用户名: 密码: 验证码:
代谢组学在天然产物毒性评价和毒理学研究中的应用进展
详细信息    查看全文 | 推荐本文 |
  • 英文篇名:Application progress on metabonomics in toxicity assessment and toxicologic studies of natural products
  • 作者:陈宵 ; 孙承业
  • 英文作者:CHEN Xiao;SUN Cheng-ye;National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention;
  • 关键词:代谢组学 ; 天然产物 ; 毒性 ; 生物标志物 ; 急性中毒
  • 英文关键词:metabolomics;;natural products;;toxicity;;biomarkers;;acute poisoning
  • 中文刊名:ZCYO
  • 英文刊名:Chinese Traditional and Herbal Drugs
  • 机构:中国疾病预防控制中心职业卫生与中毒控制所;
  • 出版日期:2019-03-12
  • 出版单位:中草药
  • 年:2019
  • 期:v.50;No.640
  • 基金:科技部科技基础性工作专项项目(2015FY111400)
  • 语种:中文;
  • 页:ZCYO201905032
  • 页数:14
  • CN:05
  • ISSN:12-1108/R
  • 分类号:217-230
摘要
为了尽可能避免毒性效应并安全使用天然产物,更全面的毒性认知已成为迫切需要。通常认为小分子代谢产物可以代表生物体的生理或病理状态,因此,基于代谢组学的毒理学研究既可以用于评价毒性,也可以鉴定天然产物的毒理学生物标志物,有助于指导临床用药并减少药物不良反应。近几十年来,代谢组学在中药单体成分、提取物和复方制剂诱导的肾毒性、肝毒性、心脏毒性和中枢神经系统的毒性评价中应用广泛。综述常用的代谢组学技术,包括样品制备、样品检测、数据处理和分析方法,以及基于代谢组学的天然产物毒理学研究等方面的进展,并对该研究的潜在问题进行探讨并对今后的发展方向进行展望。
        To avoid toxic effects as much as possible and to safely use natural products, a more comprehensive understanding of toxicity is urgently needed. We generally believe that small molecule metabolites can represent the physiological or pathological state of an organism, so metabolomics-based toxicology studies can be used to assess toxicity as well as to identify toxicological biomarkers of natural products, which helps to guide clinical medications and reduce adverse drug reactions. In recent decades, dozens of metabolomics studies have been conducted in the evaluation of nephrotoxicity, hepatotoxicity, cardiotoxicity, and toxicity of the central nervous system induced by monomer compounds, extracts, and combination preparations. This article reviews the commonly used metabolomics techniques, including sample preparation, sample testing, data processing and analysis, as well as toxicology studies of natural products based on metabolomics. Finally, the potential problems and further prospects of this kind of research are discussed.
引文
[1]Lv Y,Liu X,Yan S,et al.Metabolomic study of myocardial ischemia and intervention effects of Compound Danshen Tablets in rats using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry[J].J Pharm Biomed Anal,2010,52(1):129-135.
    [2]Nicholson J K,Lindon J C,Holmes E.‘Metabonomics’:Understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data[J].Xenobiotica,1999,29(11):1181-1189.
    [3]Aa J,Wang G,Hao H,et al.Differential regulations of blood pressure and perturbed metabolism by total ginsenosides and conventional antihypertensive agents in spontaneously hypertensive rats[J].Acta Pharmacol Sin,2010,31(8):930-937.
    [4]Town C.Functional Genomics[M].Dordrecht:Springer Netherlands,2002.
    [5]Robertson D G.Metabonomics in toxicology:A review[J].Toxicol Sci,2005,85(2):809-822.
    [6]Weckwerth W,Kahl G.The Handbook of Plant Metabolomics[M].Weinheim:Wiley-VCH Verlag GmbH&Co.KGaA,2013.
    [7]Gowda G N,Zhang S,Gu H,et al.Metabolomics-based methods for early disease diagnostics[J].Exp Rev Mol Diagns,2008,8(5):617-633.
    [8]Koek M M,Jellema R H,van der Greef J,et al.Quantitative metabolomics based on gas chromatography mass spectrometry:Status and perspectives[J].Metabolomics,2011,7(3):307-328.
    [9]Skoog D A,Holler F J,Crouch S R.Principles of Instrumental Analysis[M].Boston:Cengage Learning,2017.
    [10]Wilson I D,Plumb R,Granger J,et al.HPLC-MS-based methods for the study of metabonomics[J].JChromatogry B,2005,817(1):67-76.
