Carcinogenic Metabolic Activation Process of Naphthalene by the Cytochrome P450 Enzyme 1B1: A Computational Study

The metabolic activation and transformation of naphthalene by the cytochrome P450 enzyme (CYP 1B1) plays an important role in its potential carcinogenicity. The process has been explored by a quantum mechanics/molecular mechanics (QM/MM) computational method. Molecular dynamic simulations were performed to explore the interaction between naphthalene and CYP 1B1. Naphthalene involves α- and β-carbon, the electrophilic addition of which would result in different reaction pathways. Our computational results show that both additions on α- and β-carbon can generate naphthalene 1,2-oxide. The activation barrier for the addition on β-carbon is higher than that for the α-carbon by 2.6 kcal·mol^-1, which is possibly caused by the proximity between β-carbon and the iron-oxo group of Cpd I in the system. We also found that naphthalene 1,2-oxide is unstable and the O-C bond cleavage easily occurs via cellular hydronium ion, hydroxyl radical/anion; then it will convert to the potential ultimate carcinogen 1,2-naphthoquinone. The results demonstrate and inform a detailed process of generating naphthalene 1,2-oxide and new predictions for its conversion.