Published
2026-05-12
Section
Articles
How to Cite
基于网络毒理学与生物信息学策略分析的二嗪磷致癌毒性及其作用机制研究
裘 佳寅
浙江中医药大学药学院
陈 振金
南方医科大学南方医院，药学部/南方医科大学南方医院，临床药学中心
黄 福龙
南方医科大学南方医院，药学部/南方医科大学南方医院，临床药学中心
古 春萍
南方医科大学南方医院，药学部/南方医科大学南方医院，临床药学中心
DOI: https://doi.org/10.59429/zxyy.v3i2.13909
Keywords: 二嗪磷；网络药理学；致癌性；肿瘤；二氢叶酸还原酶
Abstract
食品安全与人体健康密切相关。二嗪磷作为一种被广泛使用的农药，已被国际癌症研究机构（International Agency for Research on Cancer，IARC）列为Ⅱ类致癌物，引发广泛关注。本研究利用 5 个毒性预测数据库对二嗪磷的致癌潜能进行分析，共筛选出二嗪磷的作用靶点 168 个、癌症相关靶点 2768 个，其中具有交集的靶点 36 个。通过 Friends 分析，筛选识别得到 20 个核心靶点。经 Metascape 功能富集分析揭示，癌症为主要富集通路，其机制可能与 MAPK 级联调控相关。利用 AutoDock 1.5.7 进行分子对接，结果表明 20 个核心靶点中有 16 个结合能小于 -5 kcal/mol，其中二氢叶酸还原酶（dihydrofolate reductase, DHFR) 结合能最低（-6.7 kcal/mol）。对 DHFR 的泛癌分析进一步阐明了其在肿瘤发生中的作用。本研究为阐明二嗪磷的分子毒性机制提供理论依据，可为后续疾病防控与治疗研究提供参考。
References
[1] Nasrollahi M, Pourbabaei AA, Etesami H, et al. Diazinon degradation by bacterial endophytes in rice plant (Oryzia sativa L.): A possible reason for reducing the efficiency of diazinon in the control of the rice stem-borer[J]. Chemosphere, 2020, 246:125759-125759. https://doi.org/10.1016/j.chemosphere.2019.125759.
[2] Madrigal JM, Gunier RB, Jones RR, et al. Contributions of nearby agricultural insecticide applications to indoor residential exposures[J]. Environ Int, 2023, 171:107657-107657. https://doi.org/10.1016/j.envint.2022.107657.
[3] European Food Safety A, Bellisai G, Bernasconi G, et al. Targeted review of maximum residue levels (MRLs) for diazinon[J]. EFSA J, 2023, 21(11):e08426-e08426. https://doi.org/10.2903/j.efsa.2023.8426.
[4] Yoon J, Lim D, Lee S, et al. Uptake of Soil-Residual Diazinon by Rotational Lettuce under Greenhouse Conditions[J]. Foods, 2022, 11(21):3510. https://doi.org/10.3390/foods11213510.
[5] Shiry N, Derakhshesh N, Alavinia SJ, et al. Anodonta cygnea, a freshwater swan mussel, exposed to diazinon: toxicity thresholds in behaviour and physiology[J]. Vet Res Commun, 2023, 47(3):1303-1319. https://doi.org/10.1007/s11259-023-10078-1.
[6] Zhu Q, Yang Y, Lao Z, et al. Acute and chronic toxicity of deltamethrin, permethrin, and dihaloacetylated heterocyclic pyrethroids in mice[J]. Pest Manag Sci, 2020, 76(12):4210-4221. https://doi.org/10.1002/ps.5978.
[7] Pereira F, Petroianu A, Geraldo JM, et al. Megavo-ltage radiotherapy effects on organs of the reticuloendothelial system[J]. Acta Cir Bras, 2023, 38:e384123. https://doi.org/10.1590/acb384123.
[8] Ali MH, Jyoti MS, Acharjee M, et al. Atrazine and diazinon inhibit oocyte maturation and ovulation in zebrafish[J]. Reprod Toxicol, 2026, 140:109172-109172. https://doi.org/10.1016/j.reprotox.2026.109172.
