Quantum Chemical Simulation of Cytochrome P450 Catalyzed Oxidation and Carcinogenic potency of Benzene Derivatives

Using an oxenoid model and quantum chemical calculations, we have investigated a dependence of carcinogenic potency of the benzene derivatives C6H5-X on a nature of substituents X. According to the model, a P450 enzyme breaks the dioxygen molecule and generates the active atomic oxygen species (oxens) which readily react with substrates. We suggest that a stability of the intermediate OC6H6-X with one tetrahedrally coordinated C atom relative to the original molecule C6H5-X determines a rate of enzyme mediated substrate biotransformation. Using Molecular Orbitals Linear Combinations of Atomic Orbitals (MO LCAO) method and a Modified Neglect of Differential Overlap (MNDO) approach, we have calculated the total energies of molecules C6H6-X and those of arene oxides OC6H6-X. A difference Delta E-min of these values determines an activation energy of oxidation reaction. We have shown that the compounds with the low Delta E-min values are non-carcinogenic, and oxidation of benzene ring seems to be the detoxication reaction here. Benzene derivatives with high Delta E-min values belong to carcinogenic compounds. The reason is a low rate of detoxication in this case.