Quantum chemical simulation of cytochrome P450 catalyzed aromatic oxidation: Metabolism, toxicity, and biodegradation of benzene derivatives

Abstract

ABSTRACT:The dependences of biological oxidation and toxicity of the mono-and multisubstituted benzene derivatives on the nature of substituents are studied using an oxenoid model and the quantum chemical calculations. According to this model, the P450 enzyme breaks the dioxygen molecules and generates the active atomic oxygen species (oxens); these species readily react with substrates. Using MO LCAO MNDO approach, we calculated the differences ⌬E of the total energies of aromatic compounds and corresponding arene oxides containing tetrahedrally coordinated carbon atoms. We obtained that the ⌬E values determine the positions of the enzyme mediated oxidation, rate of substrate biotransformation, and toxicity of the benzene derivatives. In addition to the "dynamic" reactivity index ⌬E related to the enzyme-mediated substrate biotransformation, we calculated many standard "static" reactivity indices, corresponding to the substrate molecules in the starting equilibrium geometry (the energies of the occupied and unoccupied MOs, the effective atomic charges, the free valence indices, and the superdelocalizabilities). The arene oxide stability ⌬E parameter is shown to be the most adequate characteristic of both the biological oxidation process and toxicity of benzenes. The ⌬E parameters were also used successfully to describe the features of di-and trichlorinated biphenyls bacterial metabolism.

Assessing utility values in rheumatoid arthritis: A comparison between time trade‐off and the EuroQol

“…In summary, taking into account our previous results 18, we conclude that the oxenoid model together with semiempirical quantum chemical calculations can reasonably explain the in vivo and in vitro experimental data on the positions of the enzyme‐mediated oxidation, rate of substrate biotransformation, as well as toxicity, and carcinogenicity of the mono‐ and disubstituted benzene derivatives.…”

“…The oxens readily react with substrates 16, 17. The relationships between the nature of substituents from one side and biological oxidation and acute toxicity of the benzene derivatives from another side as well as the features of metabolism of di‐ and trichlorinated biphenyls by bacteria were studied using an oxenoid model in our recent paper 18.…”

Prediction of Activation Energies for Aromatic Oxidation by Cytochrome P450

“…The results at the AM1 level are rather poor ( r 2 = 0.55 for BDE cat alone, excluding nonaromatic oxidations, and r 2 = 0.60 for our full data set with both descriptors). However, it is significantly better and faster than energies obtained for the intermediate with the methoxy-radical model ( r 2 = 0.35−0.45), a method that has been used in several previous studies. ,,, …”

“…It has previously been shown that the methoxy radical can be used as a model for compound I when studying the hydroxylation of aliphatic carbon atoms , as well as in semiempirical studies of hydroxylation of aromatic carbon atoms. ,,, Therefore, we also tested how well the activation energies and the energies of the tetrahedral intermediate, calculated with the methoxy radical could reproduce the energies in Table . As is shown in part a of Figure and Table , the activation energies calculated with the methoxy radical at the B3LYP/6−31G(d) level correlate well with the final DFT energies calculated with the full compound I model.…”

Quantitative Property-Property Relationship for Screening-Level Prediction of Intrinsic Clearance of Volatile Organic Chemicals in Rats and Its Integration within PBPK Models to Predict Inhalation Pharmacokinetics in Humans

“…Quantitative relationships between structure and metabolism rates have been investigated for a limited number of closely related compounds, even though their applicability to PBPK modeling has not been demonstrated (e.g., QSPR models for K cat and 1/ K m [ 87 ]). Other works in this area relate to the development of quantum chemical or quantum dynamic methods for prediction of activation energy or enthalpy of activation of P450 mediated reactions [ 20 , 25 , 26 , 31 , 36 , 38 , 88 – 91 ], which have not been used to derive metabolism constants for direct incorporation within rodent or human PBPK models.…”