斑马鱼模型在新精神活性物质代谢研究中的应用

许琳灏; 刘信泽; 刘伟; 向平; 杭太俊; 阳硕; 严慧

doi:10.11665/j.issn.1000-5048.20220511

斑马鱼模型在新精神活性物质代谢研究中的应用

许琳灏^1,2,
刘信泽^1,2,
刘伟¹,
向平¹,
杭太俊²,
阳硕^1,2,
严慧¹

1.
司法鉴定科学研究院上海市法医学重点实验室上海市司法鉴定专业技术服务平台司法部司法鉴定重点实验室，上海 200063
2.
中国药科大学药学院，南京 210009

基金项目: 上海市人才发展资助项目（No.2019095）；上海市自然科学基金资助项目（No.19ZR1458800）；上海市法医学重点实验室资助项目（No.21DZ2270800）；上海市司法鉴定专业技术服务平台资助项目（No.19DZ2292700）

计量
- 文章访问数: 448
- HTML全文浏览量: 6
- PDF下载量: 685
出版历程
- 收稿日期: 2022-05-09
- 修回日期: 2022-09-12
- 刊出日期: 2022-10-24

Application of zebrafish model in the metabolism of new psychoactive substances

1.
Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Science Platform, Key Laboratory of Forensic Science, Ministry of Justice, Academy of Forensic Science, Shanghai 200063
2.
School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China

Funds: This study was supported by Shanghai Talent Development Project (No.2019095); the Natural Science Foundation of Shanghai (No.19ZR1458800); the Project of Shanghai Key Laboratory of Forensic Medicine (No.21DZ2270800); and the Project of Shanghai Judicial Expertise Professional and Technical Service Platform (No.19DZ2292700)

摘要

摘要: 斑马鱼具有体型小、易于饲养、繁殖成本低、繁殖率高等诸多优势，是药物代谢研究的新型模式生物。本文概述斑马鱼代谢模型的构建，介绍斑马鱼模型的基因与人类高度相似性以及其发达的酶系统、较低的基质效应等优点；总结斑马鱼模型在合成大麻素类、芬太尼类、哌嗪类、合成卡西酮类等各类新精神活性物质研究中的应用；综述斑马鱼中体内常见的代谢反应包括Ⅰ相（氧化、N-脱甲基、O-脱乙基化、羟化和N-脱烷基）和Ⅱ相（硫酸化和葡萄糖醛酸化）反应，说明其代谢物种类与真实人体体液样本之间的差异主要和酶的种类有关，指出斑马鱼模型在研究新精神活性物质方面的巨大潜力和进一步研究趋势。
- 斑马鱼模型 /
- 新精神活性物质 /
- 代谢物 /
- 应用
Abstract: Zebrafish is a novel model organism for drug metabolism research because of its small size, easy feeding, low reproduction cost and high reproduction rate.This paper outlines the construction of zebrafish metabolic model, illustrating the advantages of zebrafish model with high genetic similarity to human, well-developed enzyme system, and low substrate effect; and then reviews the application of zebrafish model in the synthesis of various new psychoactive substances such as cannabinoids, fentanyl, piperazines, and synthetic cathinones.The common metabolic reactions in zebrafish, including phase I (oxidation, N-demethylation, O-deethylation, hydroxylation and N-desalkylation) and phase II (sulfation and glucuronidation) reactions, are summarized, and the differences between the metabolites of zebrafish and those of real human body fluid samples are mainly related to the types of enzymes.This paper also points out the great potential and further research trends of zebrafish model in the study of new psychoactive substances.
- zebrafish model /
- new psychoactive substance /
- metabolite /
- application

HTML全文

参考文献(66)