[9] Zhang H, Zhou Y, Pan Z, et al. Toxicity assessment of Cucurbita pepo cv Dayangua and its effects on gut microbiota in mice[J]. BMC Complement Med Ther, 2024, 24(1):243-243. https://doi.org/10.1186/s12906-024-04551-w.
[10] Lee S-H, Jung K, Chung J, et al. Comparative Study of Algae-Based Measurements of the Toxicity of 14 Manufactured Nanomaterials[J]. Int J Environ Res Public Health, 2022, 19(10):5853. https://doi.org/10.3390/ijerph19105853.
[11] Rai M, Singh AV, Paudel N, et al. Herbal concoction Unveiled: A computational analysis of phytochemicals' pharmacokinetic and toxicological profiles using novel approach methodologies (NAMs)[J]. Curr Res Toxicol, 2023, 5:100118-100118. https://doi.org/10.1016/j.crtox.2023.100118.
[12] Spînu N, Cronin MTD, Lao J, et al. Probabilistic modelling of developmental neurotoxicity based on a simplified adverse outcome pathway network[J]. Comput Toxicol, 2022, 21:100206-100206. https://doi.org/10.1016/j.comtox.2021.100206.
[13] Nili-Ahmadabadi A, Akbari Z, Ahmadimoghaddam D, et al. The role of ghrelin and tumor necrosis factor alpha in diazinon-induced dyslipidemia: insights into energy balance regulation[J]. Pestic Biochem Physiol, 2019, 157:138-142. https://doi.org/10.1016/j.pestbp.2019.03.013.
[14] Ghaemi S, Abedini F, Mousavi A, et al. Impact of pesticide diazinon on gastric cancer cell lines and the alteration of cholinergic and serotonergic pathway genes affecting cell proliferation[J]. Sci Rep, 2025, 15(1):40518-40518. https://doi.org/10.1038/s41598-025-24414-9.
[15] Kim S, Chen J, Cheng T, et al. PubChem 2019 update: improved access to chemical data[J]. Nucleic Acids Res, 2019, 47(D1):D1102-D1109. https://doi.org/10.1093/nar/gky1033.
[16] Fu L, Shi S, Yi J, et al. ADMETlab 3.0: an updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support[J]. Nucleic Acids Res, 2024, 52(W1): W422-W431. https://doi.org/10.1093/nar/gkae236.
[17] Yang H, Lou C, Sun L, et al. admetSAR 2.0: web-service
for prediction and optimization of chemical ADMET properties[J]. Bioinformatics, 2019, 35(6):1067-1069. https://doi.org/10.1093/bioinformatics/bty707.
[18] Ji C, Svensson F, Zoufir A, et al. eMolTox: prediction of molecular toxicity with confidence[J]. Bioinformatics, 2018, 34(14):2508-2509. https://doi.org/10.1093/bioinformatics/bty135.
[19] Banerjee P, Kemmler E, Dunkel M, et al. ProTox 3.0: a webserver for the prediction of toxicity of chemicals[J]. Nucleic Acids Res, 2024, 52(W1):W513-W520. https://doi.org/10.1093/nar/gkae303.
[20] Shaker B, Yu M-S, Song JS, et al. LightBBB: computational prediction model of blood-brain-barrier penetration based on LightGBM[J]. Bioinformatics, 2021, 37(8):1135-1139. https://doi.org/10.1093/bioinformatics/btaa918.
[21] Daina A, Michielin O, Zoete V. SwissTarget-Prediction:updated data and new features for efficient prediction of protein targets of small molecules[J]. Nucleic Acids Res, 2019, 47(W1):W357-W364. https://doi.org/10.1093/nar/gkz382.
[22] Gallo K, Goede A, Preissner R, et al. SuperPred 3.0:
drug classification and target prediction-a machine learning approach[J]. Nucleic Acids Res, 2022, 50(W1):W726-W731. https://doi.org/10.1093/nar/gkac297.
