Pyrrole-Hemoglobin Adducts, a More Feasible Potential Biomarker of Pyrrolizidine Alkaloid Exposure

doi:10.1021/acs.chemrestox.8b00369

	Pyrrole-Hemoglobin Adducts, a More Feasible Potential Biomarker of Pyrrolizidine Alkaloid Exposure
	Ma, Jiang 1,2,3; Ruan, Jianqing 1,2,3; Chen, Xinmeng 1,2,3; Li, Dongping 4; Yao, Sheng 2,3,5; Fu, Peter P.6; Ye, Yang 2,3,5; Gao, Hong 4; Wang, Jiyao 4; Lin, Ge 1,2,3
刊名	CHEMICAL RESEARCH IN TOXICOLOGY
	2019-06-01
卷号	32 期号:6 页码:1027-1039
ISSN号	0893-228X
DOI	10.1021/acs.chemrestox.8b00369
通讯作者	Gao, Hong(gao.hong@zs-hospital.sh.cn) ; Lin, Ge(linge@cuhk.edu.hk)
英文摘要	Pyrrolizidine alkaloids (PAs) are naturally occurring phytotoxins widely distributed in about 3% of flowering plants. The formation of PA-derived pyrrole-protein adducts is considered as a primary trigger initiating PA-induced hepatotoxicity. The present study aims to (i) further validate our previous established derivatization method using acidified ethanolic AgNO3 for the analysis of pyrrole-protein adducts and (ii) apply this method to characterize the binding tendency, dose-response, and elimination kinetics of pyrrole-protein adducts in blood samples. Two pyrrole amino acid conjugates, (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-cysteine (7-cysteine-DHP) and 9-histidine-DHP, were synthesized and used to demonstrate that acidified ethanolic AgNO3 derivatization can cleave both S-linkage and N-linkage of pyrrole-protein adducts. Subsequently, using precolumn AgNO3 derivatization followed by ultra-high-pressure liquid chromatography/mass spectrometry analysis, we quantified pyrrole-protein adducts in monocrotaline-treated rat blood protein fractions, including hemoglobin (Hb), plasma, albumin, and plasma residual protein fractions, and found that the amount of pyrrole-Hb adducts was significantly higher than that in all plasma fractions. Moreover, elimination half-life of pyrrole-Hb adducts was also significantly longer than pyrrole-protein adducts in plasma fractions (12.08 vs 2.54-2.93 days). In addition, we also tested blood samples obtained from five PA-induced liver injury patients and found that the amount of pyrrole-protein adducts in blood cells was also remarkably higher than that in plasma. In conclusion, our findings for the first time confirmed that the AgNO3 derivatization method could be used to measure both S- and N-linked pyrrole-protein adducts and also suggested that pyrrole Hb adducts with remarkably higher level and longer life span could be a better biomarker of PA exposure.
资助项目	Research Grants Council of Hong Kong (GRF)[14110714] ; Research Grants Council of Hong Kong (GRF)[14111816] ; Research Grants Council of Hong Kong (GRF)[14160817] ; Chinese University of Hong Kong[4054376]
WOS关键词	SINUSOIDAL OBSTRUCTION SYNDROME ; INDUCED LIVER-INJURY ; METABOLIC-ACTIVATION ; PROTEIN ADDUCTS ; DNA-ADDUCTS ; VENOOCCLUSIVE DISEASE ; MASS-SPECTROMETRY ; DIAGNOSIS ; BINDING ; BLOOD
WOS研究方向	Pharmacology & Pharmacy ; Chemistry ; Toxicology
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000472241800014
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289510]
专题	中国科学院上海药物研究所
通讯作者	Gao, Hong; Lin, Ge
作者单位	1.Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Hong Kong, Peoples R China 2.Chinese Univ Hong Kong, Joint Res Lab Promoting Globalizat Tradit Chinese, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 4.Fudan Univ, Div Gastroenterol, ZhongShan Hosp, Shanghai 200000, Peoples R China 5.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 6.US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA
推荐引用方式 GB/T 7714	Ma, Jiang,Ruan, Jianqing,Chen, Xinmeng,et al. Pyrrole-Hemoglobin Adducts, a More Feasible Potential Biomarker of Pyrrolizidine Alkaloid Exposure[J]. CHEMICAL RESEARCH IN TOXICOLOGY,2019,32(6):1027-1039.
APA	Ma, Jiang.,Ruan, Jianqing.,Chen, Xinmeng.,Li, Dongping.,Yao, Sheng.,...&Lin, Ge.(2019).Pyrrole-Hemoglobin Adducts, a More Feasible Potential Biomarker of Pyrrolizidine Alkaloid Exposure.CHEMICAL RESEARCH IN TOXICOLOGY,32(6),1027-1039.
MLA	Ma, Jiang,et al."Pyrrole-Hemoglobin Adducts, a More Feasible Potential Biomarker of Pyrrolizidine Alkaloid Exposure".CHEMICAL RESEARCH IN TOXICOLOGY 32.6(2019):1027-1039.