UHPLC-QQQ-MS/MS assay for the quantification of dianthrones as potential toxic markers of Polygonum multiflorum Thunb: applications for the standardization of traditional Chinese medicines (TCMs) with endogenous toxicity

Chinese Medicine - Tập 16 - Trang 1-24 - 2021
Jian-Bo Yang1, Yun-Fei Song1, Yue Liu2, Hui-Yu Gao1, Qi Wang1, Ying Wang1, Xian-Long Cheng1, Tian-Tian Zuo1, Xiao-Wen Hu1, Feng Wei1, Hong-Tao Jin3, Shu-Ting Wang3, Shuang-Cheng Ma1
1Institute for Control of Chinese Traditional Medicine and Ethnic Medicine, National Institutes for Food and Drug Control, Beijing, China
2School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
3Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Tóm tắt

The raw and processed roots of Polygonum multiflorum Thunb (PM) are commonly used in clinical practice to treat diverse diseases; however, reports of hepatotoxicity induced by Polygoni Multiflori Radix (PMR) and Polygoni Multiflori Radix Praeparata (PMRP) have emerged worldwide. Thus, it is necessary for researchers to explore methods to improve quality standards to ensure their quality and treatment effects. In the present study, an ultra-high performance liquid chromatography triple quadrupole mass spectrometry (UHPLC-QQQ-MS/MS) method was optimized and validated for the determination of dianthrones in PMR and PMRP using bianthronyl as the internal standard. Chromatographic separation with a gradient mobile phase [A: acetonitrile and B: water containing 0.1% formic acid (v/v)] at a flow rate of 0.25 mL/min was achieved on an Agilent ZORBAX SB-C18 column (2.1 mm × 50 mm, 1.8 μm). The triple quadrupole mass spectrometer (TQMS) was operated in negative ionization mode with multiple reaction monitoring for the quantitative analysis of six dianthrones. Moreover, compounds 5 and 6 were further evaluated for their cytotoxicity in HepaRG cells by CCK-8 assay. The UHPLC-QQQ-MS/MS method was first developed to simultaneously determine six dianthrones in PMR and PMRP, namely, polygonumnolides C1–C4 (1–4), trans-emodin dianthrones (5), and cis-emodin dianthrones (6). The contents of 1–6 in 90 batches of PMR were in the ranges of 0.027–19.04, 0.022–13.86, 0.073–15.53, 0.034–23.35, 0.38–83.67 and 0.29–67.00 µg/g, respectively. The contents of 1–6 in 86 batches of commercial PMRP were in the ranges of 0.020–13.03, 0.051–8.94, 0.022–7.23, 0.030–12.75, 0.098–28.54 and 0.14–27.79 µg/g, respectively. Compounds 1–4 were almost completely eliminated after reasonable processing for 24 h and the contents of compounds 5 and 6 significantly decreased. Additionally, compounds 5 and 6 showed inhibitory activity in HepaRG cells with IC50 values of 10.98 and 15.45 μM, respectively. Furthermore, a systematic five-step strategy to standardize TCMs with endogenous toxicity was proposed for the first time, which involved the establishment of determination methods, the identification of potentially toxic markers, the standardization of processing methods, the development of limit standards and a risk–benefit assessment. The results of the cytotoxicity evaluation of the dianthrones indicated that trans-emodin dianthrones (5) and cis-emodin dianthrones (6) could be selected as toxic markers of PMRP. Taking PMR and PMRP as examples, we hope this study provides insight into the standardization and internationalization of endogenous toxic TCMs, with the main purpose of improving public health by scientifically using TCMs to treat diverse complex diseases in the future.

Tài liệu tham khảo

Li CY, Niu M, Bai ZF, Zhang CG, Zhao YL, Li RY, Tu C, Li HF, Jing J, Meng YK, Ma ZJ, Feng WW, Tang JF, Zhu Y, Li JJ, Shang XY, Zou ZS, Xiao XH, Wang JB. Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum multiflorum. Front Med. 2017;11:253–65.

Huang J, Zhang JP, Bai JQ, Wei MJ, Zhang J, Huang ZH, Qu GH, Xu W, Qiu XH. Chemical profiles and metabolite study of raw and processed Polygoni multoflori radix in rats by UPLC-LTQ-Orbitrap MSn spectrometry. Chin J Nat Med. 2018;16:0375–400.

