基于质谱成像技术探究5-羟甲基糠醛肾毒性作用机制

doi:10.19803/j.1672-8629.2022.02.07

中国药物警戒 ›› 2022, Vol. 19 ›› Issue (2): 142-147.
DOI: 10.19803/j.1672-8629.2022.02.07

基于质谱成像技术探究5-羟甲基糠醛肾毒性作用机制

江海燕¹, 高杉杉², 李婕¹, 刘志刚³, 郝瑞瑞¹, 庞菲¹, 胡宇驰^{4, 5}, 贺玖明^{2, 5}, 靳洪涛^{1, 5, 6,*}

¹中国医学科学院北京协和医学院药物研究所新药安全评价研究中心,北京 100050;
²中国医学科学院北京协和医学院药物研究所天然药物活性物质与功能国家重点实验室,北京 100050;
³华南理工大学,广东广州 510006;
⁴北京市药品检定研究院,北京 102206;
⁵国家药品监督管理局创新药物安全研究与评价重点实验室,北京 102206;
⁶北京协和建昊医药技术开发有限责任公司,北京 100176

收稿日期:2020-03-24 出版日期:2022-02-15 发布日期:2022-02-15
通讯作者: ^*靳洪涛,男,研究员·博导,药物毒理学研究和评价。E-mail：jinhongtao@imm.ac.cn
作者简介:江海燕,女,硕士,质谱成像在毒理学应用。
基金资助:
国家自然科学基金资助项目（81773996）; 中国毒理学会临床毒理课题（CST2019CT105, CST2021CT101）

Mechanism of nephrotoxicity of 5-hydroxymethylfurfural based on mass spectrometry imaging

JIANG Haiyan¹, GAO Shanshan², LI Jie¹, LIU Zhigang³, HAO Ruirui¹, PANG Fei¹, HU Yuchi^{4, 5}, HE Jiuming^{2, 5}, JIN Hongtao^{1, 5, 6,*}

¹New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
²State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
³South China University of Technology, Guangzhou Guangdong 510006, China;
⁴Beijing Institute for Drug Control, Beijing 102206, China;
⁵NMPA Key Laboratory for Safety Research and Evaluation of Innovative Drug, Beijing 102206, China;
⁶Beijing Union-Genius Pharmaceutical Technology Development Co. Ltd., Beijing 100176, China

Received:2020-03-24 Online:2022-02-15 Published:2022-02-15

摘要/Abstract

摘要： 目的从组学水平可视化5-羟甲基糠醛（5-HMF）给药后肾脏组织代谢的时空变化,探索可能的肾毒性机制。方法 5-HMF 300 mg·kg^-1静脉给药ICR小鼠（给药组）,对照组给予生理盐水,于1、4、24 h时间点分别取材肾组织,制作冰冻组织切片;采用空气动力辅助解吸电喷雾离子化质谱成像（AFADESI-MSI）技术,获取各类代谢物在组织切片中的空间分布;按肾脏的解剖区域提取代谢物信息,结合时空的多变量统计分析,筛选并鉴定毒性相关差异代谢物进行通路富集分析。结果两组间主要差异代谢物有苯丙氨酸、腺苷、腺嘌呤、次黄嘌呤、鸟苷单磷酸、FA-22∶6等,重要的代谢通路为嘌呤代谢、丙氨酸天冬氨酸和谷氨酸代谢、精氨酸合成、三羧酸循环和嘧啶代谢5个通路。同时发现长链脂肪酸和磷脂类上调,提示5-HMF毒性机制还可能与扰乱脂肪酸氧化和脂质代谢相关。将不同时间点的差异代谢物进行对比,挖掘出次黄嘌呤、FA-22∶6、LPG-22∶6可作为潜在的毒性预测标志物,给药后4 h为最佳检测时间。结论该方法实现了5-HMF引起肾脏代谢的时空分析,揭示了5-HMF可能的肾毒性机制,展现了质谱成像技术应用于药物毒理学方面的优势。

关键词: 5-羟甲基糠醛, 质谱成像, 肾毒性, 空间分辨代谢组学, 毒性预测

Abstract: Objective To explore the spatial and temporal metabolic profiles of kidney after 5-hydroxymethylfurfural (5-HMF) administration and elucidate possible mechanisms of the nephrotoxicity from the omics level. Methods ICR mice were divided into control group and administration group, which were intravenously injected with saline and 5-HMF (300 mg·kg^-1), respectively. Kidney tissues were collected at 1, 4 and 24 hours time points, and then the frozen renal tissue sections were scanned and visualized by air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI). Microregional metabolic information was extracted, and then the differential metabolites at each time point were screened out for identification and pathway enrichment analysis. Results The main difference metabolites between the administration group and the control group were phenylalanine, adenosine, adenine, hypoxanthine, guanosine monophosphate, FA-22∶6 and others. The important metabolic pathways are purine metabolism, alanine aspartate and glutamate metabolism, arginine biosynthesis, TCA cycle and pyrimidine metabolism. Meanwhile, long chain fatty acids and phospholipids were up-regulated, suggesting that the toxicity mechanism of 5-HMF may also be related to the disruption of fatty acid oxidation and lipid metabolism. By comparing the different metabolites at each time point, hypoxanthine, FA-22∶ 6 and LPG-22∶ 6 could be used as potential toxicity prediction biomarkers, and the best detection time was 4 h after administration. Conclusion This method can realize the spatiotemporal analysis of kidney metabolism caused by 5-HMF, reveal the possible nephrotoxicity mechanism of 5-HMF, and demonstrate the advantages of mass spectrometry imaging technology in drug toxicology studies.

