Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum multiflorum

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 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.

Keywords

Polygonum multiflorum / idiosyncratic hepatotoxicity / metabolomics / stilbene / cis-transisomerization

References

[1] Stickel F, Patsenker E, Schuppan D. Herbal hepatotoxicity. J Hepatol 2005; 43(5): 901–910 

[2] Stedman C. Herbal hepatotoxicity. Semin Liver Dis 2002; 22(2): 195–206 

[3] Teschke R, Eickhoff A. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps. Front Pharmacol 2015; 6: 72 

[4] Dong Q, Li N, Li Q, Zhang CE, Feng WW, Li GQ, Li RY, Tu C, Han X, Bai ZF, Zhang YM, Niu M, Ma ZJ, Xiao XH, Wang JB. Screening for biomarkers of liver injury induced by Polygonum multiflorum: a targeted metabolomic study. Front Pharmacol 2015; 6: 217 

[5] But PP, Tomlinson B, Lee KL. Hepatitis related to the Chinese medicine Shou-wu-pian manufactured from Polygonum multiflorum. Vet Hum Toxicol 1996; 38(4): 280–282

[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): 457–467

[7] Wang JB, Li CY, Zhu Y, Song HB, Bai ZF, Xiao XX. Integrated evidence chain-based identification of Chinese herbal medicine- induced hepatotoxicity and rational usage: exemplification by Polygonum multiflorum (He shou wu). Chin Sci Bull 2016; 61(09): 971–980 (in Chinese)

[8] Shaw PJ, Ganey PE, Roth RA. Idiosyncratic drug-induced liver injury and the role of inflammatory stress with an emphasis on an animal model of trovafloxacin hepatotoxicity. Toxicol Sci 2010; 118(1):7–18

[9] Björnsson ES. Drug-induced liver injury: an overview over the most critical compounds. Arch Toxicol 2015; 89(3): 327–334

[10] Poulsen KL, Olivero-Verbel J, Beggs KM, Ganey PE, Roth RA. Trovafloxacin enhances lipopolysaccharide-stimulated production of tumor necrosis factor-α by macrophages: role of the DNA damage response. J Pharmacol Exp Ther 2014; 350(1): 164–170

[11] Roth RA, Ganey PE. Animal models of idiosyncratic drug-induced liver  injury—current  status. Crit  Rev  Toxicol  2011; 41(9): 723–739 

[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)

[13] Wang JB, Xiao XH, Du XX, Zou ZS, Song HB, Guo XX. Identification and early diagnosis for traditional Chinese medicine-induced liver injury based on translational toxicology. China J Chin Materia Medica (Zhongguo Zhong Yao Za Zhi) 2014; 39(1): 5–9 (in Chinese)

[14] Wu X, Chen X, Huang Q, Fang D, Li G, Zhang G. Toxicity of raw and processed roots of Polygonum multiflorum. Fitoterapia 2012; 83(3): 469–475

[15] Lin CM, Singh SB, Chu PS, Dempcy RO, Schmidt JM, Pettit GR, Hamel E. Interactions of tubulin with potent natural and synthetic analogs of the antimitotic agent combretastatin: a structure-activity study. Mol Pharmacol 1988; 34(2): 200–208

[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): 313–320 

[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-β-D- glucoside in Radix Polygoni multiflori by HPLC/DAD/MS. Chin Pharm J (Zhongguo Yao Xue Za Zhi) 2009(7):541–544 (in Chinese)

[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): 950–966, quiz 967 

[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): 1165–1172

[20] Luyendyk JP, Lehman-McKeeman 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): 635–643

[21] Sajish M, Schimmel P. A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. Nature 2015; 519(7543): 370–373

[22] Langcake P, Pryce RJ. Production of resveratrol by Vitis vinifera and other members of Vitaceae as a response to infection or injury. Physiol Plant Pathol 1976; 9(1): 77–86 

[23] Crowell JA, Korytko PJ, Morrissey RL, Booth TD, Levine BS. Resveratrol-associated renal toxicity. Toxicol Sci 2004; 82(2):614–619

[24] Minezawa N, Gordon MS. Photoisomerization of stilbene: a spin-flip density functional theory approach. J Phys Chem A 2011; 115(27): 7901–7911

