In Silico simulation of Cytochrome P450-Mediated metabolism of aromatic amines: A case study of N-Hydroxylation

Ecotoxicology and Environmental Safety

Lingmin Jin¹  Chenchen Wang²  Fangxing Yang²  Huanni Zhang²  Li Ji²  Fangjie Guo²  Haiying Yu²  Runqian Song³ 

[1] Quality and Safety Engineering Institute of Food and Drug, School of Management Engineering and Electronic Commerce, Zhejiang Gongshang University, Hangzhou, Zhejiang 310018, China;College of Environmental and Resource Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, China;College of Geography and Environmental Sciences, Zhejiang Normal University, Yingbin Avenue 688, Jinhua 321004, China;

关键词: Aromatic amines;    Cytochrome P450 enzymes;    Activation energy;    Bond dissociation energy;    Hydroxylation;   

DOI  :  

来源: DOAJ

【 摘 要 】

Aromatic amines, the widely used raw materials in industry, cause long-term exposure to human bodies. They can be metabolized by cytochrome P450 enzymes to form active electrophilic compounds, which will potentially react with nucleophilic DNA to exert carcinogenesis. The short lifetime and versatility of the oxidant (a high-valent iron (IV)-oxo species, compound I) of P450 enzymes prompts us to use theoretical methods to investigate the metabolism of aromatic amines. In this work, the density functional theory (DFT) has been employed to simulate the hydroxylation metabolism through H-abstraction and to calculate the activation energy of this reaction for 28 aromatic amines. The results indicate that the steric effects, inductive effects and conjugative effects greatly contribute to the metabolism activity of the chemicals. The further correlation reveals that the dissociation energy of -NH2 (BDEN-H) can successfully predict the time-consuming calculated activation energy (R2 for aromatic and heteroaromatic amines are 0.93 and 0.86, respectively), so BDEN-H can be taken as a key parameter to characterize the relative stability of aromatic amines in P450 enzymes and further to quickly assess their potential toxicity. The validation results prove such relationship has good statistical performance (qcv2 for aromatic and heteroaromatic amines are 0.95 and 0.90, respectively) and can be used to other aromatic amines in the application domain, greatly reducing computational cost and providing useful support for experimental research.

【 授权许可】

Unknown