系统毒理学——法医毒物学发展的机遇与挑战
|
摘要
随着生命科学新理论和新技术的发展和渗透,形成了基于基因组学、蛋白组学和代谢组学等组学技术的系统毒理学,赋予法医毒物学新的研究平台,使之从研究思路、方法和理念发生了根本性转变。综述了组学技术及其在法医毒物学领域的研究进展,以及组学技术发展和应用亟待突破的方法标准化、组学数据库和多组学信息集成等关键问题,提出法医毒物学研究应更加注重人群研究和应用价值。系统毒理学有望在探索毒物代谢酶的基因多态性与毒物代谢规律之间的关系、阐明毒物对机体毒性作用和机制、寻找中毒相关生物标志物,以及确定毒性剂量阈值等方面取得突破,是法医毒物学未来发展的机遇与挑战。
With the development of new technology in life science,based on genomics,proteomics,metabolomics and other techniques,systems toxicology has come into being,providing a new research platform for forensic toxicology and presenting fundamental changes in research idea and approach.This paper mainly reviews applications of omics technology in forensic toxicology,as well as key issues such as method standardization,omics database and integration of multi-omics information.The forensic toxicology studies should pay more attention to population study and application value.Systems toxicology is a promising tool to explore the relationship between gene polymorphisms of metabolic enzyme and poison metabolism,clarify toxic effect and mechanism of toxicants,discover poisoning related biomarkers,and determine dose threshold of poisons.It raises opportunities and challenges for forensic toxicology.
With the development of new technology in life science,based on genomics,proteomics,metabolomics and other techniques,systems toxicology has come into being,providing a new research platform for forensic toxicology and presenting fundamental changes in research idea and approach.This paper mainly reviews applications of omics technology in forensic toxicology,as well as key issues such as method standardization,omics database and integration of multi-omics information.The forensic toxicology studies should pay more attention to population study and application value.Systems toxicology is a promising tool to explore the relationship between gene polymorphisms of metabolic enzyme and poison metabolism,clarify toxic effect and mechanism of toxicants,discover poisoning related biomarkers,and determine dose threshold of poisons.It raises opportunities and challenges for forensic toxicology.
引文
[1]王先良,徐顺清.系统毒理学及其应用[J].生态毒理学报,2006,(4):289-294.
[2]李杰,李柯佳,张臣,等.计算系统毒理学:形成、发展及应用[J].科学通报,2015,60(19):1751-1760.
[3]楼宜嘉.基于系统生物学的药物毒理学研究进展[J].中国药理学与毒理学杂志,2012,26(4):476-481.
[4]张天宝.毒物基因组学的研究现状和对毒理学今后发展的影响[J].毒理学杂志,2005,19(2):83-88.
[5]Waters M,Boorall G,Bushel P,et al.Toxicogenomics and Systems Toxicology:Aims and Prospects[J].Nature Review Genetics,2004,5:936-948.
[6]Heijne W H,Kienhuis A S,Van Ommen B,et al.Systems Toxicology:Application of Toxicogenomics,Transcriptomics,Proteomics and Metabolomics in Toxicology[J].Expert Review of Proteomics,2005,2:767-780.
[7]张伟.定量蛋白质组学质谱采集技术进展[J].分析化学,2014,42(12):1859-1868.
[8]Roux A,Lison D,Junot C,et al.Applications of Liquid Chromatography Coupled to Mass Spectrometry-Based Metabolomics in Clinical Chemistry and Toxicology:A Review[J].Clinical Biochemistry,2011,44:119-135.
[9]王中钰,陈景文,乔显亮,等.面向化学品风险评价的计算(预测)毒理学[J].中国科学:化学,2016,46(2):222-240.
[10]朱永亮,叶祖光计算毒理学与中药毒性预测的研究进展[J].中国新药杂志,2011,20(24):2424-2429.
[11]唐才明,金佳滨,彭先芝.环境污染物计算毒理学分析及环境行为模拟研究进展[J].环境监控与预警,2016,8(2):1-9.
[12]吴明健,王玫,杨瑞琴,等.代谢组学及其在法医毒理学中的应用[J].中国法医学杂志,2013,28(1):37-40.
[13]严慧,沈敏.代谢组学在法医毒理学的应用进展[J].法医学杂志,2015,(3):219-226.
[14]Musshoff A F,Stamer U M,Madea B.Pharmacogenetics and Forensic Toxicology[J].Forensic Sci Int,2010,203:53-62.
[15]施妍.法医毒理学中药物代谢与中国汉族人群CYP基因多态性的关联分析[D].上海:复旦大学基础医学院,2013.
