculations, Ji et al. [52] investigated the
metabolic scenario of two examples of halogenated alkanes, CHCl 3 and CCl 4 catalyzed by P450 enzymes. Results revealed two distinct pathways for the reaction of
CHCl 3 with Compound I under both aerobic and anaerobic conditions. CHCl 3 was
aerobically oxidized through C–H hydroxylation to C(OH)Cl 3 , which further undergoes dehydrochlorination with the assistance of water molecules, leading to Cl 2 O.
Under anaerobic conditions, however, CHCl 3 preferably reacted with the divalent
ferroporphyrin via reductive dehalogenation. For the perchlorinated CCl 4 , aerobic
oxidation via C–Cl abstraction was energetically infeasible, whereas a low O 2 concentration environment effectively obtained Cl 2 O and ClO· as products. Aside from
halogenated alkanes, alkenes with unsaturated C=C bonds are increasingly concerned
due to their potential to be transformed into toxic epoxide intermediates. Zhang et al.
[53] computed the activation barriers (E, in kcal/mol) for epoxidation of 36 alkenes
catalyzed by Compound I by using DFT calculations and found a strong linear correlation between E and the ionization potential (IP) of these alkenes (Fig. 17.14): For
alkene molecules with dipole moment <2.2 debyes (D), E = 5.044IP − 31.315,
whereas E = 2.666IP − 16.066 for those with >2.2 D dipole moments. These correlations can serve as quick prediction tools for the epoxidation reactivity of alkenes
oxidized by Compound I.
17.3.2.5 Metabolism of Substituted Phenolic Compounds Catalyzed
by P450 Enzymes: A Novel Ipso-Substitution Pathway
Substituted phenolic compounds (SPCs), including bisphenol analogues, alkylphenols, and chlorophenols, are ubiquitous environmental contaminants that have drawn
widespread attention due to their potential endocrine disrupting properties. Recent
in vitro studies indicated that P450-catalyzed metabolism significantly enhances the
endocrine disrupting activity of SPCs by arousing an alternative ipso-substitution
pathway that converts them to hydroquinone with elimination of substituents at the
ipso-position, the mechanism of which is far beyond elucidated. Ji et al. [54] investi-
359
Results revealed that the H-shift pathway leading to the hydroxylamine derivative
has a higher barrier than the one generating the epoxide analogue. Therefore, the
deamination of PFOSA to PFOS proceeds via an epoxidation mechanism, wherein
the initial O-addition (N-oxidation) step is rate-determining. By contrasting the activation barrier for N-dealkylation of N-EtPFOSA to that for deamination of PFOSA,
it can be concluded that transformation of PFOSA to PFOS is the rate-limiting step
in the whole process of PreFOS biotransformation, which supports the in vitro observation [51].
17.3.2.4 Metabolism of Halogenated Alkanes and Alkenes Catalyzed
by P450 Active Species
Halogenated alkyl moieties are frequently found in insecticides, pesticides, disinfection by-products, etc. By using DFT calculations, Ji et al. [52] investigated the
metabolic scenario of two examples of halogenated alkanes, CHCl 3 and CCl 4 catalyzed by P450 enzymes. Results revealed two distinct pathways for the reaction of
CHCl 3 with Compound I under both aerobic and anaerobic conditions. CHCl 3 was
aerobically oxidized through C–H hydroxylation to C(OH)Cl 3 , which further undergoes dehydrochlorination with the assistance of water molecules, leading to Cl 2 O.
Under anaerobic conditions, however, CHCl 3 preferably reacted with the divalent
ferroporphyrin via reductive dehalogenation. For the perchlorinated CCl 4 , aerobic
oxidation via C–Cl abstraction was energetically infeasible, whereas a low O 2 concentration environment effectively obtained Cl 2 O and ClO· as products. Aside from
halogenated alkanes, alkenes with unsaturated C=C bonds are increasingly concerned
due to their potential to be transformed into toxic epoxide intermediates. Zhang et al.
[53] computed the activation barriers (E, in kcal/mol) for epoxidation of 36 alkenes
catalyzed by Compound I by using DFT calculations and found a strong linear correlation between E and the ionization potential (IP) of these alkenes (Fig. 17.14): For
alkene molecules with dipole moment <2.2 debyes (D), E = 5.044IP − 31.315,
whereas E = 2.666IP − 16.066 for those with >2.2 D dipole moments. These correlations can serve as quick prediction tools for the epoxidation reactivity of alkenes
oxidized by Compound I.
17.3.2.5 Metabolism of Substituted Phenolic Compounds Catalyzed
by P450 Enzymes: A Novel Ipso-Substitution Pathway
Substituted phenolic compounds (SPCs), including bisphenol analogues, alkylphenols, and chlorophenols, are ubiquitous environmental contaminants that have drawn
widespread attention due to their potential endocrine disrupting properties. Recent
in vitro studies indicated that P450-catalyzed metabolism significantly enhances the
endocrine disrupting activity of SPCs by arousing an alternative ipso-substitution
pathway that converts them to hydroquinone with elimination of substituents at the
ipso-position, the mechanism of which is far beyond elucidated. Ji et al. [54] investi-