The role of formation of pyrrole-ATP synthase subunit beta adduct in pyrrolizidine alkaloid-induced hepatotoxicity

doi:10.1007/s00204-018-2309-6

	The role of formation of pyrrole-ATP synthase subunit beta adduct in pyrrolizidine alkaloid-induced hepatotoxicity
	Lu, Yao 1,2,3; Ma, Jiang 1,2,3; Song, Zijing 1,2,3; Ye, Yang1,3 ; Fu, Peter P.4; Lin, Ge 1,2,3
刊名	ARCHIVES OF TOXICOLOGY
	2018-11
卷号	92 期号:11 页码:3403-3414
关键词	Pyrrolizidine alkaloid Retrorsine ATP5B Mitochondrial damage Pyrrole-protein adduct
ISSN号	0340-5761
DOI	10.1007/s00204-018-2309-6
文献子类	Article
英文摘要	Pyrrolizidine alkaloids (PAs) are one of the most significant groups of hepatotoxic phytotoxins. It is well-studied that metabolic activation of PAs generates reactive pyrrolic metabolites that rapidly bind to cellular proteins to form pyrrole-protein adducts leading to hepatotoxicity. Pyrrole-protein adducts all contain an identical core pyrrole moiety regardless of structures of the different PAs; however, the proteins forming pyrrole-protein adducts are largely unknown. The present study revealed that ATP synthase subunit beta (ATP5B), a critical subunit of mitochondrial ATP synthase, was a protein bound to the reactive pyrrolic metabolites forming pyrrole-ATP5B adduct. Using both anti-ATP5B antibody and our prepared anti-pyrrole-protein antibody, pyrrole-ATP5B adduct was identified in the liver of rats, hepatic sinusoidal endothelial cells, and HepaRG hepatocytes treated with retrorsine, a well-studied representative hepatotoxic PA. HepaRG cells were then used to further explore the consequence of pyrrole-ATP5B adduct formation. After treatment with retrorsine, significant amounts of pyrrole-ATP5B adduct were formed in HepaRG cells, resulting in remarkably reduced ATP synthase activity and intracellular ATP level. Subsequently, mitochondrial membrane potential and respiration were reduced, leading to mitochondria-mediated apoptotic cell death. Moreover, pre-treatment of HepaRG cells with a mitochondrial membrane permeability transition pore inhibitor significantly reduced retrorsine-induced toxicity, further revealing that mitochondrial dysfunction caused by pyrrole-ATP5B adduct formation significantly contributed to PA intoxication. Our findings for the first time identified ATP5B as a protein covalently bound to the reactive pyrrolic metabolites of PAs to form pyrrole-ATP5B adduct, which impairs mitochondrial function and significantly contributes to PA-induced hepatotoxicity.
资助项目	Research Grant Council of Hong Kong (GRF)[14111816] ; Research Grant Council of Hong Kong (GRF)[14110714] ; CUHK Direct Grant[4054302]
WOS关键词	SINUSOIDAL-OBSTRUCTION SYNDROME ; HEPATIC VENOOCCLUSIVE DISEASE ; METABOLIC-ACTIVATION ; ENDOTHELIAL-CELLS ; LIVER-DISEASE ; TOXICITY ; HEPATOCYTES ; PROTEIN ; INJURY ; INHIBITION
WOS研究方向	Toxicology
语种	英语
出版者	SPRINGER HEIDELBERG
WOS记录号	WOS:000447916100013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279521]
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.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China; 2.Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China; 3.Chinese Univ Hong Kong, Joint Res Lab Promoting Globalizat Tradit Chinese, Hong Kong, Hong Kong, Peoples R China; 4.US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA
推荐引用方式 GB/T 7714	Lu, Yao,Ma, Jiang,Song, Zijing,et al. The role of formation of pyrrole-ATP synthase subunit beta adduct in pyrrolizidine alkaloid-induced hepatotoxicity[J]. ARCHIVES OF TOXICOLOGY,2018,92(11):3403-3414.
APA	Lu, Yao,Ma, Jiang,Song, Zijing,Ye, Yang,Fu, Peter P.,&Lin, Ge.(2018).The role of formation of pyrrole-ATP synthase subunit beta adduct in pyrrolizidine alkaloid-induced hepatotoxicity.ARCHIVES OF TOXICOLOGY,92(11),3403-3414.
MLA	Lu, Yao,et al."The role of formation of pyrrole-ATP synthase subunit beta adduct in pyrrolizidine alkaloid-induced hepatotoxicity".ARCHIVES OF TOXICOLOGY 92.11(2018):3403-3414.