Wang Mei, Gao Yanpeng, Luo Na, Chen Guanhui, Niu Xiaolin, Li Guiying, An Taicheng
Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Institute of Environmental Health and Pollution Control, Guangdong University of Technology, Guangzhou 510006, China.
Guangzhou Key Laboratory of Environmental Catalysis and Pollution Control, Key Laboratory for City Cluster Environmental Safety and Green Development of the Ministry of Education, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China.
Environ Health (Wash). 2023 Oct 5;1(6):383-393. doi: 10.1021/envhealth.3c00064. eCollection 2023 Dec 15.
Polycyclic aromatic hydrocarbon (PAH) derivatives have a widespread presence in the environment and even the human body, but their metabolism and potential risk remain unclear. In this study, we used molecular dynamics simulations and density functional theory to calculate the metabolic mechanism of 1-nitropyrene (1-NP), an important PAH derivative. The results showed that cytochrome P450 enzymes (CYPs) can metabolize 1-NP, with CYP 2A13 and CYP 2E1 being important enzyme isoforms, because they had lower binding affinities (-16.48 and -13.90 kcal/mol) to 1-NP than other CYPs (-2.38 to -7.89 kcal/mol). Additionally, these CYPs can metabolize 1-NP through epoxidation and hydroxylation pathways. Compared to hydroxylation, epoxidation had a lower energy barrier of 9.42 kcal/mol, and 4,5-epoxide-1-nitropyrene and 9,10-epoxide-1-nitropyrene were identified as the major epoxidation products through electrophilic addition. In addition, 6-hydroxy-1-nitropyrene and 8-hydroxy-1-nitropyrene were the major hydroxylated metabolites. Health risks revealed that electrophilicity of epoxides increased the risk of binding to DNA, and both 1-NP and its four important metabolites cause adverse effects on the gastrointestinal system and lung. In summary, this study revealed the metabolic mechanism of 1-NP by human CYPs and formation of toxic metabolites, and more attention should be paid to the nitro-derivatives of PAHs in the future.
多环芳烃（PAH）衍生物广泛存在于环境甚至人体中，但其代谢过程和潜在风险仍不明确。在本研究中，我们使用分子动力学模拟和密度泛函理论来计算一种重要的PAH衍生物1-硝基芘（1-NP）的代谢机制。结果表明，细胞色素P450酶（CYPs）能够代谢1-NP，其中CYP 2A13和CYP 2E1是重要的酶亚型，因为它们与1-NP的结合亲和力（-16.48和-13.90千卡/摩尔）低于其他CYPs（-2.38至-7.89千卡/摩尔）。此外，这些CYPs可以通过环氧化和羟基化途径代谢1-NP。与羟基化相比，环氧化的能垒较低，为9.42千卡/摩尔，通过亲电加成确定4,5-环氧-1-硝基芘和9,10-环氧-1-硝基芘为主要环氧化产物。此外，6-羟基-1-硝基芘和8-羟基-1-硝基芘是主要的羟基化代谢产物。健康风险表明，环氧化物的亲电性增加了与DNA结合的风险，1-NP及其四种重要代谢产物均会对胃肠道系统和肺部产生不良影响。总之，本研究揭示了人类CYPs对1-NP的代谢机制以及有毒代谢产物的形成，未来应更加关注PAHs的硝基衍生物。