Chinese Pharmacopoeia Commission. Pharmacopoeia of the People’s Republic of China. Beijing: China Medical Science and Technology Press; 2020. p. 183–4.

Lin LF, Ni BR, Lin HM, Zhang M, Li XC, Yin XB, Qu CH, Ni J. Traditional usages, botany, phytochemistry, pharmacology and toxicology of Polygonum multiflorum thumb.: a review. J Ethnopharmacol. 2015;159:158–83.

Liu Y, Wang Q, Yang JB, Guo XX, Liu WX, Ma SC, Li SP. Polygonum multiflorum Thunb.: a review on chemical analysis, processingn mechanism, quality evaluation, and hepatotoxicity. Front Pharmacol. 2018;9:364.

Lei X, Chen J, Ren JT, Li Y, Zhai JB, Mu W, Zhang L, Zheng WK, Tian GH, Shang HC. Liver damage associated with Polygonum multiflorum thumb.: a systematic review of case reports and case series. Evid Based Compl Altern Med. 2015. https://doi.org/10.1155/2015/459749.

Park GJ, Mann SP, Ngu MC. Acute hepatitis induced by Shou-Wu-Pian, a herbal product derived from Polygonum multiflorum. J Gastroenol Hepatol. 2001;16:115–7.

Yu HL, Yu DM, Song HB, Ren JT. Literature study on adverse drug reactions and analysis of risk factors of Polygonum multiflorum Thunb and its common preparations. Chin J PV. 2018;15:470–5.

Han LF, Wang P, Wang YL, Zhao QY, Zheng F, Dou ZY, Yang WZ, Hu LM, Liu CX. Rapid discovery of the potential toxic compounds in Polygonum multiflorum by UHPLC/Q-Orbitrap-MS-based metabolomics and correlation analysis. Front Pharmacol. 2019;10:329.

Han LF, Wu B, Pan GX, Wang YF, Song XB, Gao XM. UPLC-PDA analysis for simultaneous quantification of four active compounds in crude and processed rhizome of Polygonum multiflorum Thunb. Chromatographia. 2009;70:657–9.

Yang JB, Li WF, Liu Y, Wang Q, Cheng XL, Wei F, Wang AG, Jin HT, Ma SC. Acute toxicity screening of different extractions, components and constituents of Polygonum multiflorum thunb, on zebrafish (Danio rerio) embryos in vivo. Biomed Pharmacother. 2018;99:205–13.

Yang JB, Liu Y, Wang Q, Ma SC, Wang AG, Cheng XL, Wei F. Characterization and identification of the chemical constituents of Polygonum multiflorum Thunb, by high-performance liquid chromatography coupled with ultraviolet detection and linear ion trap FT-ICR hybrid mass spectrometry. J Pharm Biomed. 2019;172:149–66.

Yang JB, Li L, Dai Z, Wu Y, Geng XC, Li B, Ma SC, Wang AG, Su YY. Polygonumnolides C1–C4, minor dianthrone glycosides from the roots of Polygonum multiflorum Thunb. J Asian Nat Prod Res. 2016;18:813–22.

Yang JB, Tian JY, Dai Z, Ye F, Ma SC, Wang AG. a-Glucosidase inhibitors extracted from the roots of Polygonum multiflorum Thunb. Fitoterapia. 2017;117:65–70.

Yang JB, Yan Z, Ren J, Dai Z, Ma SC, Wang AG, Su YY. Polygonumnolides A1–B3, minor dianthrone derivatives from the roots of Polygonum multiflorum Thunb. Arch Pharm Res. 2018;41:617–24.

Wang Q, Wang YD, Li Y, Wen BY, Dai Z, Ma SC, Zhang YJ. Identification and characterization of the structure-activity relationships involved in UGT1A1 inhibition by anthraquinone and dianthrone constituents of Polygonum multiflorum. Sci Rep. 2017;7:17592.

Li HY, Yang JB, Li WF, Qiu CX, Wang ST, Song YF, Gao HY, Liu Y, Wang Q, Wang Y, Cheng XL, Wei F, Jin HT, Ma SC. In vivo hepatotoxicity screening of different extracts, components, and constituents of Polygoni multiflori Thunb. in zebrafish (Danio rerio) larvae. Biomed Pharmacother. 2020;131:110524.

