Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum multiflorum
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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.
KeywordsPolygonum multiflorum idiosyncratic hepatotoxicity metabolomics stilbene cis-trans isomerization
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This work was supported by the National Natural Science Foundation of China (Nos. 81403126 and 81503350), the National Key Technology R&D Program (No. 2015ZX 09501-004-001-008), China’s Post-doctoral Science Fund (No. 2016M590065), the National TCM Industry Science and Technology Program (No. 201507004-04), Beijing Nova Program (No. Z16111000490000), and the Beijing Natural Science Foundation (No. 7152142).
- 6.Wang J, Ma Z, Niu M, Zhu Y, Liang Q, Zhao Y, Song J, Bai Z, Zhang Y, Zhang P, Li N, Meng Y, Li Q, Qin L, Teng G, Cao J, Li B, Chen S, Li Y, Zou Z, Zhou H, Xiao X. Evidence chain-based causality identification in herb-induced liver injury: exemplification of a well-known liver-restorative herb Polygonum multiflorum. Front Med 2015; 9(4): 457–467CrossRefPubMedGoogle Scholar
- 7.Wang JB, Li CY, Zhu Y, Song HB, Bai ZF, Xiao XX. Integrated evidence chain-based identification of Chinese herbal medicineinduced hepatotoxicity and rational usage: exemplification by Polygonum multiflorum (He shou wu). Chin Sci Bull 2016; 61 (09): 971–980 (in Chinese)Google Scholar
- 12.Li CY, Li XF, Tu C, Li N, Ma ZJ, Pang JY, Jia GL, Cui HR, You Y, Song HB, Du XX, Zhao YL, Wang JB, Xiao XH. The idiosyncratic hepatotoxicity of Polygonum multiflorum based on endotoxin model. Acta Pharmaceutica Sinica (Yao Xue Xue Bao) 2015; 50 (1): 28–33 (in Chinese)Google Scholar
- 13.Wang JB, Xiao XH, Du XX, Zou ZS, Song HB, Guo XX. Identification and early diagnosis for traditional Chinese medicineinduced liver injury based on translational toxicology. China J Chin Materia Medica (Zhongguo Zhong Yao Za Zhi) 2014; 39(1): 5–9 (in Chinese)Google Scholar
- 16.Siles R, Ackley JF, Hadimani MB, Hall JJ, Mugabe BE, Guddneppanavar R, Monk KA, Chapuis JC, Pettit GR, Chaplin DJ, Edvardsen K, Trawick ML, Garner CM, Pinney KG. Combretastatin dinitrogen-substituted stilbene analogues as tubulin-binding and vascular-disrupting agents. J Nat Prod 2008; 71(3): 313–320CrossRefPubMedGoogle Scholar
- 17.Sun JL, Huang XL, Wu HQ, Huang F. Determination of content and light stability of cis-and trans-2,3,5,4′-tetrahydroxystilbene-2-O-ß-D-glucoside in Radix Polygoni multiflori by HPLC/DAD/MS. Chin Pharm J (Zhongguo Yao Xue Za Zhi) 2009(7): 541–544 (in Chinese)Google Scholar
- 18.Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, Fontana RJ; Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol 2014; 109(7): 950–966CrossRefPubMedGoogle Scholar
- 19.Xiao XH, Li XH, Zhu Y, Wang JB, Li L, Zhang T, Liu CH, Sun KW, Yang HS, Guo YM. Guideline for diagnosis and treatment of herb-induced liver injury. China J Chin Materia Medica (Zhongguo Zhongyao Zazhi) 2016; (7): 1165–1172Google Scholar
- 20.Luyendyk JP, Lehman-Mc Keeman LD, Nelson DM, Bhaskaran VM, Reilly TP, Car BD, Cantor GH, Deng X, Maddox JF, Ganey PE, Roth RA. Coagulation-dependent gene expression and liver injury in rats given lipopolysaccharide with ranitidine but not with famotidine. J Pharmacol Exp Ther 2006; 317(2): 635–643CrossRefPubMedGoogle Scholar
- 29.Zhu Y, Li YG, Wang Y, Wang LP, Wang JB, Wang RL, Wang LF, Meng YK, Wang ZX, Xiao XH. Analysis of clinical characteristics in 595 patients with herb-induced liver injury. Chin J Integr Tradit Western Med (Zhongguo Zhong Xi Yi Jie He Za Zhi) 2016; 36 (1): 44–48 (in Chinese)Google Scholar
- 30.El Kasmi KC, Anderson AL, Devereaux MW, Vue PM, Zhang W, Setchell KD, Karpen SJ, Sokol RJ. Phytosterols promote liver injury and Kupffer cell activation in parenteral nutrition-associated liver disease. Sci Transl Med 2013; 5(206): 206ra137Google Scholar
- 41.Zizioli D, Tiso N, Guglielmi A, Saraceno C, Busolin G, Giuliani R, Khatri D, Monti E, Borsani G, Argenton F, Finazzi D. Knockdown of pantothenate kinase 2 severely affects the development of the nervous and vascular system in zebrafish, providing new insights into PKAN disease. Neurobiol Dis 2016; 85: 35–48CrossRefPubMedPubMedCentralGoogle Scholar