[1]	.https：//www.unodc.org/LSS/Page/NPS.
[2]	Brandt SD，King LA，Evans-Brown M. The new drug phenomenon［J］. Drug Test Anal，2014，6（7/8）：587-597.
[3]	Wagmann L，Maurer HH. Bioanalytical methods for new psychoactive substances［J］. Handb Exp Pharmacol，2018，252：413-439.
[4]	Meyer MR. New psychoactive substances：an overview on recent publications on their toxicodynamics and toxicokinetics［J］. Arch Toxicol，2016，90（10）：2421-2444.
[5]	Meyer MR. Toxicokinetics of NPS：Update 2017［M］. City：Handb Exp Pharmacol，2018.
[6]	Diao XX，Huestis MA. New synthetic cannabinoids metabolism and strategies to best identify optimal marker metabolites［J］. Front Chem，2019，7：109.
[7]	Streisinger G，Walker C，Dower N，et al. Production of clones of homozygous diploid zebra fish （Brachydanio rerio）［J］. Nature，1981，291（5813）：293-296.
[8]	Carten JD，Bradford MK，Farber SA. Visualizing digestive organ morphology and function using differential fatty acid metabolism in live zebrafish［J］. Dev Biol，2011，360（2）：276-285.
[9]	Ho SY，Pack M，Farber SA. Analysis of small molecule metabolism in zebrafish［J］. Methods Enzymol，2003，364：408-426.
[10]	Thompson ED，Burwinkel KE，Chava AK，et al. Activity of Phase I and Phase II enzymes of the benzo［a］pyrene transformation pathway in zebrafish （Danio rerio） following waterborne exposure to arsenite［J］. Comp Biochem Physiol C Toxicol Pharmacol，2010，152（3）：371-378.
[11]	Zhang Q，Ji CY，Yan L，et al. The identification of the metabolites of chlorothalonil in zebrafish （Danio rerio） and their embryo toxicity and endocrine effects at environmentally relevant levels［J］. Environ Pollut，2016，218：8-15.
[12]	Weigt S，Huebler N，Strecker R，et al. Zebrafish （Danio rerio） embryos as a model for testing proteratogens［J］. Toxicology，2011，281（1/2/3）：25-36.
[13]	Fleming A，Sato M，Goldsmith P. High-throughput in vivo screening for bone anabolic compounds with zebrafish［J］. J Biomol Screen，2005，10（8）：823-831.
[14]	Kithcart A，MacRae CA. Using zebrafish for high-throughput screening of novel cardiovascular drugs［J］. JACC Basic Transl Sci，2017，2（1）：1-12.
[15]	Brugman S. The zebrafish as a model to study intestinal inflammation［J］. Dev Comp Immunol，2016，64：82-92.
[16]	Capiotti KM，Antonioli RJunior，Kist LW，et al. Persistent impaired glucose metabolism in a zebrafish hyperglycemia model［J］. Comp Biochem Physiol B Biochem Mol Biol，2014，171：58-65.
[17]	Pinho BR，Reis SD，Guedes-Dias P，et al. Pharmacological modulation of HDAC1 and HDAC6 in vivo in a zebrafish model：therapeutic implications for Parkinson''s disease［J］. Pharmacol Res，2016，103：328-339.
[18]	Shams S，Rihel J，Ortiz JG，et al. The zebrafish as a promising tool for modeling human brain disorders：a review based upon an IBNS symposium［J］. Neurosci Biobehav Rev，2018，85：176-190.
[19]	Hu BX，Dong X，Fan HW，et al. Cardiotoxicity evaluation of three novel proteasome inhibitors in zebrafish［J］. J China Pharm Univ（中国药科大学学报），2019，50（4）：452-458.
[20]	Wan YL，Zhong H，Chen L，et al. Synthesis，anti-melanoma activity and acute toxicity of aporphine alkaloids in zebrafish［J］. J China Pharm Univ（中国药科大学学报），2021，52（5）：529-535.
[21]	de Souza Anselmo C，Sardela VF，Matias BF，et al. Is zebrafish （Danio rerio） a tool for human-like metabolism study［J］？ Drug Test Anal，2017，9（11/12）：1685-1694.
[22]	Sneddon LU，Halsey LG，Bury NR. Considering aspects of the 3Rs principles within experimental animal biology［J］. J Exp Biol，2017，220（Pt 17）：3007-3016.
[23]	Brox S，Seiwert B，Haase N，et al. Metabolism of clofibric acid in zebrafish embryos （Danio rerio） as determined by liquid chromatography-high resolution-mass spectrometry［J］. Comp Biochem Physiol C Toxicol Pharmacol，2016，185/186：20-28.
[24]	Shen WW，Wei YJ，Tang DQ，et al. Metabolite profiles of ginsenosides Rk1 and Rg5 in zebrafish using ultraperformance liquid chromatography/quadrupole-time-of-flight MS［J］. J Ginseng Res，2017，41（1）：78-84.
[25]	Jones HS，Trollope HT，Hutchinson TH，et al. Metabolism of ibuprofen in zebrafish larvae［J］. Xenobiotica，2012，42（11）：1069-1075.