[16]Jannetto P J,Wong S H,Gock S B,et al.Pharmacogenomics as Molecular Autopsy for Postmortem Forensic Toxicology:Genotyping Cytochrome P450 2D6 for Oxycodone Cases[J].J Anal Toxicol,2002,26(7):438-447.
[17]Jin M,Gock S B,Jannetto P J,et al.Pharmacogenomics as Molecular Autopsy for Forensic Toxicology:Genotyping Cytochrome P450 3A4*1B and 3A5*3 for 25 Fentanyl Cases[J].J Anal Toxicol,2005,29(7):590-598.
[18]Zackrisson A L,Holmgren P,Gladh A B,et al.Fatal Intoxication Cases:Cytochrome P450 2D6 and 2C19 Genotype Distributions[J].Eur J Clin Pharmacol,2004,60(8):547-552.
[19]Levo A,Koski A,Ojanpera I,el al.Post-Mortem SNP Analysis of CYP2D6 Gene Reveals Correlation between Genotype and Opioid Drug(Tramadol)Metabolite Ratios in Blood[J].Forensic Sci Int,2003,135(1):9-15.
[20]Koski A,Sistonen J,Ojanpera I,et al.CYP2D6 and CYP2C19 Genotypes and Amitriptyline Metabolite Ratios in a Series of Medicolegal Autopsies[J].Forensic Sci Int,2006,158(2-3):177-183.
[21]Shen M,Shi Y,Xiang P.CYP3A4 and CYP2C19 Genetic Polymorphisms and Zolpidem Metabolism in the Chinese Han Population:A Pilot Study[J].Forensic Sci Int,2013,(227):77-81.
[22]Holm N B,Nielsen L M,Linnet K.CYP3A4 Mediates Oxidative Metabolism of the Synthetic Cannabinoid AKB-48[J].AAPS J,2015,17(5):1237-1245.
[23]Vevelstad M,0iestad E L,Bremer S,et al.Is Toxicity of PMMA(paramethoxymethamphetamine)Associated with Cytochrome P450 Pharmacogenetics?[J].Forensic Sci Int,2016,261:137-147.
[24]Haufroid V,Hantson Philippe.CYP2D6 Genetic Polymorphisms and Their Relevance for Poisoning Due to Amfetamines,Opioid Analgesics and Antidepressants[J].Clinical Toxicology,2015,53:501-510.
[25]Gasche Y.Codeine Intoxication Associated with Ultrarapid CYP2D6 Metabolism[J].N Engl J Med,2004,351(27):2827-2831.
[26]Jornil J.A Poor Metabolier of Both CYP2C19 and CYP2D6Identified by Mechanistic Pharmacokinetic Simulation in a Fatal Drug Poisoning Case Involving Venlafaxine[J].Forensic Sci Int,2013,226:26-31.
[27]Zheng T,Liu L,Aa J,et al.Metabolic Phenotype of Rats Exposed to Heroin and Potential Markers of Heroin Abuse[J].Drug Alcohol Depend,2013,127(1-3):177-186.
[28]Yang S,Salmeron B J,Ross T J,et al.Lower Glutamate Levels in Rostral Anterior Cingulate of Chronic Cocaine Users-A1H-MRS Study Using TE-Averaged PRESS at 3T with an Optimized Quantification Strategystrategy[J].Psychiatry Res,2009,174(3):171-176.
[29]Feng Z,Sun X,Yang J,et al.Metabonomics Analysis of Urine and Plasma from Rats Given Long-Term and LowDose Dimethoate by Ultra-Performance Liquid Chromatography-Mass Spectrometry[J].Chem Biol Interact,2012,199(3):143-153.
[30]Hao D F,Xu W,Wang H,et al.Metabolomic Analysis of the Toxic Effect of Chronic Low-Dose Exposure to Acephate on Rats Using Ultra-Performance Liquid Chromatography-Mass Spectrometry[J].Ecotoxicol Environ Saf,2012,83:25-33.
[31]Shima N,Miyawaki I,Bando K,et al.Influences of Methamphetamine-Induced Acute Intoxication on Urinary and Plasma Metabolic Profiles in the Rat[J].Toxicology,2011,287:29-37.
[32]Shima N,Miyawaki I,Bando K,el al.Influences of Methamphetamine-Induced Acute Intoxication on Urinary and Plasma Metabolic Profiles in the Rat[J].Toxicology,2011,287(1-3):29-37.
[33]Dudka I,Kossowska B,Senhadri H,et al.Metabonomic Analysis of Serum of Workers Occupationally Exposed to Arsenic,Cadmium and Lead for Biomarker Research:A Prelim inary Study[J].Environ Int,2014,68:71-81.
[34]Deng M,Zhang M,Huang X,et al.A Gas Chromatography-Mass Spectrometry Based Study on Serum Metabolomics in Rats Chronically Poisoned with Hydrogen Sulfide[J].J Forensic Leg Med,2015,(32):59-63.
