代谢组学技术在中药毒性机制及解毒机制研究中的应用

摘要/Abstract

摘要： 目的探讨代谢组学在中药毒性评价中的应用。方法对国内外关于中药毒性机制和解毒机制的报道进行整理、分析与归纳。结果代谢组学在中药毒性机制研究中已涉及肝脏、肾脏、肺脏、心脏、神经系统、生殖系统和胃肠道等靶器官，炮制方法和中药配伍方法，可以减轻中药的靶器官损伤。结论从中药毒性机制研究到解毒机制研究，代谢组学的发展把以经验为基础的传统评价转变为以科学方法和标准为基础的现代化评价，使中药研究更具科学性、规范性和标准性。

关键词: 代谢组学, 中药, 毒性机制, 解毒机制

Abstract: Objective To explore the application of metabolomics in the evaluation of traditional Chinese medicine (TCM) toxicity.Methods The reports on toxicity mechanism and detoxification mechanism of TCM have been collated, analyzed and summarized.Results Metabolomics has been involved in the study of the toxicity mechanism of TCM, including liver, kidney, lung, heart, nervous system, reproductive system, gastrointestinal tract and other target organs. And processing methods and the compatibility of TCM were found to reduce the target organ damage.Conclusion From TCM toxicity mechanism research to detoxification mechanism research, the traditional evaluation based on experience is transformed into a modern evaluation based on scientific methods and standards. The development of metabolomics would make the research of TCM more scientific, normative and standard.

Key words: metabolomics, TCM, toxicity mechanism, detoxification mechanism

中图分类号:

R932

温艳清,王琳,赵楠,孙琦, 孟繁浩. 代谢组学技术在中药毒性机制及解毒机制研究中的应用[J]. 中国药物警戒, 2018, 15(5): 280-285.

WEN Yan-qing,WANG Lin,ZHAO Nan,SUN Qi,MENG Fan-hao. Application of Metabolomics in Studies on Toxicity Mechanism and Detoxification Mechanism of Traditional Chinese Medicines[J]. Chinese Journal of Pharmacovigilance, 2018, 15(5): 280-285.