[26]	Wang GW，Chen HY，Du ZK，et al. In vivo metabolism of organophosphate flame retardants and distribution of their main metabolites in adult zebrafish［J］. Sci Total Environ，2017，590/591：50-59.
[27]	Alderton W，Berghmans S，Butler P，et al. Accumulation and metabolism of drugs and CYP probe substrates in zebrafish larvae［J］. Xenobiotica，2010，40（8）：547-557.
[28]	Chng HT，Ho HK，Yap CW，et al. An investigation of the bioactivation potential and metabolism profile of zebrafish versus human［J］. J Biomol Screen，2012，17（7）：974-986.
[29]	Richter LHJ，Herrmann J，Andreas A，et al. Tools for studying the metabolism of new psychoactive substances for toxicological screening purposes — A comparative study using pooled human liver S9，HepaRG cells，and zebrafish larvae［J］. Toxicol Lett，2019，305：73-80.
[30]	Park YM，Meyer MR，Müller R，et al. Drug administration routes impact the metabolism of a synthetic cannabinoid in the zebrafish larvae model［J］. Molecules，2020，25（19）：4474.
[31]	Diekmann H，Hill A. ADMETox in zebrafish［J］. Drug Discov Today Dis Models，2013，10（1）：e31-e35.
[32]	Howe K，Clark MD，Torroja CF，et al. The zebrafish reference genome sequence and its relationship to the human genome［J］. Nature，2013，496（7446）：498-503.
[33]	Goldstone JV，McArthur AG，Kubota A，et al. Identification and developmental expression of the full complement of Cytochrome P450 genes in Zebrafish［J］. BMC Genomics，2010，11：643.
[34]	Xu CJ，Li CYT，Kong ANT. Induction of phase I，II and III drug metabolism/transport by xenobiotics［J］. Arch Pharm Res，2005，28（3）：249-268.
[35]	Tseng HP，Hseu TH，Buhler DR，et al. Constitutive and xenobiotics-induced expression of a novel CYP3A gene from zebrafish larva［J］. Toxicol Appl Pharmacol，2005，205（3）：247-258.
[36]	Almazroo OA，Miah MK，Venkataramanan R. Drug metabolism in the liver［J］. Clin Liver Dis，2017，21（1）：1-20.
[37]	Huang HY，Wu Q. Cloning and comparative analyses of the zebrafish Ugt repertoire reveal its evolutionary diversity［J］. PLoS One，2010，5（2）：e9144.
[38]	Christen V，Fent K. Tissue-，sex- and development-specific transcription profiles of eight UDP-glucuronosyltransferase genes in zebrafish （Danio rerio） and their regulation by activator of aryl hydrocarbon receptor［J］. Aquat Toxicol，2014，150：93-102.
[39]	Jang M，Yang W，Shin I，et al. Determination of AM-2201 metabolites in urine and comparison with JWH-018 abuse［J］. Int J Legal Med，2014，128（2）：285-294.
[40]	De Brabanter N，Esposito S，Geldof L，et al. In vitro and in vivo metabolisms of 1-pentyl-3-（4-methyl-1-naphthoyl）indole （JWH-122）［J］. Forensic Toxicol，2013，31（2）：212-222.
[41]	Nadja W，Frederike N，Doerr AA，et al. Comparison of in vitro and in vivo models for the elucidation of metabolic patterns of 7-azaindole-derived synthetic cannabinoids exemplified using cumyl-5F-P7AICA［J］. Drug Test Anal，2020，13（1）：74-90.
[42]	de Souza Anselmo C，Sardela VF，de Sousa VP，et al. Zebrafish （Danio rerio）：a valuable tool for predicting the metabolism of xenobiotics in humans［J］？ Comp Biochem Physiol C Toxicol Pharmacol，2018，212：34-46.
[43]	Qi MJ，Shi MZ，Han YL. Application of zebrafish in field of pharmacy［J］. Chin Pharmacol Bull（中国药理学通报），2018，34（7）：903-906.
[44]	Li ZH，Alex D，Siu SO，et al. Combined in vivo imaging and omics approaches reveal metabolism of icaritin and its glycosides in zebrafish larvae［J］. Mol BioSyst，2011，7（7）：2128-2138.
[45]	European Monitoring Centre for Drugs and Drug Addiction. 2010 Annual Report on the State of the Drugs Problem in Europe［EB/OL］https：//www.emcdda.europa.eu/publications/annual-report/2010.
[46]	Kemp AM，Clark MS，Dobbs T，et al. Top 10 facts You need to know about synthetic cannabinoids：not so nice spice［J］. Am J Med，2016，129（3）：240-244.e1.
[47]	Dresen S，Ferreirós N，Pütz M，et al. Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds［J］. J Mass Spectrom，2010，45（10）：1186-1194.
