Quantum chemical metabolism‐based simulation of carcinogenic potency of benzene derivatives

Abstract

AbstractUsing an oxenoid model, we investigated dependences of carcinogenic potency of the benzenes C6H5‐X on a nature of substituents X. According to the model, a P450 enzyme breaks a dioxygen molecule and generates the oxens, which readily react with substrates. We suggest that a stability of the intermediate OC6H6‐X with tetrahedrally coordinated C atom relative to the molecule C6H5‐X determines a rate of substrate biotransformation. Using MO LCAO MNDO approach, we calculated the total energies of molecules C6H6‐X and arene oxides OC6H6‐X. A difference ΔEmin of these values determines activation energy of oxidation reaction. The compounds with the low ΔEmin values are noncarcinogenic. Benzene derivatives with high ΔEmin values belong to carcinogenic compounds series. The carcinogenicity of amino‐ and nitro‐substituted benzenes is also determined by N‐oxidation of amino and reduction of the nitro group. As the phenylhydroxylamines XC6H4NHOH and nitrenium ions XC6OH4NH+ are the common metabolites of the nitro‐ and amino‐substituted benzenes and nitrenium ions XC6H4NH+ are the ultimate carcinogens, we use the differences ΔEN = E(XC6H4NH+) − E(XC6H4NHOH) as the second parameter characterizing the carcinogenic activity of amino‐ and nitro‐substituted benzenes. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010