参考文献

[1] 向菲,张晓刚. 近5年中药不良反应文献的统计分析[J]. 中国中药杂志, 2011,36(19):2755-2758.
[2] Taylar J, King R D, Altmann T, et al. Application of metabolomic to plant genotype discrimination using statistics and machine learning[J]. Bioinformatics, 2002, 18(S2): S241-S248.
[3] Cui F, Zhu P, Ji J, et al. Gas chromatography-mass spectrometry metabolomic study of lipopolysaccharides toxicity on rat basophilic leukemia cells[J]. Chem Biol Interact, 2018, 281: 81-88.
[4] Qiu P, Sun J, Man S, et al. Curcumin Attenuates N-Nitrosodiethyl-amine-Induced Liver Injury in Mice by Utilizing the Method of Metabonomics[J]. J Agric Food Chem, 2017, 65(9): 2000-2007.
[5] Go evac D, Damjanovi A, Stanojkovi T P, et al. Identification of cytotoxic metabolites from Mahonia aquifolium using 1H NMR-based metabolomics approach[J]. J Pharm Biomed Anal, 2018, 150:9-14.
[6] Fu Q, Liu D, Wang Y, et al. Metabolomic profiling of Campylob-
acter jejuni with resistance gene ermB by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry and tandem quadrupole mass spectrometry[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2018, 1079: 62-68.
[7] Pramai P, Abdul Hamid N A, Mediani A, et al. Metabolite profiling, antioxidant, and α-glucosidase inhibitory activities of germinated rice: nuclear-magnetic-resonance-based metabolomics study[J]. J Food Drug Anal, 2018, 26(1): 47-57.
[8] Ma N, Liu X, Kong X, et al. Feces and liver tissue metabonomics studies on the regulatory effect of aspirin eugenol eater in hyperlipidemic rats[J]. Lipids Health Dis, 2017, 16(1): 240.
[9] Liu Y R, Huang R Q, Liu L J, et al. Metabonomics study of urine from Sprague-Dawley rats exposed to Huang-yao-zi using 1H NMR spectroscopy[J]. J Pharm Biomed Anal, 2010, 52(1): 136-141.
[10] 邵凤,刘林生,阿基业. GC/TOF-MS代谢组学技术研究雷公藤甲素在大鼠体内的急性毒性[J]. 中国药科大学学报, 2014,45(6):703-709.
[11] Xia X H, Yuan Y Y, Liu M. The assessment of the chronic hepatotoxicity induced by Polygoni Multiflori Radix in rats: A pilot study by using untargeted metabolomics method[J]. J Ethnoph-armacol, 2017, 203: 182-190.
[12] Zhang C E, Niu M, Li Q, et al. Urine metabolomics study on the liver injury in rats induced by raw and processed Polygonum multiflorum integrated with pattern recognition and pathways analysis[J]. J Ethnopharmacol, 2016, 194: 299-306.
[13] Zhao D S, Jiang L L, Fan Y X, et al. Investigation of Dioscorea bulbifera Rhizome-Induced Hepatotoxicity in Rats by a Multisample Integrated Metabolomics Approach[J]. Chem Res Toxicol, 2017, 30(10): 1865-1873.
[14] Wei Z, Qian Q, Dong X, et al. Metabolomic approach to understand the acute and chronic hepatotoxicity of Veratrum nigrum extract in mice based on ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry[J]. Toxicol Mech Methods, 2017, 27(9): 687-696.
[15] Huo T, Fang Y, Zhao L, et al. 1H NMR-based metabonomic study of sub-chronic hepatotoxicity induced by realgar[J]. J Ethnop-harmacol, 2016, 192: 1-9.
[16] Man S, Qiu P, Li J, et al. Global metabolic profiling for the study of Rhizoma Paridis saponins-induced hepatotoxicity in rats[J]. Environ Toxicol, 2017, 32(1): 99-108.
[17] Xiong A, Yang F, Fang L, et al. Metabolomic and genomic evidence for compromised bile acid homeostasis by senecionine, a hepatotoxic pyrrolizidine alkaloid[J]. Chem Res Toxicol, 2014, 27(5): 775-786.
[18] Xue L M, Zhang Q Y, Han P, et al. Hepatotoxic constituents and toxicological mechanism of Xanthium strumarium L. fruits[J]. J Ethnopharmacol, 2014, 152(2): 272-282.
[19] Lu F, Cao M, Wu B, et al. Urinary metabonomics study on toxicity biomarker discovery in rats treated with Xanthii Fructus[J]. J Ethnopharmacol, 2013, 149(1): 311-320.
[20] Shen H, Wu J, Di LQ, et al. Enhancement by Glycyrrhizae Radix of hepatic metabolism of hypaconitine, a major bioactive and toxic component of Aconiti Laterlis Radix, evaluated by HPLC-TQ-MS/MS analysis[J]. Biomed Chromatogr, 2013, 27(5): 556-562.
