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

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posted on 2019-02-22, 00:00 authored by Lei Bao, Wen Liu, Yanwei Li, Xueyu Wang, Fei Xu, Zhongyue Yang, Yue Yue, Chenpeng Zuo, Qingzhu Zhang, Wenxing Wang
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.

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