    [11]Wei R,Li G,Seymour A B.High-throughput and multiplexed LC/MS/MRM method for targeted metabolomics[J].Anal Chem,2010,82(13):5527-5533.
    [12]Yuan M,Breitkopf S B,Yang X,et al.A positive/negative ion-switching,targeted mass spectrometry-based metabolomics platform for bodily fluids,cells,and fresh and fixed tissue[J].Nature Protocols,2012,7(5):872.
    [13]Villas-B?as S G,Delicado D G,Akesson M,et al.Simultaneous analysis of amino and nonamino organic acids as methyl chloroformate derivatives using gas chromatography-mass spectrometry[J].Anal Biochem,2003,322(1):134-138.
    [14]Kitson F G,Larsen B S,McEwen C N.Gas Chromatography and Mass Spectrometry:A Practical Guide[M].Salt Lake:Academic Press,1996.
    [15]Sato S,Soga T,Nishioka T,et al.Simultaneous determination of the main metabolites in rice leaves using capillary electrophoresis mass spectrometry and capillary electrophoresis diode array detection[J].Plant J,2004,40(1):151-163.
    [16]Lenz E M,Bright J,Knight R,et al.Metabonomics with1H-NMR spectroscopy and liquid chromatography-mass spectrometry applied to the investigation of metabolic changes caused by gentamicin-induced nephrotoxicity in the rat[J].Biomarkers,2005,10(2/3):173-187.
    [17]Gao D,Wei H,Guo G,et al.Microfluidic cell culture and metabolism detection with electrospray ionization quadrupole time-of-flight mass spectrometer[J].Anal Chem,2010,82(13):5679-5685.
    [18]Nielsen J,Jewett M C.Metabolomics:A Powerful Tool in Systems Biology[M].Berlin:Springer Berlin Heidelberg,2007.
    [19]van den Berg R A,Hoefsloot H C,Westerhuis J A,et al.Centering,scaling,and transformations:improving the biological information content of metabolomics data[J].BMC Genom,2006,7(1):142.
    [20]Lindon J C,Nicholson J K,Holmes E,et al.Summary recommendations for standardization and reporting of metabolic analyses[J].Nat Biotechnol,2005,23(7):833.
    [21]Broadhurst D I,Kell D B.Statistical strategies for avoiding false discoveries in metabolomics and related experiments[J].Metabolomics,2006,2(4):171-196.
    [22]杜智,刘树业,刘运德.临床代谢组学[M].天津:天津科技翻译出版有限公司,2013.
    [23]Tsai D M,Kang J J,Lee S S,et al.Metabolomic analysis of complex chinese remedies:Examples of induced nephrotoxicity in the mouse from a series of remedies containing aristolochic acid[J].Evid Based Compl Alternat Med,2013,2013:263757.
    [24]Makowski G S.Advances in Clinical Chemistry[M].Amsterdam:Elsevier,2014.
    [25]Zhang X,Wu H,Liao P,et al.NMR-based metabonomic study on the subacute toxicity of aristolochic acid in rats[J].Food Chem Toxicol,2006,44(7):1006-1014.
    [26]Chen M,Su M,Zhao L,et al.Metabonomic study of aristolochic acid-induced nephrotoxicity in rats[J].JProteome Res,2006,5(4):995-1002.
    [27]Zhao Y Y,Tang D D,Chen H,et al.Urinary metabolomics and biomarkers of aristolochic acid nephrotoxicity by UPLC-QTOF/HDMS[J].Bioanalysis,2015,7(6):685-700.
    [28]Chan W,Cai Z.Aristolochic acid induced changes in the metabolic profile of rat urine[J].J Pharm Biomed Anal,2008,46(4):757-762.
    [29]Ni Y,Su M,Qiu Y,et al.Metabolic profiling using combined GC-MS and LC-MS provides a systems understanding of aristolochic acid-induced nephrotoxicity in rat[J].FEBS Lett,2007,581(4):707-711.
    [30]Chen M,Su M,Zhao L,et al.Metabonomic study of aristolochic acid-induced nephrotoxicity in rats[J].JProteome Res,2006,5(4):995-1002.
    [31]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.
    [32]Liu X,Liu Y,Cheng M,et al.Acute nephrotoxicity of aristolochic acid in vitro:Metabolomics study for intracellular metabolic time-course changes[J].Biomarkers,2016,21(3):233-242.
