Chapter 17
Xenobiotic Metabolism by Cytochrome
P450 Enzymes: Insights Gained
from Molecular Simulations
Zhiqiang Fu and Jingwen Chen
Abstract Accurate chemical risk assessment requires consideration of the
metabolism functioned by the vast majority of enzymes, since neglecting these
metabolic pathways (and toxic metabolites) may lead to inaccurate evaluation of
their adverse effects on human health. Traditional in vivo or in vitro methods toward
this end can be confronted with obstacles, e.g., the huge and ever-increasing number
of chemicals, cost and labor-intensive tests, and lack of chemical standards in analysis. Instead, molecular simulations (in silico) are deemed as a promising alternative,
which has gradually proven to be feasible for gaining insights into toxicological disposition of xenobiotic chemicals. In this chapter, we review recent progress in molecular simulations of xenobiotic metabolism catalyzed by the typical phase I enzyme:
cytochrome P450 enzymes (CYPs). The first section describes the significance of
xenobiotic metabolism in chemical risk assessment. Then, the versatile functionality
of CYPs in xenobiotic metabolism is briefly summarized by introducing some of the
fundamental reactions, e.g., C–H hydroxylation, phenyl oxidation, and heteroatom
(N, P, S) oxidation. The last section presents case studies of molecular simulations
for metabolism of typical environmental contaminants (e.g., brominated flame retardants, chlorinated alkanes, substituted phenolic compounds), with an emphasis on
mechanistic insights gained from quantum chemical density functional theory (DFT)
calculations with the active species of CYPs.
Keywords Xenobiotic chemicals · P450 enzymes · Density functional theory ·
Metabolic mechanisms · Compound I · Environmental contaminants
Z. Fu · J. Chen (B)
Key Laboratory of Industrial Ecology and Environmental Engineering (Ministry of Education),
School of Environmental Science and Technology,
Dalian University of Technology, Dalian 116024, China
e-mail: jwchen@dlut.edu.cn
Z. Fu
e-mail: fuzq@dlut.edu.cn
© Springer Nature Switzerland AG 2019
H. Hong (ed.), Advances in Computational Toxicology, Challenges and Advances
in Computational Chemistry and Physics 30,
https://doi.org/10.1007/978-3-030-16443-0_17
337
Xenobiotic Metabolism by Cytochrome
P450 Enzymes: Insights Gained
from Molecular Simulations
Zhiqiang Fu and Jingwen Chen
Abstract Accurate chemical risk assessment requires consideration of the
metabolism functioned by the vast majority of enzymes, since neglecting these
metabolic pathways (and toxic metabolites) may lead to inaccurate evaluation of
their adverse effects on human health. Traditional in vivo or in vitro methods toward
this end can be confronted with obstacles, e.g., the huge and ever-increasing number
of chemicals, cost and labor-intensive tests, and lack of chemical standards in analysis. Instead, molecular simulations (in silico) are deemed as a promising alternative,
which has gradually proven to be feasible for gaining insights into toxicological disposition of xenobiotic chemicals. In this chapter, we review recent progress in molecular simulations of xenobiotic metabolism catalyzed by the typical phase I enzyme:
cytochrome P450 enzymes (CYPs). The first section describes the significance of
xenobiotic metabolism in chemical risk assessment. Then, the versatile functionality
of CYPs in xenobiotic metabolism is briefly summarized by introducing some of the
fundamental reactions, e.g., C–H hydroxylation, phenyl oxidation, and heteroatom
(N, P, S) oxidation. The last section presents case studies of molecular simulations
for metabolism of typical environmental contaminants (e.g., brominated flame retardants, chlorinated alkanes, substituted phenolic compounds), with an emphasis on
mechanistic insights gained from quantum chemical density functional theory (DFT)
calculations with the active species of CYPs.
Keywords Xenobiotic chemicals · P450 enzymes · Density functional theory ·
Metabolic mechanisms · Compound I · Environmental contaminants
Z. Fu · J. Chen (B)
Key Laboratory of Industrial Ecology and Environmental Engineering (Ministry of Education),
School of Environmental Science and Technology,
Dalian University of Technology, Dalian 116024, China
e-mail: jwchen@dlut.edu.cn
Z. Fu
e-mail: fuzq@dlut.edu.cn
© Springer Nature Switzerland AG 2019
H. Hong (ed.), Advances in Computational Toxicology, Challenges and Advances
in Computational Chemistry and Physics 30,
https://doi.org/10.1007/978-3-030-16443-0_17
337