A fragmentation-based method for the differentiation of glutathione conjugates by high-resolution mass spectrometry with electrospray ionization

doi:10.1016/j.aca.2013.06.022

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	A fragmentation-based method for the differentiation of glutathione conjugates by high-resolution mass spectrometry with electrospray ionization
	Xie, Cen; Zhong, Dafang; Chen, Xiaoyan
刊名	ANALYTICA CHIMICA ACTA
	2013-07-25
卷号	788 页码:89-98
关键词	Glutathione conjugates Electrospray ionization-mass spectrometry Fragmentation pattern Detection Structural differentiation
ISSN号	0003-2670
DOI	10.1016/j.aca.2013.06.022
文献子类	Article
英文摘要	Idiosyncratic reactions are one of the major causes of drug treatment limitations or market withdrawals, and likely involve the formation of reactive metabolites. Because of their unstable nature, reactive species are usually discovered as stable conjugates by glutathione (GSH) trapping rather than by direct detection. The GSH conjugates are then detected by neutral loss scanning of 129 Da or precursor ion scanning at m/z 272, but the conjugation sites can only be identified by comparison with reference standards. In the present study, the fragmentation behaviors of 52 GSH conjugates belonging to five structural classes (aliphatic, aromatic, benzylic, disulfide, and thioester) were investigated in both positive and negative electrospray ionization modes by high-resolution mass spectrometry with suitable collision energies such that the relative abundance of the parent ion was approximately 50% of the most abundant product ion. Several structural-diagnostic fragmentations were identified: aliphatic conjugates gave i/j-type ions upon cleavage of the C-S bond between the drug and GSH, and d/k-type ions formed by the cleavage of the cysteinyl C-S bond, with approximately equal intensity, in both positive and negative modes, whereas aromatic conjugates only possessed d/k-type ions, and benzylic conjugates primarily yielded i/j-type ions. Disulfide conjugates typically produced dehydrogenated GS-fragment ions ([i-2H]-type) in negative mode, and thioester conjugates displayed sequential losses of pyroglutamic acid and water ([e-H2O]-type) in positive mode. A fragmentation-based method was thus established to facilitate the discrimination of these five classes of GSH conjugates, thereby providing insight into the bioactivation mechanisms and supporting lead optimization. (C) 2013 Elsevier B.V. All rights reserved.
资助项目	National Natural Science Foundation of China[81173115] ; National Basic Research Program of China[2009CB930300]
WOS关键词	HUMAN LIVER-MICROSOMES ; IN-VITRO ; HUMAN HEPATOCYTES ; QUINONE METHIDE ; DRUG-REACTIONS ; IDENTIFICATION ; BIOACTIVATION ; METABOLITES ; ACID ; VIVO
WOS研究方向	Chemistry
语种	英语
出版者	ELSEVIER SCIENCE BV
WOS记录号	WOS:000321497700013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277534]
专题	上海药物代谢研究中心
通讯作者	Chen, Xiaoyan
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Metab & Pharmacokinet Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Xie, Cen,Zhong, Dafang,Chen, Xiaoyan. A fragmentation-based method for the differentiation of glutathione conjugates by high-resolution mass spectrometry with electrospray ionization[J]. ANALYTICA CHIMICA ACTA,2013,788:89-98.
APA	Xie, Cen,Zhong, Dafang,&Chen, Xiaoyan.(2013).A fragmentation-based method for the differentiation of glutathione conjugates by high-resolution mass spectrometry with electrospray ionization.ANALYTICA CHIMICA ACTA,788,89-98.
MLA	Xie, Cen,et al."A fragmentation-based method for the differentiation of glutathione conjugates by high-resolution mass spectrometry with electrospray ionization".ANALYTICA CHIMICA ACTA 788(2013):89-98.