    [33]Zhao Y,Wang H,Cheng X,et al.Metabolomics analysis reveals the association between lipid abnormalities and oxidative stress,inflammation,fibrosis,and Nrf2dysfunction in aristolochic acid-induced nephropathy[J].Sci Rep,2015,5:12936.
    [34]Chen H,Cao G,Chen D,et al.Metabolomics insights into activated redox signaling and lipid metabolism dysfunction in chronic kidney disease progression[J].Redox Bioly,2016,10:168-178.
    [35]Michl J,Bello O,Kite G C,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].Frontiers Pharmacol,2017,8:215.
    [36]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.
    [37]Ma C,Bi K,Su D,et al.Serum and kidney metabolic changes of rat nephrotoxicity induced by morning glory seed[J].Food Chem Toxicol,2010,48(10):2988-2993.
    [38]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.
    [39]Yu Y,Ma C,Bi K,et al.A metabonomic analysis of urine from rats treated with rhizoma alismatis using ultra-performance liquid chromatography/mass spectrometry[J].Rapid Commun Mass Spectrom,2011,25(18):2633-2640.
    [40]Gu L,Wang X,Liu Z,et al.A study of Semen Strychni-induced renal injury and herb-herb interaction of Radix Glycyrrhizae extract and/or Rhizoma Ligustici extract on the comparative toxicokinetics of strychnine and brucine in rats[J].Food Chem Toxicol,2014,68:226-233.
    [41]Gu L,Hou P,Zhang R,et al.An analytical strategy to investigate semen strychni nephrotoxicity based on simultaneous HILIC-ESI-MS/MS detection of semen strychni alkaloids,tyrosine and tyramine in HEK 293t cell lysates[J].J Chromatogr B,2016,1033:157-165.
    [42]Gu L,Wang X,Zhang Y,et al.Determination of 12potential nephrotoxicity biomarkers in rat serum and urine by liquid chromatography with mass spectrometry and its application to renal failure induced by Semen Strychni[J].J Sep Sci,2014,37(9/10):1058-1066.
    [43]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.
    [44]Hou P Y,Bi K S,Geng L L,et al.Toxic effects of Euphorbia pekinensis Rupr.and development of a validated UPLC/MS/MS method for profiling of urine metabolic changes[J].Anal Methods,2013,5(4):953-960.
    [45]Canter P H,Lee H S,Ernst E.A systematic review of randomised clinical trials of Tripterygium wilfordii for rheumatoid arthritis[J].Phytomedicine,2006,13(5):371-377.
    [46]Bao J,Dai S.A Chinese herb Tripterygium wilfordii Hook f.in the treatment of rheumatoid arthritis:Mechanism,efficacy,and safety[J].Rheumatol Int,2011,31(9):1123-1129.
    [47]Xue M,Jiang Z,Wu T,et al.Anti-inflammatory effects and hepatotoxicity of Tripterygium-loaded solid lipid nanoparticles on adjuvant-induced arthritis in rats[J].Phytomedicine,2012,19(11):998-1006.
    [48]Xue M,Zhao Y,Li X,et al.Comparison of toxicokinetic and tissue distribution of triptolide-loaded solid lipid nanoparticles vs free triptolide in rats[J].Eur J Pharm Sci,2012,47(4):713-717.
    [49]Zhou J,Xi C,Wang W,et al.Autophagy plays an important role in triptolide-induced apoptosis in cardiomyocytes[J].Toxicol Lett,2015,236(3):168-183.
    [50]Chen M,Ni Y,Duan H,et al.Mass spectrometry-based metabolic profiling of rat urine associated with general toxicity induced by the multiglycoside of Tripterygium wilfordii Hook.f[J].Chem Res Toxicol,2008,21(2):288-294.
    [51]Aa J,Shao F,Wang G,et al.Gas chromatography time-of-flight mass spectrometry based metabolomic approach to evaluating toxicity of triptolide[J].Metabolomics,2011,7(2):217-225.
    [52]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:AGC-MS based metabolomics study[J].Toxicology,2015,336:84-95.
    [53]Xue L,Zhang Q,Han P,et al.Hepatotoxic constituents and toxicological mechanism of Xanthium strumarium L.fruits[J].J Ethnopharmacol,2014,152(2):272-282.
    [54]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.
    [55]Zhang T D.Treatment of acute granulocytic leukemia with“Ai ling No.1”--Clinical analysis and experimental research[J].Chin J Modern Dev Tradit Med,1984,4(1):19.