Key words: 5-hydroxymethylfurfural, mass spectrometry imaging, nephrotoxicity, spatially resolved metabolomics, toxicity prediction

中图分类号:

R994.1

江海燕, 高杉杉, 李婕, 刘志刚, 郝瑞瑞, 庞菲, 胡宇驰, 贺玖明, 靳洪涛. 基于质谱成像技术探究5-羟甲基糠醛肾毒性作用机制[J]. 中国药物警戒, 2022, 19(2): 142-147.

JIANG Haiyan, GAO Shanshan, LI Jie, LIU Zhigang, HAO Ruirui, PANG Fei, HU Yuchi, HE Jiuming, JIN Hongtao. Mechanism of nephrotoxicity of 5-hydroxymethylfurfural based on mass spectrometry imaging[J]. Chinese Journal of Pharmacovigilance, 2022, 19(2): 142-147.

参考文献

[1] PASTORIZA DLS, ÁLVAREZ J, VéGVáRI Á, et al. Relationship between HMF intake and SMF formation in vivo: an animal and human study[J]. Molecular Nutrition & Food Research, 2017, 61(3): 1600773.
[2] LIN N, LIU TT, LIN L, et al.Comparison of in vivo immunomodulatory effects of 5-hydroxymethylfurfural and 5, 5'-oxydimethylenebis (2-furfural)[J]. Regulatory Toxicology and Pharmacology, 2016, 81: 500-511.
[3] LIN L, LIN N, LING YH, et al.Acute toxicity and cytotoxicity of 5-hydroxymethylfurfural[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2018, 15(4): 205-209.
[4] MONIEN BH, FRANK H, SEIDEL A.et al.Conversion of the common food constituent 5-hydroxymethylfurfural into a mutagenic and carcinogenic sulfuric acid ester in the mouse in vivo[J]. Chemical Research in Toxicology, 2009, 22(6): 1123-1128.
[5] JIANG HY, GAO SS, HU G, et al.Innovation in drug toxicology: application of mass spectrometry imaging technology[J]. Toxicology, 2021, 464: 153000.
[6] JIANG HY, ZHANG YX, LIU ZG, et al.Advanced applications of mass spectrometry imaging technology in quality control and safety assessments of traditional Chinese medicines[J]. Journal of Ethnopharmacology, 2021, 284: 114760.
[7] HE JM, TANG F, LUO ZG, et al.Air flow assisted ionization for remote sampling of ambient mass spectrometry and its application[J]. Rapid Communications in Mass Spectrometry, 2011, 25(7): 843-850.
[8] WANG ZH, HE BS, LIU Y, et al.In situ metabolomics in nephrotoxicity of aristolochic acids based on air flow-assisted desorption electrospray ionization mass spectrometry imaging[J]. Acta pharmaceutica Sinica B, 2020, 10(6): 1083-1093.
[9] NILSSON A, FORNGREN B, BJURSTRÖM S, et al. In situ mass spectrometry imaging and ex vivo characterization of renal crystalline deposits induced in multiple preclinical drug toxicology studies[J]. PloS One, 2012, 7(10): e47353.
[10] HUANG W, LIU CX, XIE LJ, et al.Integrated network pharm-acology and targeted metabolomics to reveal the mechanism of nephrotoxicity of triptolide[J]. Toxicol Res (Camb), 2019, 8(6): 850-861.
[11] OYARZÚN C, GARRIDO W, ALARCóN S, et al. Adenosine contribution to normal renal physiology and chronic kidney disease[J]. Molecular Aspects of Medicine, 2017, 55: 75-89.
[12] RUAN LY, ZHAO WL, LUO BZX, et al.NMR-based metabolomics approach to evaluate the toxicological risks of Tibetan medicine‘Ershiwuwei Shanhu’pill in rats[J]. Journal of Ethnopharmacology, 2022, 282: 114629.
[13] KANG H M, AHN S H, CHOI P, et al.Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development[J]. Nat Med, 2015, 21(1): 37-46.
[14] DUANN P, LIN PH.Mitochondria damage and kidney disease[J]. Adv Exp Med Biol, 2017, 982: 529-551.
[15] CUI Y,LI HS,SONG NN, et al.Metabolomics study of the effects of aristolochic acidⅠon fatty acidβoxidation, glucose metabolism and TCA cycle in mouse liver[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2019, 16(8): 449-466.
[16] XIA JF, LIANG QL, ZHONG HF, et al.Effect of Tangshen prescription on purine and pyrimidine metabolism in diabetic nephropathy[J]. Chinese Patent Drug(中成药), 2011, 33(1): 13-17.
[17] QIU JF, CHENG JD, XIE YC, et al.1,4-Dioxane exposure induces kidney damage in mice by perturbing specific renal metabolic pathways: an integrated omics insight into the underlying mechanisms[J]. Chemosphere, 2019, 228: 149-158.
[18] ZHANG S, LI C, FENG TT, et al.A metabolic profiling study of realgar-induced acute kidney injury in mice[J]. Front Pharmacol, 2021, 12: 706249.

基于质谱成像技术探究5-羟甲基糠醛肾毒性作用机制

Mechanism of nephrotoxicity of 5-hydroxymethylfurfural based on mass spectrometry imaging

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