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

文献类型：期刊论文

作者Ma, Jiang1,2,3; Ruan, Jianqing1,2,3; Chen, Xinmeng1,2,3; Li, Dongping4; Yao, Sheng2,3,5; Fu, Peter P.6; Ye, Yang2,3,5; Gao, Hong4; Wang, Jiyao4; Lin, Ge1,2,3
刊名CHEMICAL RESEARCH IN TOXICOLOGY
出版日期2019-06-01
卷号32期号:6页码:1027-1039
ISSN号0893-228X
DOI10.1021/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.
WOS关键词SINUSOIDAL OBSTRUCTION SYNDROME ; INDUCED LIVER-INJURY ; METABOLIC-ACTIVATION ; PROTEIN ADDUCTS ; DNA-ADDUCTS ; VENOOCCLUSIVE DISEASE ; MASS-SPECTROMETRY ; DIAGNOSIS ; BINDING ; BLOOD
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研究方向Pharmacology & Pharmacy ; Chemistry ; Toxicology
语种英语
WOS记录号WOS:000472241800014
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/289510]  
专题新药研究国家重点实验室
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.

入库方式： OAI收割

来源：上海药物研究所

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