    [56]Tilg H,Moschen A R.Evolution of inflammation in nonalcoholic fatty liver disease:The multiple parallel hits hypothesis[J].Hepatology,2010,52(5):1836-1846.
    [57]Lu K,Abo R P,Schlieper K A,et al.Arsenic exposure perturbs the gut microbiome and its metabolic profile in mice:an integrated metagenomics and metabolomics analysis[J].Environm Health Perspect,2014,122(3):284.
    [58]Shi X,Wei X,Koo I,et al.Metabolomic analysis of the effects of chronic arsenic exposure in a mouse model of diet-induced fatty liver disease[J].J Proteome Res,2013,13(2):547-554.
    [59]Garcia-Sevillano M A,Garcia-Barrera T,Navarro F,et al.Analysis of the biological response of mouse liver(mus musculus)exposed to As2O3 based on integrated-omics approaches[J].Metallomics,2013,5(12):1644-1655.
    [60]García-Sevillano M A,Contreras-Acuna M,García-Barrera T,et al.Metabolomic study in plasma,liver and kidney of mice exposed to inorganic arsenic based on mass spectrometry[J].Anal Bioanal Chem,2014,406(5):1455-1469.
    [61]Feng J,Hao G,Min C,et al.Metabonomics of liver toxicity from traditional Chinese medicine Huang-Yao-Zi studied by mass spectrum-based orthogonal projection method[J].Chemom Intellig Lab Syst,2014,135:201-207.
    [62]Liu Y,Huang R,Liu L,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.
    [63]Feng J,Hao G,Min C,et al.Metabonomics of liver toxicity from traditional Chinese medicine Huang-Yao-Zi studied by mass spectrum-based orthogonal projection method[J].Chemom Intellig Lab Syst,2014,135:201-207.
    [64]邱蓉丽,李磷,乐巍.补骨脂的化学成分与药理作用研究进展[J].中药材,2010,33(10):1656-1659.
    [65]胡超.基于代谢组学的补骨脂安全性评价及补骨脂酚的体内代谢研究[D].武汉:中南民族大学,2016.
    [66]胡超,汤响林,李杰,等.补骨脂醇提物对大鼠尿内源性代谢产物的影响[J].中国药理学与毒理学杂志,2015,29(6):931-938.
    [67]Wang X,Wang H,Zhang A,et al.Metabolomics study on the toxicity of aconite root and its processed products using ultraperformance liquid-chromatography/electrospray-ionization synapt high-definition mass spectrometry coupled with pattern recognition approach and ingenuity pathways analysis[J].J Proteome Res,2012,11(2):1284-1301.
    [68]Cai Y,Gao Y,Tan G,et al.Myocardial lipidomics profiling delineate the toxicity of traditional Chinese medicine Aconiti Lateralis Radix praeparata[J].JEthnopharmacol,2013,147(2):349-356.
    [69]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.
    [70]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-HDMScoupled with pattern recognition methods[J].Mol Biosyst,2012,8(4):1206-1221.
    [71]Zhan Z,Fan C,Ding J,et al.Novel diterpenoids with potent inhibitory activity against endothelium cell HMECand cytotoxic activities from a well-known TCM plant Daphne genkwa[J].Bioorg Med Chem,2005,13(3):645-655.
    [72]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.
    [73]Tang B,Ding J,Yang Y,et al.Systems biochemical responses of rats to Kansui and vinegar-processed Kansui exposure by integrated metabonomics[J].JEthnopharmacol,2014,153(2):511-520.
    [74]Ji X,Huang B,Wang G,et al.The ethnobotanical,phytochemical and pharmacological profile of the genus Pinellia[J].Fitoterapia,2014,93:1-17.
    [75]Zhang Z,Zhao Y,Cheng X,et al.General toxicity of Pinellia ternata(Thunb.)Berit.in rat:A metabonomic method for profiling of serum metabolic changes[J].JEthnopharmacol,2013,149(1):303-310.
    [76]Zhang Z,Zhao Y,Cheng X,et al.Metabonomic study of biochemical changes in the rat urine induced by Pinellia ternata(Thunb.)Berit.[J].J Pharm Biomed Anal,2013,85:186-193.
    [77]Zhou Y,Liao Q,Lin M,et al.Combination of(1)HNMR-and GC-MS-based metabonomics to study on the toxicity of Coptidis Rhizome in rats[J].PLoS One,2014,9(2):e88281.