[48]	Krotulski AJ，Cannaert A，Stove C，et al. The next generation of synthetic cannabinoids：detection，activity，and potential toxicity of pent-4en and but-3en analogues including MDMB-4en-PINACA［J］. Drug Test Anal，2021，13（2）：427-438.
[49]	The National Drug Control Office informed the entire category of synthetic cannabinoids flutamide and other 18 new psychoactive substances China became the first country in the world to list the entire category of synthetic cannabinoid substances［J］. Shanghai Chem Ind（上海化工），2021，46（04）：70.
[50]	Sardela VF，Anselmo CS，Nunes I，et al. Zebrafish （Danio rerio） water tank model for the investigation of drug metabolism：progress，outlook，and challenges［J］. Drug Test Anal，2018，10（11/12）：1657-1669.
[51]	Xu DQ，Zhang WF，Li J，et al. Analysis of AMB-FUBINACA biotransformation pathways in human liver microsome and zebrafish systems by liquid chromatography-high resolution mass spectrometry［J］. Front Chem，2019，7：240.
[52]	Xu DQ，Dai Y，Zhang WF，et al. Rapid identification of MDMB-CHMINACA metabolites using zebrafish and human liver microsomes as the biotransformation system by LC-QE-HF-MS［J］. J Anal Toxicol，2021，44（9）：1012-1026.
[53]	Yue LN，Xiang P，Shen BH，et al. Metabolism of 4F-MDMB-BICA in zebrafish by liquid chromatography-high resolution mass spectrometry［J］. Drug Test Anal，2021，13（6）：1223-1229.
[54]	Yue LN，Yan H，Xiang P，et al. Investigation on metabolites of 5F-MDMB-PICA in zebrafish by liquid chromatography-quadrupe/orbitrap mass spectrometry［J］. J Instrum Anal（分析测试学报），2021，40（5）：690-698.
[55]	Yue LN，Xiang P，Song FY，et al. Metabolism of new psychoactive substances 4F-MDMB-BUTINACA in zebrafish［J］. J Forensic Med（法医学杂志），2021，37（4）：493-499.
[56]	Morales-Noé A，Esteve-Turrillas FA，Armenta S. Metabolism of third generation synthetic cannabinoids using zebrafish larvae［J］. Drug Test Anal，2022，14（4）：594-603.
[57]	Gampfer TM，Wagmann L，Park YM，et al. Toxicokinetics and toxicodynamics of the fentanyl homologs cyclopropanoyl-1-benzyl-4′-fluoro-4-anilinopiperidine and furanoyl-1-benzyl-4-anilinopiperidine［J］. Arch Toxicol，2020，94（6）：2009-2025.
[58]	Kirla KT，Groh KJ，Poetzsch M，et al. Importance of toxicokinetics to assess the utility of zebrafish larvae as model for psychoactive drug screening using Meta-chlorophenylpiperazine （mCPP） as example［J］. Front Pharmacol，2018，9：414.
[59]	Wagmann L，Frankenfeld F，Park YM，et al. How to study the metabolism of new psychoactive substances for the purpose of toxicological screenings-a follow-up study comparing pooled human liver S9，HepaRG cells，and zebrafish larvae［J］. Front Chem，2020，8：539.
[60]	Truver MT，Watanabe S，?strand A，et al. 5F-MDMB-PICA metabolite identification and cannabinoid receptor activity［J］. Drug Test Anal，2020，12（1）：127-135.
[61]	Mogler L，Franz F，Wilde M，et al. Phase I metabolism of the carbazole-derived synthetic cannabinoids EG-018，EG-2201，and MDMB-CHMCZCA and detection in human urine samples［J］. Drug Test Anal，2018，10（9）：1417-1429.
[62]	Haschimi B，Mogler L，Halter S，et al. Detection of the recently emerged synthetic cannabinoid 4F-MDMB-BINACA in "legal high" products and human urine specimens［J］. Drug Test Anal，2019，11（9）：1377-1386.
[63]	Richter LHJ，Maurer HH，Meyer MR. Metabolic fate of the new synthetic cannabinoid 7''N-5F-ADB in rat，human，and pooled human S9 studied by means of hyphenated high-resolution mass spectrometry［J］. Drug Test Anal，2019，11（2）：305-317.
[64]	Hei H，Wang JF，Zhang WF，et al. Study of the in vitro and in vivo metabolism of a novel synthetic cannabinoid PX-2 in human liver microsomes and zebrafish［J］. Int J Mass Spectrom，2020，456：116388.
[65]	Krotulski AJ，Papsun DM，de Martinis BS，et al. N-ethyl pentylone （ephylone） intoxications：quantitative confirmation and metabolite identification in authentic human biological specimens［J］. J Anal Toxicol，2018，42（7）：467-475.
[66]	Cooman T，Hoover B，Sauvé B，et al. The metabolism of valerylfentanyl using human liver microsomes and zebrafish larvae［J］. Drug Test Anal，2022，14（6）：1116-1129.