[25] Zaki MA, Balachandran P, Khan S, Wang M, Mohammed R, Hetta MH, Pasco DS, Muhammad I. Cytotoxicity and modulation of cancer-related signaling by (Z)- and (E)-3,4,3′,5′-tetramethoxystilbene isolated from Eugenia rigida. J Nat Prod 2013; 76(4): 679–684

[26] Woods JA, Hadfield JA, Pettit GR, Fox BW, McGown AT. The interaction with tubulin of a series of stilbenes based on combretastatin A-4. Br J Cancer 1995; 71(4): 705–711

[27] Manis JP. Knock out, knock in, knock down—genetically manipulated mice and the Nobel Prize. N Engl J Med 2007; 357(24): 2426–2429

[28] Tong C, Li P, Wu NL, Yan Y, Ying QL. Production of p53 gene knock-out rats by homologous recombination in embryonic stem cells. Nature 2010; 467(7312): 211–213

[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)

[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): 206ra137

[31] Mitchell D, Wagner C, Stone WJ, Wilkinson GR, Schenker S. Abnormal regulation of plasma pyridoxal 5′-phosphate in patients with liver disease. Gastroenterology 1976; 71(6): 1043–1049

[32] Myers BA, Dubick MA, Reynolds RD, Rucker RB. Effect of vitamin B-6 (pyridoxine) deficiency on lung elastin cross-linking in perinatal and weanling rat pups. Biochem J 1985; 229(1): 153–160

[33] Canellakis ES, Jaffe JJ, Mantsavinos R, Krakow JS. Pyrimidine metabolism. IV. A comparison of normal and regenerating rat liver. J Biol Chem 1959; 234(8): 2096–2099

[34] Fausto N, Brandt JT, Kesner L. Possible interactions between the urea cycle and synthesis of pyrimidines and polyamines in regenerating liver. Cancer Res 1975; 35(2): 397–404

[35] Barbul A. Arginine: biochemistry, physiology, and therapeutic implications. J Parenter Enteral Nutr 1986; 10(2): 227–238

[36] Satriano J. Arginine pathways and the inflammatory response: interregulation of nitric oxide and polyamines. Amino Acids 2004; 26(4): 321–329

[37] Corraliza IM, Soler G, Eichmann K, Modolell M. Arginase induction by suppressors of nitric oxide synthesis (IL-4, IL-10 and PGE2) in murine bone-marrow-derived macrophages. Biochem Biophys Res Commun 1995; 206(2): 667–673

[38] Bronte V, Zanovello P. Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 2005; 5(8): 641–654 

[39] Block  WD, Westhoff  MH, Steele  BF. Histidine metabolism in the human adult: histidine blood tolerance, and the effect of continued free L-histidine ingestion on the concentration of imidazole compounds in blood and urine. J Nutr 1967; 91(2):189–194

[40] Machado  MV, Kruger  L, Jewell  ML, Michelotti  GA, Pereira Tde  A, Xie G, Moylan CA, Diehl AM. Vitamin B5 and N-acetylcysteine in nonalcoholic steatohepatitis: a preclinical study in a dietary mouse model. Dig Dis Sci 2016; 61(1):137–148 

[41] Zizioli  D, Tiso N, Guglielmi  A, Saraceno  C, Busolin  G, Giuliani  R, Khatri  D, Monti  E, Borsani  G, Argenton  F, Finazzi  D. Knock-down 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; 85:35–48

Acknowledgements

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).

Compliance with ethics guidelines

Chunyu Li, Ming Niu, Zhaofang Bai, Congen Zhang, Yanling Zhao, Ruiyu Li, Can Tu, Huifang Li, Jing Jing, Yakun Meng, Zhijie Ma, Wuwen Feng, Jinfa Tang, Yun Zhu, Jinjie Li, Xiaoya Shang, Zhengsheng Zou, Xiaohe Xiao, and Jiabo Wang declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the Ethics Committee of the 302 Military Hospital and the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients involved in this study.

Electronic Supplementary Material

ƒSupplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s11684-017-0508-9 and is accessible for authorized users.

RIGHTS & PERMISSIONS

2017 Higher Education Press and Springer-Verlag Berlin Heidelberg