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

The dependences of biological oxidation and toxicity of the mono- and multi- substituted 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 tri- chlorinated biphenyls bacterial metabolism. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem 107: 2454-2478, 2007