[35]Vicente-Rodriguez M,Gramage E,Herradon G,et al.Phosphoproteomic Analysis of the Striatum from Pleiotrophin Knockout and Midkine Knockout Mice Treated with Cocaine Reveals Regulation of Oxidative Stress-Related Proteins Potentially Underlying Cocaine-Induced Neurotoxicity and Neurodegeneration[J].Toxicology,2013,314:166-173.
[36]Funakoshi-Hirose I,Aki T,Unuma K,et al.Distinct Effects of Methamphetamine on Autophagy-Lysosome and Ubiquitin-Proteasome Systems in HL-1 Cultured Mouse Atrial Cardiomyocytes[J].Toxicology,2013,312:74-82.
[37]Chen J,Zhu G,Xia W,et al.Proteomic Analysis of Rat Retina after Methanol Intoxication[J].Toxicology,2012,293:89-96.
[38]颜贤忠,孙博,杜祥博.代谢组学技术在毒理学研究中的应用进展[J].国际药学研究杂志,2014,41(4):379-393.
[2]李杰,李柯佳,张臣,等.计算系统毒理学:形成、发展及应用[J].科学通报,2015,60(19):1751-1760.
[3]楼宜嘉.基于系统生物学的药物毒理学研究进展[J].中国药理学与毒理学杂志,2012,26(4):476-481.
[4]张天宝.毒物基因组学的研究现状和对毒理学今后发展的影响[J].毒理学杂志,2005,19(2):83-88.
[5]Waters M,Boorall G,Bushel P,et al.Toxicogenomics and Systems Toxicology:Aims and Prospects[J].Nature Review Genetics,2004,5:936-948.
[6]Heijne W H,Kienhuis A S,Van Ommen B,et al.Systems Toxicology:Application of Toxicogenomics,Transcriptomics,Proteomics and Metabolomics in Toxicology[J].Expert Review of Proteomics,2005,2:767-780.
[7]张伟.定量蛋白质组学质谱采集技术进展[J].分析化学,2014,42(12):1859-1868.
[8]Roux A,Lison D,Junot C,et al.Applications of Liquid Chromatography Coupled to Mass Spectrometry-Based Metabolomics in Clinical Chemistry and Toxicology:A Review[J].Clinical Biochemistry,2011,44:119-135.
[9]王中钰,陈景文,乔显亮,等.面向化学品风险评价的计算(预测)毒理学[J].中国科学:化学,2016,46(2):222-240.
[10]朱永亮,叶祖光计算毒理学与中药毒性预测的研究进展[J].中国新药杂志,2011,20(24):2424-2429.
[11]唐才明,金佳滨,彭先芝.环境污染物计算毒理学分析及环境行为模拟研究进展[J].环境监控与预警,2016,8(2):1-9.
[12]吴明健,王玫,杨瑞琴,等.代谢组学及其在法医毒理学中的应用[J].中国法医学杂志,2013,28(1):37-40.
[13]严慧,沈敏.代谢组学在法医毒理学的应用进展[J].法医学杂志,2015,(3):219-226.
[14]Musshoff A F,Stamer U M,Madea B.Pharmacogenetics and Forensic Toxicology[J].Forensic Sci Int,2010,203:53-62.
[15]施妍.法医毒理学中药物代谢与中国汉族人群CYP基因多态性的关联分析[D].上海:复旦大学基础医学院,2013.
[16]Jannetto P J,Wong S H,Gock S B,et al.Pharmacogenomics as Molecular Autopsy for Postmortem Forensic Toxicology:Genotyping Cytochrome P450 2D6 for Oxycodone Cases[J].J Anal Toxicol,2002,26(7):438-447.
[17]Jin M,Gock S B,Jannetto P J,et al.Pharmacogenomics as Molecular Autopsy for Forensic Toxicology:Genotyping Cytochrome P450 3A4*1B and 3A5*3 for 25 Fentanyl Cases[J].J Anal Toxicol,2005,29(7):590-598.
[18]Zackrisson A L,Holmgren P,Gladh A B,et al.Fatal Intoxication Cases:Cytochrome P450 2D6 and 2C19 Genotype Distributions[J].Eur J Clin Pharmacol,2004,60(8):547-552.
[19]Levo A,Koski A,Ojanpera I,el al.Post-Mortem SNP Analysis of CYP2D6 Gene Reveals Correlation between Genotype and Opioid Drug(Tramadol)Metabolite Ratios in Blood[J].Forensic Sci Int,2003,135(1):9-15.
