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Guanine Alkylation by the Potent Carcinogen Aflatoxin B1: Quantum Chemical Calculations

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journal contribution
posted on 20.08.2007, 00:00 by Urban Bren, F. Peter Guengerich, Janez Mavri
We report a series of ab initio and density functional theory simulations of guanine alkylation by aflatoxin B1 exo-8,9-epoxide. This reaction represents an initial step of carcinogenesis associated with aflatoxin B1, a potent genotoxic fungal metabolite. Effects of hydration were considered in the framework of the Langevin dipoles solvation model and the solvent reaction field method of Tomasi and co-workers. In silico-calculated activation free energies are in good agreement with the experimental value of 15.1 kcal/mol. This agreement presents strong evidence in favor of the validity of the proposed SN2 reaction mechanism and points to the applicability of quantum chemical methods in studies of reactions associated with carcinogenesis. In addition, we predict that the preference of aflatoxin B1 exo-8,9-epoxide over the endo stereoisomer for the reaction with guanine exists in the aqueous solution and is only further amplified in the DNA duplex. Finally, through comparison with an analogous reaction between 3a,6a-dihydrofuro[2,3-b]furan exo-4,5-epoxide and guanine, we show that the large planar body of aflatoxin B1 does not enhance its reactivity and related carcinogenicity. This explains why the planar region of related mycotoxins sterigmatocystin and aflatoxin G1 could have been evolutionarily optimized in a different way.