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.