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题名: Theoretical insights into the reductive metabolism of CCl4 by cytochrome P450 enzymes and the CCl4-dependent suicidal inactivation of P450
作者: Li, Xiao-Xi1, 2;  Zheng, Qing-Chuan1;  Wang, Yong2;  Zhang, Hong-Xing1
刊名: DALTON TRANSACTIONS
发表日期: 2014-10-21
DOI: 10.1039/c4dt02065k
卷: 43, 期:39, 页:14833-14840
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Chemistry, Inorganic & Nuclear
研究领域[WOS]: Chemistry
英文摘要: The anaerobic metabolism of CCl4 by P450 enzymes was investigated using quantum chemical calculations. It was found that under anaerobic conditions, the substrate CCl4 might undergo one or two subsequent one-electron reductions to generate different reactive metabolites, trichloromethyl radical ((CCl3)-C-center dot) and dichlorocarbene (:CCl2) respectively. Meanwhile, it was the reduced ferrous haem complex rather than the unreduced ferric haem complex that could directly achieve such reductions. Based on the formation of the former reactive metabolite, a further one-electron reduction could take place with the assistance of a proton to yield the latter reactive species, i.e., a further reductive dechloridation of (CCl3)-C-center dot could take place via a novel S(E)3 mechanism. In addition, the (CCl3)-C-center dot species was capable of binding covalently to the meso-carbon atom of the prosthetic group, leading to the suicidal destruction of P450 enzymes. Whereas the :CCl2 species was involved in the CCl4-dependent reversible P450 inhibition as its hydrolysis product, CO, but was not significantly involved in the CCl4-dependent irreversible P450 destruction. It is obvious that the reductive metabolism of CCl4 to reactive intermediates by P450 enzymes is an essential prerequisite for its toxicity.
关键词[WOS]: CARBON-TETRACHLORIDE METABOLISM ;  DENSITY-FUNCTIONAL THERMOCHEMISTRY ;  MECHANISM-BASED INACTIVATION ;  LIVER MICROSOMAL CYTOCHROME-P-450 ;  LIPID-PEROXIDATION ;  ANAEROBIC REDUCTION ;  HALOGENATED ALKANES ;  IN-VITRO ;  TETRACHLOROMETHANE METABOLISM ;  TRICHLOROMETHYL RADICALS
语种: 英语
WOS记录号: WOS:000342965200043
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/145658
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Jilin Univ, Inst Theoret Chem, State Key Lab Theoret & Computat Chem, Changchun 130023, Peoples R China
2.Chinese Acad Sci, Dalian Inst Chem Phys, Dalian 116023, Peoples R China

Recommended Citation:
Li, Xiao-Xi,Zheng, Qing-Chuan,Wang, Yong,et al. Theoretical insights into the reductive metabolism of CCl4 by cytochrome P450 enzymes and the CCl4-dependent suicidal inactivation of P450[J]. DALTON TRANSACTIONS,2014,43(39):14833-14840.
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