Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum multiflorum.
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 trans-SG 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.
China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing, 100039, China.|Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, China.
Chunyu
C
Li
China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing, 100039, China.
Ming
M
Niu
China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing, 100039, China.
Zhaofang
Z
Bai
China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing, 100039, China.
Congen
C
Zhang
China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing, 100039, China.
Yanling
Y
Zhao
China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing, 100039, China.
Ruiyu
R
Li
China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing, 100039, China.
Can
C
Tu
Shanxi University of Traditional Chinese Medicine, Taiyuan, 030619, China.
Huifang
H
Li
Integrative Medical Center, 302 Military Hospital, Beijing, 100039, China.
Jing
J
Jing
China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing, 100039, China.
Yakun
Y
Meng
China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing, 100039, China.|Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Zhijie
Z
Ma
China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing, 100039, China.
Wuwen
W
Feng
China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing, 100039, China.
Jinfa
J
Tang
Integrative Medical Center, 302 Military Hospital, Beijing, 100039, China.
Yun
Y
Zhu
Beijing Union University, Beijing, 100101, China.
Jinjie
J
Li
Beijing Union University, Beijing, 100101, China.
Xiaoya
X
Shang
Diagnosis and Treatment Center for Non-infectious Diseases, 302 Military Hospital, Beijing, 100039, China.
Zhengsheng
Z
Zou
Integrative Medical Center, 302 Military Hospital, Beijing, 100039, China. pharmacy302xxh@126.com.
Xiaohe
X
Xiao
China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing, 100039, China. pharm_sci@126.com.
Jiabo
J
Wang
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D004365:Drugs, Chinese Herbal / Q000633:toxicity*; D000068676:Fallopia multiflora / Q000737:chemistry*; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008516:Medicine, Chinese Traditional; D055432:Metabolomics; D010936:Plant Extracts / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013267:Stilbenes / Q000633:toxicity*
D004365:Drugs, Chinese Herbal; D008070:Lipopolysaccharides; D010936:Plant Extracts; D013267:Stilbenes; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
Polygonum multiflorum; cis-trans isomerization; idiosyncratic hepatotoxicity; metabolomics; stilbene