[21] Hu X, Shen J, Pu X, et al. Urinary Time- or Dose-Dependent Metabolic Biomarkers of Aristolochic Acid-Induced Nephrotoxicity in Rats[J]. Toxicol Sci, 2017, 156(1): 123-132.
[22] Dong G, Wang J, Guo P, et al. Toxicity assessment of Arisaematis Rhizoma in rats by a (1)H NMR-based metabolomics approach[J]. Mol Biosyst, 2015, 11(2): 407-417.
[23] Ma C, Bi K, Zhang M, et al. Metabonomic study of biochemical changes in the urine of Morning Glory Seed treated rat[J]. J Pharm Biomed Anal, 2010, 53(3): 559-566.
[24] Michl J, Bello O, Kite GC, et al. Medicinally Used Asarum Species: High-Resolution LC-MS Analysis of Aristolochic Acid Analogs and In vitro Toxicity Screening in HK-2 Cells[J]. Front Pharmacol, 2017, 8: 215.
[25] 刘霞,肖瑛,高红昌,等. 基于1H NMR代谢组学方法分析马兜铃酸I诱导的雌雄小鼠急性肾毒性[J]. 高等学校化学学报, 2010,31(5):927-932.
[26] Li A, Guo X, Xie J, et al. Validation of biomarkers in cardiotoxicity induced by Periplocin on neonatal rat cardiomyocytes using UPLC-Q-TOF/MS combined with a support vector machine[J]. J Pharm Biomed Anal, 2016, 123: 179-185.
[27] Cai Y, Gao Y, Tan G, et al. Myocardial lipidomics profiling delineate the toxicity of traditional Chinese medicine Aconiti Lateralis radix praeparata[J]. J Ethnopharmacol, 2013, 147(2): 349-356.
[28] Wei L, Xue R, Zhang P, et al. (1)H NMR-Based Metabolomics and Neurotoxicity Study of Cerebrum and Cerebellum in Rats Treated with Cinnabar, a Traditional Chinese Medicine[J]. OMICS, 2015, 19(8): 490-498.
[29] Zhang S N, Li X Z, Lu F, et al. Cerebral potential biomarkers discovery and metabolic pathways analysis of α-synucleinopathies and the dual effects of Acanthopanax senticosus Harms on central nervous system through metabolomics analysis[J]. J Ethnopharmacol, 2015, 163: 264-272.
[30] 谢辉辉,谢彤,徐建亚,等. 基于代谢组学方法研究乌头碱和苯甲酰乌头原碱对BeWo细胞的毒性机制[J]. 分析化学, 2015,43(12):1808-1813.
[31] Ma B, Qi H, Li J, et al. Triptolide disrupts fatty acids and peroxisome proliferator-activated receptor (PPAR) levels in male mice testes followed by testicular injury: A GC-MS based metab-olomics study[J]. Toxicology, 2015, 336: 84-95.
[32] Zhou Y, Liao Q, Lin M, et al. Combination of 1H NMR- and GC-MS-based metabonomics to study on the toxicity of Coptidis Rhizome in rats[J]. PLoS One, 2014, 9(2): e88281.
[33] Um S, Park J, Chung M, et al. Nuclear magnetic resonance-based metabolomics for prediction of gastric damage induced by indomethacin in rats[J]. Analytica chimica acta, 2012, 722(2): 87-94.
[34] Yang Z, Hou J J, Qi P, et al. Colon-derived uremic biomarkers induced by the acute toxicity of Kansui radix: A metabolomics study of rat plasma and intestinal contents by UPLC-QTOF-MS(E)[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2016, 1026: 193-203.
[35] 梁琦,倪诚,颜贤忠,等. 广防己、粉防己的肝肾毒性及代谢组学比较研究[J]. 中国中药杂志, 2010,35(21):2882-2888.
[36] 沈淑洁,水素芳,肖炳坤,等. 基于液质联用技术的金铃子散亚急性毒性代谢组学[J]. 中国中药杂志, 2017,42(4):777-782.
[37] 韩亮,冯毅凡,江涛,等. 蛇床子超临界提取物肝肾毒性及代谢组学的初步研究[J]. 中药新药与临床药理, 2012,23(2):131-135.
[38] 祁乃喜,刘玉梅,何翠翠,等. 中药毒性的代谢组学研究(Ⅱ):吡咯里西啶类生物碱的肝肾毒性[J]. 南京中医药大学学报, 2012,28(5):448-451.
[39] Xu C, Rezeng C, Li J, et al. 1H NMR-Based Metabolomics Study of the Toxicological Effects in Rats Induced by "Renqing Mangjue" Pill, a Traditional Tibetan Medicine[J]. Front Pharmacol, 2017, 8:602.
[40] Fan Y, Liu S, Chen X, et al. Toxicological effects of Nux Vomica in rats urine and serum by means of clinical chemistry, histopathology and 1H NMR-based metabonomics approach[J]. J Ethnopharmacol, 2018, 210: 242-253.
[41] Qian Y, Peng Y, Shang E, et al. Metabolic profiling of the hepatotoxicity and nephrotoxicity of Ginkgolic acids in rats using ultra-performance liquid chromatography-high-definition mass spectrometry[J]. Chem Biol Interact, 2017, 273: 11-17.
