Computational insight into biotransformation of halophenols by cytochrome P450: Mechanism and reactivity for epoxidation

被引:12
作者
Han, Cenyang [1 ]
Zhu, Wenyou [2 ]
Ma, Guangcai [1 ]
Chen, Yewen [1 ]
Li, Xinqi [1 ]
Wei, Xiaoxuan [1 ]
Yu, Haiying [1 ]
机构
[1] Zhejiang Normal Univ, Coll Geog & Environm Sci, Yingbin Ave 688, Jinhua 321004, Zhejiang, Peoples R China
[2] Xuzhou Univ Technol, Sch Mat & Chem Engn, Xuzhou 221018, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
Halophenol; Epoxidation; Cytochrome P450; Quantum chemical calculation; 2-STATE REACTIVITY; BASIS-SETS; AB-INITIO; CHLOROPHENOLS; PERFORMANCE; THERMOCHEMISTRY; MICROEXTRACTION; HYDROXYLATION; SPECTROMETRY; METABOLISM;
D O I
10.1016/j.chemosphere.2021.131708
中图分类号
X [环境科学、安全科学];
学科分类号
08 ; 0830 ;
摘要
Halophenols (XPs) have aroused great interests due to their high toxicity and low biodegradability. Previous experimental studies have shown that XPs can be catalytically transformed into epoxides and haloquinones by cytochrome P450 enzymes (CYPs). However, these metabolites have never been detected directly. Moreover, the effects of the reaction site and the type and number of halogen substituents on the biotransformation reactivity of halophenols still remain unknown. In this work, we performed density functional theory (DFT) calculations to simulate the CYP-mediated biotransformation of 36 XPs with mono-, di-, and tri-halogen (F, Cl, and Br) substitutions to unravel the mechanism and relevant kinetics of XPs epoxidation. The whole epoxidation process consists of initial rate-determining O-addition and subsequent ring-closure steps. The simulation results show that the epoxidation in low-spin (LS) state is kinetically preferred over that in high-spin (HS) state, and the formation of epoxide metabolite is strongly exothermic. For all XPs, the epoxidation reactivity follows the order of ortho/para O-addition > meta O-addition. Moreover, the O-addition with higher energy barriers roughly corresponds to chlorophenols and fluorophenols with more halogen atoms. Compared with dichlorophenols, the additional ortho-Cl substitution on trichlorophenols can slightly increase the energy barriers of meta O-addition. By contrast, the additional inclusion of an ortho-Cl to monochlorophenols enhances the meta O-addition reactivity of dichlorophenols. Overall, the present work clarifies the biotransformation routes of XPs to produce epoxides, and identifies the key factors affecting the epoxidation reactivity, which are beneficial in understanding comprehensively the metabolic fate and toxicity of XPs.
引用
收藏
页数:9
相关论文
共 50 条
  • [21] Computational Prediction of Inhibitors and Inducers of the Major Isoforms of Cytochrome P450
    Rudik, Anastassia
    Dmitriev, Alexander
    Lagunin, Alexey
    Filimonov, Dmitry
    Poroikov, Vladimir
    MOLECULES, 2022, 27 (18):
  • [22] Probing the Role of the Hinge Segment of Cytochrome P450 Oxidoreductase in the Interaction with Cytochrome P450
    Campelo, Diana
    Esteves, Francisco
    Palma, Bernardo Brito
    Gomes, Bruno Costa
    Rueff, Jose
    Lautier, Thomas
    Urban, Philippe
    Truan, Gilles
    Kranendonk, Michel
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2018, 19 (12)
  • [23] Computational Investigation of the Bisphenolic Drug Metabolism by Cytochrome P450: What Factors Favor Intramolecular Phenol Coupling
    Chai, Lihong
    Zhang, Huanni
    Guo, Fangjie
    Song, Runqian
    Yu, Haiying
    Ji, Li
    CHEMICAL RESEARCH IN TOXICOLOGY, 2022, 35 (03) : 440 - 449
  • [24] Understanding the Mechanistic Requirements for Efficient and Stereoselective Alkene Epoxidation by a Cytochrome P450 Enzyme
    Coleman, Tom
    Kirk, Alicia M.
    Chao, Rebecca R.
    Podgorski, Matthew N.
    Harbort, Joshua S.
    Churchman, Luke R.
    Bruning, John B.
    Bernhardt, Paul, V
    Harmer, Jeffrey R.
    Krenske, Elizabeth H.
    De Voss, James J.
    Bell, Stephen G.
    ACS CATALYSIS, 2021, 11 (04) : 1995 - 2010
  • [25] Identification of the human cytochrome P450 enzymes involved in the in vitro biotransformation of lynestrenol and norethindrone
    Korhonen, Tuomas
    Turpeinen, Miia
    Tolonen, Ari
    Laine, Kari
    Pelkonen, Olavi
    JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2008, 110 (1-2) : 56 - 66
  • [26] Genetic insight into cytochrome P450 in Chinese from the Chinese Millionome Database
    Qi, Guangzhao
    Han, Chao
    Sun, Ya
    Zhou, Yubing
    BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, 2020, 126 (04) : 341 - 352
  • [27] The Curious Case of Benzbromarone: Insight into Super-Inhibition of Cytochrome P450
    Parashar, Abhinav
    Gade, Sudeep Kumar
    Potnuru, Mahesh
    Madhavan, Nandita
    Manoj, Kelath Murali
    PLOS ONE, 2014, 9 (03):
  • [28] Enantioselective metabolism of novel chiral insecticide Paichongding by human cytochrome P450 3A4: A computational insight*
    Ma, Guangcai
    Wang, Qiuyi
    Ma, Kan
    Chen, Yewen
    Lu, Jiayu
    Zhang, Jing
    Wang, Xueyu
    Wei, Xiaoxuan
    Yu, Haiying
    ENVIRONMENTAL POLLUTION, 2023, 333
  • [29] Theoretical Study of Hydroxylation of α- and β-Pinene by a Cytochrome P450 Monooxygenase Model
    Shaya, Janah
    Aloum, Lujain
    Lu, Chung-Shin
    Corridon, Peter R.
    Aoudi, Abdulrahman
    Shunnar, Abeer
    Alefishat, Eman
    Petroianu, Georg
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2023, 24 (06)
  • [30] Novel Mechanism of Decyanation of GDC-0425 by Cytochrome P450
    Takahashi, Ryan H.
    Halladay, Jason S.
    Siu, Michael
    Chen, Yuan
    Hop, Cornelis E. C. A.
    Khojasteh, S. Cyrus
    Ma, Shuguang
    DRUG METABOLISM AND DISPOSITION, 2017, 45 (05) : 430 - 440