Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum multiflorum
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RESEARCH ARTICLE
Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum multiflorum Chunyu Li1,2,*, Ming Niu1,*, Zhaofang Bai1,*, Congen Zhang1, Yanling Zhao1, Ruiyu Li1, Can Tu1, Huifang Li7, Jing Jing3, Yakun Meng1, Zhijie Ma1,4, Wuwen Feng1, Jinfa Tang1, Yun Zhu3, Jinjie Li6, Xiaoya Shang6,
Zhengsheng Zou5, Xiaohe Xiao (✉)3,a, Jiabo Wang (✉)1,b
1 China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing 100039, China; 2Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China; 3Integrative Medical Center, 302 Military Hospital, Beijing 100039, China; 4Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; 5Diagnosis and Treatment Center for Non-infectious Diseases, 302 Military Hospital, Beijing 100039, China; 6Beijing Union University, Beijing 100101, China; 7Shanxi University of Traditional Chinese Medicine, Taiyuan 030619, China
© Higher Education Press and Springer-Verlag Berlin Heidelberg 2017
Abstract The main constituents of a typical medicinal herb, Polygonum multiflorum (Heshouwu in Chinese), that induces idiosyncratic liver injury remain unclear. Our previous work has shown that cotreatment with a nontoxic dose of lipopolysaccharide (LPS) and therapeutic dose of Heshouwu can induce liver injury in rats, whereas the solo treatment cannot induce observable injury. In the present work, using the constituent “knock-out” and “knock-in” strategy, we found that the ethyl acetate (EA) extract of Heshouwu displayed comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Results indicated a significant elevation of plasma alanine aminotransferase, aspartate aminotransferase, and liver histologic changes, whereas other separated fractions failed to induce liver injury. The mixture of EA extract with other separated fractions induced comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Chemical analysis further revealed that 2,3,5,4'-tetrahydroxy trans-stilbene-2-O-β-glucoside (trans-SG) and its cis-isomer were the two major compounds in EA extract. Furthermore, the isolated cis-, and not its trans-isomer, displayed comparable idiosyncratic hepatotoxicity to EA extract in LPS-treated rats. Higher contents of cis-SG were detected in Heshouwu liquor or preparations from actual liver intoxication patients associated with Heshouwu compared with general collected samples. In addition, plasma metabolomics analysis showed that cis-SG-disturbing enriched pathways remarkably differed from trans-SG ones in LPS-treated rats. All these results suggested that cis-SG was closely associated with the idiosyncratic hepatotoxicity of Heshouwu. Considering that the cis-trans isomerization of transSG was mediated by ultraviolet light or sunlight, our findings serve as reference for controlling photoisomerization in drug discovery and for the clinical use of Heshouwu and stilbene-related medications. Keywords
Pol
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