[42] Miao Y J, Shi Y Y, Li F Q, et al. Metabolomics study on the toxicity of Annona squamosa by ultraperformance liquid-chromat-
ography high-definition mass spectrometry coupled with pattern recognition approach and metabolic pathways analysis[J]. J Ethnopharmacol, 2016, 184: 187-195.
[43] Zhang Z H, Zhao Y Y, Cheng X L, et al. Metabonomic study of biochemical changes in the rat urine induced by Pinellia ternata (Thunb.) Berit[J]. J Pharm Biomed Anal, 2013, 85(1): 186-193.
[44] Wang H, Bai J, Chen G, et al. A metabolic profiling analysis of the acute hepatotoxicity and nephrotoxicity of Zhusha Anshen Wan compared with cinnabar in rats using (1)H NMR spectroscopy[J]. J Ethnopharmacol, 2013, 146(2): 572-580.
[45] Tang B, Ding J, Wu F, et al. 1H NMR-based metabonomics study of the urinary biochemical changes in Kansui treated rat[J]. J Ethnopharmacol, 2012, 141(1): 134-142.
[46] Wang Z, Liu J Q, Xu J D, et al. UPLC/ESI-QTOF-MS-based metabolomics survey on the toxicity of triptolide and detoxication of licorice[J]. Chin J Nat Med, 2017, 15(6): 474-480.
[47] Xu W, Wang H, Chen G, et al. A metabolic profiling analysis of the acute toxicological effects of the realgar (As2S2) combined with other herbs in Niuhuang Jiedu Tablet using 1H NMR spectroscopy[J]. J Ethnopharmacol, 2014, 153(3): 771-781.
[48] Yan Y, Zhang A, Dong H, et al. Toxicity and Detoxification Effects of Herbal Caowu via Ultra Performance Liquid Chromato-
graphy/Mass Spectrometry Metabolomics Analyzed using Pattern Recognition Method[J]. Pharmacogn Mag, 2017, 13(52): 683-692.
[49] Dong G, Wei D, Wang J, et al. Study of the cardiotoxicity of Venenum Bufonis in rats using an 1H NMR-based metabolomics approach[J]. PLoS One, 2015, 10(3): e0119515.
[50] Dong H, Zhang A, Sun H, et al. Ingenuity pathways analysis of urine metabolomics phenotypes toxicity of Chuanwu in Wistar rats by UPLC-Q-TOF-HDMS coupled with pattern recognition methods[J]. Mol Biosyst, 2012, 8(4): 1206-1221.
[51] Sun B, Li L, Wu S, et al. Metabolomic analysis of biofluids from rats treated with Aconitum alkaloids using nuclear magnetic resonance and gas chromatography/time-of-flight mass spectrometry[J]. Anal Biochem, 2009, 395(2): 125-133.
[52] Sui Z, Li Q, Zhu L, et al. An integrative investigation of the toxicity of Aconiti kusnezoffii radix and the attenuation effect of its processed drug using a UHPLC-Q-TOF based rat serum and urine metabolomics strategy[J]. J Pharm Biomed Anal, 2017, 145: 240-247.
[53] Chen Y, Duan J A, Guo J, et al. Yuanhuapine-induced intestinal and hepatotoxicity were correlated with disturbance of amino acids, lipids, carbohydrate metabolism and gut microflora function: A rat urine metabonomic study[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2016, 1026: 183-192.
[54] Guo P, Wang J, Dong G, et al. NMR-based metabolomics approach to study the chronic toxicity of crude ricin from castor bean kernels on rats[J]. Mol Biosyst, 2014, 10(9): 2426-2440.
[55] Dong H, Yan G L, Han Y, et al. UPLC-Q-TOF/MS-based metabolomic studies on the toxicity mechanisms of traditional Chinese medicine Chuanwu and the detoxification mechanisms of Gancao, Baishao, and Ganjiang[J]. Chin J Nat Med, 2015, 13(9): 687-698.
[56] Su G, Chen G, An X, et al. Metabolic Profiling Analysis of the Alleviation Effect of Treatment with Baicalin on Cinnabar Induced Toxicity in Rats Urine and Serum[J]. Front Pharmacol, 2017, 8: 271.
[57] Liu Y M, Hui R R, He C C, et al. A metabonomic approach to a unique detoxification effect of co-use of Euphorbia kansui and Zizyphus jujuba[J]. Phytother Res, 2013, 27(11):1621-1628.
[58] Su T, Tan Y, Tsui M S, et al. Metabolomics reveals the mechanisms for the cardiotoxicity of Pinelliae Rhizoma and the toxicity-reducing effect of processing[J]. Sci Rep, 2016, 6: 34692.