    [78]Wei L,Liao P,Wu H,et al.Metabolic profiling studies on the toxicological effects of realgar in rats by 1H-NMRspectroscopy[J].Toxicol Appl Pharmacol,2009,234(3):314-325.
    [79]Fan G,Zhou L,Lai X R,et al.Discussion on the investigation idea of quality control of Chinese materia medica based on metabolomics technology[J].World Sci Technol,2010,12(6):870-875.
    [80]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].JEthnopharmacol,2014,153(3):771-781.
    [81]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 using1H NMR spectroscopy[J].J Ethnopharmacol,2013,146(2):572-580.
    [82]Ni Y,Su M,Qiu Y,et al.Metabolic profiling using combined GC-MS and LC-MS provides a systems understanding of aristolochic acid-induced nephrotoxicity in rat[J].FEBS Lett,2007,581(4):707-711.
    [83]Chan W,Lee K C,Liu N,et al.Liquid chromatography/mass spectrometry for metabonomics investigation of the biochemical effects induced by aristolochic acid in rats:the use of information-dependent acquisition for biomarker identification[J].Rapid Commun Mass Spectrom,2008,22(6):873-880.
    [84]Zhao Y,Tang D,Chen H,et al.Urinary metabolomics and biomarkers of aristolochic acid nephrotoxicity by UPLC-QTOF/HDMS[J].Bioanalysis,2015,7(6):685-700.
    [85]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.
    [86]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:AGC-MS based metabolomics study[J].Toxicology,2015,336:84-95.
    [87]Chen Y,Duan J,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,2016,1026:183-192.
    [88]赵剑宇,颜贤忠,彭双清.利用代谢组学技术研究中药关木通的肾毒性作用[J].世界科学技术-中医药现代化,2007,9(5):54-59.
    [89]赵剑宇,颜贤忠,彭双清.关木通肾毒性的代谢组学研究[J].中草药,2006,37(5):725-730.
    [90]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):2882-2887.
    [91]梁琦,倪诚,谢鸣,等.广防己的肾毒性及代谢组学研究[J].中西医结合学报,2009,7(8):746-752.
    [92]Huang Y,Tian Y,Li G,et al.Discovery of safety biomarkers for realgar in rat urine using UFLC-IT-TOF/MS and 1H-NMR based metabolomics[J].Anal Bioanalyt Chem,2013,405(14):4811-4822.
    [93]Wei L,Liao P,Wu H,et al.Toxicological effects of cinnabar in rats by NMR-based metabolic profiling of urine and serum[J].Toxicol Appl Pharmacol,2008,227(3):417-429.
    [94]Shi X,Wei X,Koo I,et al.Metabolomic analysis of the effects of chronic arsenic exposure in a mouse model of diet-induced fatty liver disease[J].J Proteome Res,2013,13(2):547-554.
    [95]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-HDMScoupled with pattern recognition methods[J].Mol Biosyst,2012,8(4):1206-1221.
    [96]Wang X,Wang H,Zhang A,et al.Metabolomics study on the toxicity of aconite root and its processed products using ultraperformance liquid-chromatography/electrospray-ionization synapt high-definition mass spectrometry coupled with pattern recognition approach and ingenuity pathways analysis[J].J Proteome Res,2011,11(2):1284-1301.
    [97]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].PLo S One,2015,10(3):e119515.
    [98]Zhang Z,Zhao Y,Cheng X,et al.General toxicity of Pinellia ternata(Thunb.)Berit.in rat:A metabonomic method for profiling of serum metabolic changes[J].JEthnopharmacol,2013,149(1):303-310.
    [99]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.
    [100]Tsai D,Kang J,Lee S,et al.Metabolomic analysis of complex Chinese remedies:Examples of induced nephrotoxicity in the mouse from a series of remedies containing aristolochic acid[J].Evidence-Based Compl Alternat Med,2013,2013:263757.
    [101]Xu W,Wang H,Chen G,et al.1H-NMR-based metabonomics study on the toxicity alleviation effect of other traditional Chinese medicines in Niuhuang Jiedu tablet to realgar(As2S2)[J].J Ethnopharmacol,2013,148(1):88-98.
    [102]Zhang P J,Li Y M,Zhang Y N,et al.Application and prospect of toxicity quality markers of traditional Chinese medicine based on metabolomics[J].Chin Herb Med,2018,10(2):108-115.

© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号

地址:北京市海淀区学院路29号 邮编:100083

电话:办公室:(+86 10)66554848;文献借阅、咨询服务、科技查新:66554700