An unusual double radical homolysis mechanism for the unexpected activation of the aldoxime nerve-agent antidotes by polyhalogenated quinoid carcinogens under normal physiological conditions

CORC > 生态环境研究中心 > 中国科学院生态环境研究中心 > 环境化学与生态毒理学国家重点实验室

	An unusual double radical homolysis mechanism for the unexpected activation of the aldoxime nerve-agent antidotes by polyhalogenated quinoid carcinogens under normal physiological conditions
	Xie, Lin-Na ; Shao, Jie ; Huang, Chun-Hua ; Li, Feng ; Xu, Dan ; Kalyanaraman, Balaraman ; Zhu, Ben-Zhan
刊名	FREE RADICAL BIOLOGY AND MEDICINE
	2019
卷号	130 页码:1-7
关键词	Radical homolysis mechanism Iminyl radical Tetrachloro-1, 4-benzoquinone (TCBQ) Pyridinium aldoximes Nerve-agent antidotes Polyhalogenated quinoid carcinogens
ISSN号	0891-5849
英文摘要	We have recently shown that the pyridinium aldoximes, best-known as therapeutic antidotes for chemical warfare nerve-agents, could markedly detoxify the carcinogenic tetrachloro-1,4-benzoquinone (TCBQ) via an unusual double Beckmann fragmentation mechanism. However, it is still not clear why pralidoxime (2-PAM) cannot provide full protection against TCBQ-induced biological damages even when 2-PAM was in excess. Here we show, unexpectedly, that TCBQ can also activate pralidoxime to generate a reactive iminyl radical intermediate in two-consecutive steps, which was detected and unequivocally characterized by the complementary application of ESR spin-trapping, HPLC/MS and nitrogen-15 isotope-labeling studies. The same iminyl radical was observed when TCBQ was substituted by other halogenated quinones. The end product of iminyl radical was isolated and identified as its corresponding reactive and toxic aldehyde. Based on these data, we proposed that the reaction of 2-PAM and TCBQ might be through the following two competing pathways: a nucleophilic attack of 2-PAM on TCBQ forms an unstable transient intermediate, which can decompose not only heterolytically to form 2-CMP via double Beckmann fragmentation, but also homolytically leading to the formation of a reactive iminyl radical in double-steps, which then via H abstraction and further hydrolyzation to form its corresponding more toxic aldehyde. Analogous radical homolysis mechanism was observed with other halogenated quinones and pyridinium aldoximes. This study represents the first detection and identification of reactive iminyl radical intermediates produced under normal physiological conditions, which provides direct experimental evidence to explain only the partial protection by 2-PAM against TCBQ-induced biological damages, and also the potential side-toxic effects induced by 2-PAM and other pyridinium aldoxime nerve-agent antidotes.
内容类型	期刊论文
源URL	[http://ir.rcees.ac.cn/handle/311016/42900]
专题	生态环境研究中心_环境化学与生态毒理学国家重点实验室
作者单位	1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Med Coll Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA 3.Chinese Acad Sci, Res Ctr Ecoenvironm Sci, State Key Lab Environm Chem & Ecotoxicol, POB 2871, Beijing 100085, Peoples R China
推荐引用方式 GB/T 7714	Xie, Lin-Na,Shao, Jie,Huang, Chun-Hua,et al. An unusual double radical homolysis mechanism for the unexpected activation of the aldoxime nerve-agent antidotes by polyhalogenated quinoid carcinogens under normal physiological conditions[J]. FREE RADICAL BIOLOGY AND MEDICINE,2019,130:1-7.
APA	Xie, Lin-Na.,Shao, Jie.,Huang, Chun-Hua.,Li, Feng.,Xu, Dan.,...&Zhu, Ben-Zhan.(2019).An unusual double radical homolysis mechanism for the unexpected activation of the aldoxime nerve-agent antidotes by polyhalogenated quinoid carcinogens under normal physiological conditions.FREE RADICAL BIOLOGY AND MEDICINE,130,1-7.
MLA	Xie, Lin-Na,et al."An unusual double radical homolysis mechanism for the unexpected activation of the aldoxime nerve-agent antidotes by polyhalogenated quinoid carcinogens under normal physiological conditions".FREE RADICAL BIOLOGY AND MEDICINE 130(2019):1-7.