17 Xenobiotic Metabolism by Cytochrome P450 …
361
molecular simulation studies with cluster models and DFT calculations are shown
to provide a mechanism-based explicit prediction for the metabolism of xenobiotics
catalyzed by P450 enzymes. Modeling the whole enzyme using hybrid quantum
mechanics/molecular mechanics (QM/MM) methodology with accurate force field
parameters and intensive samplings from molecular dynamic simulations may further
resolve the difference of metabolic kinetics and product distribution among various
P450 isoforms or other enzymes that participate in xenobiotic disposition in biota.
From a broader aspect, effective identification of the molecular initiating events
(MIEs) that lead eventually to adverse outcomes requires accurate simulation of
the interactions between xenobiotic chemicals and bio-macromolecules. Molecular
simulations are undeniably applicable for this purpose and could further be adopted
to develop quantitative predictive models for various parameters (binding constants,
partition coefficients, even transformation rate constants, etc.) that determine the fate
and toxicity of xenobiotic chemicals, provided that the computing capacity is greatly
advanced and certain environmental/biological systems are properly treated. With a
combination of these simulation techniques and quantitative models, it is possible
to compile computational toxicology models/software that enable precise prediction
of xenobiotic disposition and toxicology through a simple mouse clicking.
References
1. Rendic S, Guengerich FP (2012) Contributions of human enzymes in carcinogen metabolism.
Chem Res Toxicol 25(7):1316–1383
2. Hamers T, Kamstra JH, Sonneveld E, Murk AJ, Visser TJ, Van Velzen MJM, Brouwer
A, Bergman A (2008) Biotransformation of brominated flame retardants into potentially
endocrine-disrupting metabolites, with special attention to 2,2’,4,4’-tetrabromodiphenyl ether
(BDE-47). Mol Nutr Food Res 52(2):284–298
3. Coon MJ (2005) Cytochrome P450: nature’s most versatile biological catalyst. Annu rev pharmacol 45:1–25
4. Shaik S, Cohen S, Wang Y, Chen H, Kumar D, Thiel W (2010) P450 enzymes: their structure,
reactivity, and selectivity-modeled by QM/MM calculations. Chem Rev 110(2):949–1017
5. Wang B, Zhou SF (2009) Synthetic and natural compounds that interact with human cytochrome
P450 1A2 and implications in drug development. Curr Med Chem 16(31):4066–4218
6. Gross MS, Butryn DM, McGarrigle BP, Aga DS, Olson JR (2015) Primary role of cytochrome
P450 2B6 in the oxidative metabolism of 2,2 ,4,4 ,6-pentabromodiphenyl ether (BDE-100) to
hydroxylated bdes. Chem Res Toxicol 28(4):672–681
7. Rendic S, Guengerich FP (2015) Survey of human oxidoreductases and cytochrome P450
enzymes involved in the metabolism of xenobiotic and natural chemicals. Chem Res Toxicol
28(1):38–42
8. Shaik S, Kumar D, de Visser SP, Altun A, Thiel W (2005) Theoretical perspective on the
structure and mechanism of cytochrome P450 enzymes. Chem Rev 105(6):2279–2328
9. Wang BJ, Li CS, Dubey KD, Shaik S (2015) Quantum mechanical/molecular mechanical
calculated reactivity networks reveal how cytochrome P450cam and its T252A mutant select
their oxidation pathways. J Am Chem Soc 137(23):7379–7390
10. Rittle J, Green MT (2010) Cytochrome P450 Compound I: capture, characterization, and C-H
bond activation kinetics. Science 330(6006):933–937
11. Blomberg MRA, Borowski T, Himo F, Liao RZ, Siegbahn PEM (2014) Quantum chemical
studies of mechanisms for metalloenzymes. Chem Rev 114(7):3601–3658
361
molecular simulation studies with cluster models and DFT calculations are shown
to provide a mechanism-based explicit prediction for the metabolism of xenobiotics
catalyzed by P450 enzymes. Modeling the whole enzyme using hybrid quantum
mechanics/molecular mechanics (QM/MM) methodology with accurate force field
parameters and intensive samplings from molecular dynamic simulations may further
resolve the difference of metabolic kinetics and product distribution among various
P450 isoforms or other enzymes that participate in xenobiotic disposition in biota.
From a broader aspect, effective identification of the molecular initiating events
(MIEs) that lead eventually to adverse outcomes requires accurate simulation of
the interactions between xenobiotic chemicals and bio-macromolecules. Molecular
simulations are undeniably applicable for this purpose and could further be adopted
to develop quantitative predictive models for various parameters (binding constants,
partition coefficients, even transformation rate constants, etc.) that determine the fate
and toxicity of xenobiotic chemicals, provided that the computing capacity is greatly
advanced and certain environmental/biological systems are properly treated. With a
combination of these simulation techniques and quantitative models, it is possible
to compile computational toxicology models/software that enable precise prediction
of xenobiotic disposition and toxicology through a simple mouse clicking.
References
1. Rendic S, Guengerich FP (2012) Contributions of human enzymes in carcinogen metabolism.
Chem Res Toxicol 25(7):1316–1383
2. Hamers T, Kamstra JH, Sonneveld E, Murk AJ, Visser TJ, Van Velzen MJM, Brouwer
A, Bergman A (2008) Biotransformation of brominated flame retardants into potentially
endocrine-disrupting metabolites, with special attention to 2,2’,4,4’-tetrabromodiphenyl ether
(BDE-47). Mol Nutr Food Res 52(2):284–298
3. Coon MJ (2005) Cytochrome P450: nature’s most versatile biological catalyst. Annu rev pharmacol 45:1–25
4. Shaik S, Cohen S, Wang Y, Chen H, Kumar D, Thiel W (2010) P450 enzymes: their structure,
reactivity, and selectivity-modeled by QM/MM calculations. Chem Rev 110(2):949–1017
5. Wang B, Zhou SF (2009) Synthetic and natural compounds that interact with human cytochrome
P450 1A2 and implications in drug development. Curr Med Chem 16(31):4066–4218
6. Gross MS, Butryn DM, McGarrigle BP, Aga DS, Olson JR (2015) Primary role of cytochrome
P450 2B6 in the oxidative metabolism of 2,2 ,4,4 ,6-pentabromodiphenyl ether (BDE-100) to
hydroxylated bdes. Chem Res Toxicol 28(4):672–681
7. Rendic S, Guengerich FP (2015) Survey of human oxidoreductases and cytochrome P450
enzymes involved in the metabolism of xenobiotic and natural chemicals. Chem Res Toxicol
28(1):38–42
8. Shaik S, Kumar D, de Visser SP, Altun A, Thiel W (2005) Theoretical perspective on the
structure and mechanism of cytochrome P450 enzymes. Chem Rev 105(6):2279–2328
9. Wang BJ, Li CS, Dubey KD, Shaik S (2015) Quantum mechanical/molecular mechanical
calculated reactivity networks reveal how cytochrome P450cam and its T252A mutant select
their oxidation pathways. J Am Chem Soc 137(23):7379–7390
10. Rittle J, Green MT (2010) Cytochrome P450 Compound I: capture, characterization, and C-H
bond activation kinetics. Science 330(6006):933–937
11. Blomberg MRA, Borowski T, Himo F, Liao RZ, Siegbahn PEM (2014) Quantum chemical
studies of mechanisms for metalloenzymes. Chem Rev 114(7):3601–3658