Mai LP, Guéritte F, Dumontet V, Tri MV, Hill B, Thoison O, Guénard D, Sévenet T. Cytotoxicity of rhamnosylanthraquinones and rhamnosyl anthrones from Rhamnus nepalensis. J Nat Prod. 2001;64:1162–8.

Ha F, Li RM, Zhang LL, Yan XJ. Transformation relationship of four sennoside components in Rhei Radix et Rhizoma under the heating condition. Chin Tradit Pat Med. 2012;34:2169–73.

Song HB, Du XX, Guo XX, Ren JT, Yang L, Pang Y. Safety and risk factor analysis on Polygoni multiflora radix base on ancient traditional Chinese medicine literatures. China J Chin Mater Med. 2015;40:985–8.

Zhang L, Bai ZF, Li CY, Huhuang WY, Sha MC, Liu ZX, He Q, Li YM, Liu YP, Xiao XH, Wang JB. Study on idiosyncratic liver injury and content of cis-2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside in radix Polygoni multiflori Preparata. Acta Pharm Sin B. 2017;52:1041–7.

Chan CO, Xie XJ, Wan SW, Zhou GL, Yuen ACY, Mok DKW, Chen SB. Qualitative and quantitative analysis of sesquiterpene lactones in Centipeda minima by UPLC-Orbitrap-MS & UPLC-QQQ-MS. J Pharm Biomed. 2019;174:360–6.

Saito J, Okamura A, Takeuchi K, Hanioka K, Okada A, Ohata T. High content analysis assay for prediction of human hepatotoxicity in HepaRG and HepG2 cells. Toxicol In Vitro. 2016;33:63–70.

Gripon P, Rumin S, Urban S. Infection of a human hepatoma cell line by hepatitis B virus. Proc Natl Acad Sci USA. 2002;99:15655–60.

Rebelo SP, Costa R, Estrada M, Shevchenko V, Brito C, Alves PM. HepaRG microencapsulated spheroids in DMSO-free culture: novel culturing approaches for enhanced xenobiotic and biosynthetic metabolism. Arch Toxicol. 2015;89:1347–58.

Jackson JP, Li L, Chamberlain ED, Wang H, Ferguson SS. Contextualizing hepatocyte functionality of cryopreserved HepaRG cell cultures. Drug Metab Dispos. 2016;44:1463–79.

Ge CL, Cheng G, Yu JP, Xu DJ. The influence of chemical components of Polygonum multiflorum after the nine-time repeat of the steaming and sun-drying traditional processing. Chin Med J Res Prac. 2017;31:43–7.

Lv Y, Wang JB, Ji Y, Zhao YL, Ma ZJ, Li Q, Zou ZS, Liang QS, Teng GJ, Yan D, Zhang P, Xiao XH, Yu CY. Influence of extracting solvent on hepatocytes toxicity of Polygonum multiflorum. Chin J Exp Tradit Med Formulae. 2013;19:268–72.

Lin LF. Study on components and mechanism of liver injury induced by polygonum multiflorum. Beijing: Beijing University of Chinese Medicine; 2016.

Xiao R. Study on the basis and quality control of hepatotoxicity of polygonum multiflorum. Hunan: Hunan University of Chinese Medicine; 2018.

Yang Q, Li XY, Zhao XM, Sun R. System analysis on adverse drug reaction of Chinese patent medicine containing Polygoni multiflori Radix. Chin Tradit Herb Drugs. 2017;48:1878–87.

Zhu Y, Liu SH, Wang JB, Song HB, Li YG, He TT, Ma X, Wang ZX, Wang LP, Zhou K, Bai YF, Zou ZS, Xiao XH. Clinical analysis of drug-induced liver injury caused by Polygonum multiflorum and its preparations. Chin J Integr Tradit West Med. 2015;35:1442–7.

Xu N, Shi HY, Li XY, Zhang LL, Sun R. Progress and cause analysis on cause of adverse reactions of Polygoni multiflori radix preparations. Chin J Exp Tradit Med Formulae. 2017;23:208–14.

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Chinese Medicine

Tập 16

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