[20]Koski A,Sistonen J,Ojanpera I,et al.CYP2D6 and CYP2C19 Genotypes and Amitriptyline Metabolite Ratios in a Series of Medicolegal Autopsies[J].Forensic Sci Int,2006,158(2-3):177-183.
[21]Shen M,Shi Y,Xiang P.CYP3A4 and CYP2C19 Genetic Polymorphisms and Zolpidem Metabolism in the Chinese Han Population:A Pilot Study[J].Forensic Sci Int,2013,(227):77-81.
[22]Holm N B,Nielsen L M,Linnet K.CYP3A4 Mediates Oxidative Metabolism of the Synthetic Cannabinoid AKB-48[J].AAPS J,2015,17(5):1237-1245.
[23]Vevelstad M,0iestad E L,Bremer S,et al.Is Toxicity of PMMA(paramethoxymethamphetamine)Associated with Cytochrome P450 Pharmacogenetics?[J].Forensic Sci Int,2016,261:137-147.
[24]Haufroid V,Hantson Philippe.CYP2D6 Genetic Polymorphisms and Their Relevance for Poisoning Due to Amfetamines,Opioid Analgesics and Antidepressants[J].Clinical Toxicology,2015,53:501-510.
[25]Gasche Y.Codeine Intoxication Associated with Ultrarapid CYP2D6 Metabolism[J].N Engl J Med,2004,351(27):2827-2831.
[26]Jornil J.A Poor Metabolier of Both CYP2C19 and CYP2D6Identified by Mechanistic Pharmacokinetic Simulation in a Fatal Drug Poisoning Case Involving Venlafaxine[J].Forensic Sci Int,2013,226:26-31.
[27]Zheng T,Liu L,Aa J,et al.Metabolic Phenotype of Rats Exposed to Heroin and Potential Markers of Heroin Abuse[J].Drug Alcohol Depend,2013,127(1-3):177-186.
[28]Yang S,Salmeron B J,Ross T J,et al.Lower Glutamate Levels in Rostral Anterior Cingulate of Chronic Cocaine Users-A1H-MRS Study Using TE-Averaged PRESS at 3T with an Optimized Quantification Strategystrategy[J].Psychiatry Res,2009,174(3):171-176.
[29]Feng Z,Sun X,Yang J,et al.Metabonomics Analysis of Urine and Plasma from Rats Given Long-Term and LowDose Dimethoate by Ultra-Performance Liquid Chromatography-Mass Spectrometry[J].Chem Biol Interact,2012,199(3):143-153.
[30]Hao D F,Xu W,Wang H,et al.Metabolomic Analysis of the Toxic Effect of Chronic Low-Dose Exposure to Acephate on Rats Using Ultra-Performance Liquid Chromatography-Mass Spectrometry[J].Ecotoxicol Environ Saf,2012,83:25-33.
[31]Shima N,Miyawaki I,Bando K,et al.Influences of Methamphetamine-Induced Acute Intoxication on Urinary and Plasma Metabolic Profiles in the Rat[J].Toxicology,2011,287:29-37.
[32]Shima N,Miyawaki I,Bando K,el al.Influences of Methamphetamine-Induced Acute Intoxication on Urinary and Plasma Metabolic Profiles in the Rat[J].Toxicology,2011,287(1-3):29-37.
[33]Dudka I,Kossowska B,Senhadri H,et al.Metabonomic Analysis of Serum of Workers Occupationally Exposed to Arsenic,Cadmium and Lead for Biomarker Research:A Prelim inary Study[J].Environ Int,2014,68:71-81.
[34]Deng M,Zhang M,Huang X,et al.A Gas Chromatography-Mass Spectrometry Based Study on Serum Metabolomics in Rats Chronically Poisoned with Hydrogen Sulfide[J].J Forensic Leg Med,2015,(32):59-63.
[35]Vicente-Rodriguez M,Gramage E,Herradon G,et al.Phosphoproteomic Analysis of the Striatum from Pleiotrophin Knockout and Midkine Knockout Mice Treated with Cocaine Reveals Regulation of Oxidative Stress-Related Proteins Potentially Underlying Cocaine-Induced Neurotoxicity and Neurodegeneration[J].Toxicology,2013,314:166-173.
[36]Funakoshi-Hirose I,Aki T,Unuma K,et al.Distinct Effects of Methamphetamine on Autophagy-Lysosome and Ubiquitin-Proteasome Systems in HL-1 Cultured Mouse Atrial Cardiomyocytes[J].Toxicology,2013,312:74-82.
[37]Chen J,Zhu G,Xia W,et al.Proteomic Analysis of Rat Retina after Methanol Intoxication[J].Toxicology,2012,293:89-96.
[38]颜贤忠,孙博,杜祥博.代谢组学技术在毒理学研究中的应用进展[J].国际药学研究杂志,2014,41(4):379-393.