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Carcinogenic Metabolic Activation Process of Naphthalene by the Cytochrome P450 Enzyme 1B1: A Computational Study.
Chem Res Toxicol. 2019 04 15; 32(4):603-612.CR

Abstract

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.

Authors+Show Affiliations

Environment Research Institute , Shandong University , Qingdao 266237 , People's Republic of China.Environment Research Institute , Shandong University , Qingdao 266237 , People's Republic of China.Environment Research Institute , Shandong University , Qingdao 266237 , People's Republic of China.Environment Research Institute , Shandong University , Qingdao 266237 , People's Republic of China.Shenzhen Research Institute of Shandong University , Shenzhen 518057 , People's Republic of China.Department of Chemical Engineering , Massachusetts Institute of Technology , Cambridge , Massachusetts 02139 , United States.Environment Research Institute , Shandong University , Qingdao 266237 , People's Republic of China.Environment Research Institute , Shandong University , Qingdao 266237 , People's Republic of China.Environment Research Institute , Shandong University , Qingdao 266237 , People's Republic of China.Environment Research Institute , Shandong University , Qingdao 266237 , People's Republic of China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30794404

Citation

Bao, Lei, et al. "Carcinogenic Metabolic Activation Process of Naphthalene By the Cytochrome P450 Enzyme 1B1: a Computational Study." Chemical Research in Toxicology, vol. 32, no. 4, 2019, pp. 603-612.
Bao L, Liu W, Li Y, et al. Carcinogenic Metabolic Activation Process of Naphthalene by the Cytochrome P450 Enzyme 1B1: A Computational Study. Chem Res Toxicol. 2019;32(4):603-612.
Bao, L., Liu, W., Li, Y., Wang, X., Xu, F., Yang, Z., Yue, Y., Zuo, C., Zhang, Q., & Wang, W. (2019). Carcinogenic Metabolic Activation Process of Naphthalene by the Cytochrome P450 Enzyme 1B1: A Computational Study. Chemical Research in Toxicology, 32(4), 603-612. https://doi.org/10.1021/acs.chemrestox.8b00297
Bao L, et al. Carcinogenic Metabolic Activation Process of Naphthalene By the Cytochrome P450 Enzyme 1B1: a Computational Study. Chem Res Toxicol. 2019 04 15;32(4):603-612. PubMed PMID: 30794404.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carcinogenic Metabolic Activation Process of Naphthalene by the Cytochrome P450 Enzyme 1B1: A Computational Study. AU - Bao,Lei, AU - Liu,Wen, AU - Li,Yanwei, AU - Wang,Xueyu, AU - Xu,Fei, AU - Yang,Zhongyue, AU - Yue,Yue, AU - Zuo,Chenpeng, AU - Zhang,Qingzhu, AU - Wang,Wenxing, Y1 - 2019/03/01/ PY - 2019/2/23/pubmed PY - 2020/2/27/medline PY - 2019/2/23/entrez SP - 603 EP - 612 JF - Chemical research in toxicology JO - Chem. Res. Toxicol. VL - 32 IS - 4 N2 - 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. SN - 1520-5010 UR - https://www.unboundmedicine.com/medline/citation/30794404/Carcinogenic_Metabolic_Activation_Process_of_Naphthalene_by_the_Cytochrome_P450_Enzyme_1B1:_A_Computational_Study L2 - https://dx.doi.org/10.1021/acs.chemrestox.8b00297 DB - PRIME DP - Unbound Medicine ER -