Cytotoxicity of pyrrolizidine alkaloid in human hepatic parenchymal and sinusoidal endothelial cells: Firm evidence for the reactive metabolites mediated pyrrolizidine alkaloid-induced hepatotoxicity

doi:10.1016/j.cbi.2015.09.011

	Cytotoxicity of pyrrolizidine alkaloid in human hepatic parenchymal and sinusoidal endothelial cells: Firm evidence for the reactive metabolites mediated pyrrolizidine alkaloid-induced hepatotoxicity
	Yang, Mengbi 2,3; Ruan, Jianqing 2,3; Fu, Peter P 1; Lin, Ge 2,4
刊名	Chemico-biological interactions
	2016-01-05
卷号	243 页码:119-26
ISSN号	1872-7786
DOI	10.1016/j.cbi.2015.09.011
文献子类	Article
英文摘要	Pyrrolizidine alkaloids (PAs) widely distribute in plants and can cause hepatic sinusoidal obstruction syndrome (HSOS), which typically presents as a primary sinusoidal endothelial cell damage. It is well-recognized that after ingestion, PAs undergo hepatic cytochromes P450 (CYPs)-mediated metabolic activation to generate dehydropyrrolizidine alkaloids (DHPAs), which are hydrolyzed to dehydroretronecine (DHR). DHPAs and DHR are reactive metabolites having same core pyrrole moiety, and can bind proteins to form pyrrole-protein adducts, which are believed as the primary cause for PA-induced HSOS. However, to date, the direct evidences supporting the toxicity of DHPAs and DHR in the liver, in particular in the sinusoidal endothelial cells, are lacking. Using human hepatic sinusoidal endothelial cells (HSEC) and HepG2 (representing hepatic parenchymal cells), cells that lack CYPs activity, this study determined the direct cytotoxicity of dehydromonocrotaline, a representative DHPA, and DHR, but no cytotoxicity of the intact PA (monocrotaline) in both cell lines, confirming that reactive metabolites mediate PA intoxication. Comparing with HepG2, HSEC had significantly lower basal glutathione (GSH) level, and was significantly more susceptible to the reactive metabolites with severer GSH depletion and pyrrole-protein adducts formation. The toxic potency of two reactive metabolites was also compared. DHPA was more reactive than DHR, leading to severer toxicity. In conclusion, our results unambiguously provided the first direct evidence for the critical role of DHPA and DHR in the reactive metabolites-mediated PA-induced hepatotoxicity, which occurs predominantly in HSEC due to severe GSH depletion and the significant formation of pyrrole-protein adducts in HSEC.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/266829]
专题	中国科学院上海药物研究所
通讯作者	Lin, Ge
作者单位	1.National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA; 2.School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; 3.Joint Research Laboratory for Promoting Globalization of Traditional Chinese Medicines Between The Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China; 4.Joint Research Laboratory for Promoting Globalization of Traditional Chinese Medicines Between The Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China
推荐引用方式 GB/T 7714	Yang, Mengbi,Ruan, Jianqing,Fu, Peter P,et al. Cytotoxicity of pyrrolizidine alkaloid in human hepatic parenchymal and sinusoidal endothelial cells: Firm evidence for the reactive metabolites mediated pyrrolizidine alkaloid-induced hepatotoxicity[J]. Chemico-biological interactions,2016,243:119-26.
APA	Yang, Mengbi,Ruan, Jianqing,Fu, Peter P,&Lin, Ge.(2016).Cytotoxicity of pyrrolizidine alkaloid in human hepatic parenchymal and sinusoidal endothelial cells: Firm evidence for the reactive metabolites mediated pyrrolizidine alkaloid-induced hepatotoxicity.Chemico-biological interactions,243,119-26.
MLA	Yang, Mengbi,et al."Cytotoxicity of pyrrolizidine alkaloid in human hepatic parenchymal and sinusoidal endothelial cells: Firm evidence for the reactive metabolites mediated pyrrolizidine alkaloid-induced hepatotoxicity".Chemico-biological interactions 243(2016):119-26.