[23] Nickel J, Gohlke B-O, Erehman J, et al. SuperPred: update on drug classification and target prediction[J]. Nucleic Acids Res, 2014, 42(Web Server issue):W26-W31. https://doi.org/10.1093/nar/gku477.
[24] Keiser MJ, Roth BL, Armbruster BN, et al. Relating protein pharmacology by ligand chemistry[J]. Nat Biotechnol, 2007, 25(2):197-206. https://doi.org/10.1038/nbt1284.
[25] Kuhn M, Von Mering C, Campillos M, et al. STITCH: interaction networks of chemicals and proteins[J]. Nucleic Acids Res, 2008, 36(Database issue):D684-D688. https://doi.org/10.1093/nar/gkm795.
[26] Stelzer G, Rosen N, Plaschkes I, et al. The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses[J]. Curr Protoc Bioinformatics, 2016, 54:1.30.31-31.30.33. https://doi.org/10.1002/cpbi.5.
[27] Hamosh A, Amberger JS, Bocchini C, et al. Online Mendelian Inheritance in Man (OMIM®): Victor McKusick's magnum opus[J]. Am J Med Genet A, 2021, 185(11):3259-3265. https://doi.org/10.1002/ajmg.a.62407.
[28] Piñero J, Bravo À, Queralt-Rosinach N, et al. DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants[J]. Nucleic Acids Res, 2017, 45(D1):D833-D839. https://doi.org/ 10.1093/nar/gkw943.
[29] Stark C, Breitkreutz B-J, Reguly T, et al. BioGRID: a general repository for interaction datasets[J]. Nucleic Acids Res, 2006, 34(Database issue):D535-D539. https://doi.org/10.1093/nar/gkj109.
[30] Szklarczyk D, Gable AL, Lyon D, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets[J]. Nucleic Acids Res, 2019, 47(D1):D607-D613. https://doi.org/10.1093/nar/gky1131.
[31] Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets[J]. Nat Commun, 2019, 10(1):1523-1523. https://doi.org/10.1038/s41467-019-09234-6.
[32] Varadi M, Bertoni D, Magana P, et al. AlphaFold Protein Structure Database in 2024: providing structure coverage for over 214 million protein sequences[J]. Nucleic Acids Res, 2024, 52(D1):D368-D375. https://doi.org/10.1093/nar/gkad1011.
[33] El-Hachem N, Haibe-Kains B, Khalil A, et al. AutoDock and AutoDockTools for Protein-Ligand Docking: Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1(BACE1) as a Case Study[J]. Methods Mol Biol, 2017, 1598:391-403. https://doi.org/10.1007/978-1-4939-6952-4_20.
[34] Li T, Fu J, Zeng Z, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells[J]. Nucleic Acids Res, 2020, 48(W1):W509-W514. https://doi.org/10.1093/nar/gkaa407.
[35] Tang Z, Kang B, Li C, et al. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis[J]. Nucleic Acids Res, 2019, 47(W1):W556-W560. https://doi.org/10.1093/nar/gkz430.
[36] Zhao M-A, Gu H, Zhang C-J, et al. Metabolism of insecticide diazinon by Cunninghamella elegans ATCC36112[J]. RSC Adv, 2020, 10(33):19659-19668. https://doi.org/10.1039/d0ra02253e.
[37] Abdel-Daim MM, Taha R, Ghazy EW, et al. Synergistic ameliorative effects of sesame oil and alpha-lipoic acid against subacute diazinon toxicity in rats: hematological, biochemical, and antioxidant studies[J]. Can J Physiol Pharmacol, 2016, 94(1):81-88. https://doi.org/10.1139/cjpp-2015-0131.
[38] Ahmadi A, Heidarian E, Ghatreh-Samani K. Modulatory effects of artichoke (Cynara scolymus L.) leaf extract against oxidative stress and hepatic TNF-α gene expression in acute diazinon-induced liver injury in rats[J]. J Basic Clin Physiol Pharmacol, 2019, 30(5). https://doi.org/10.1515/jbcpp-2018-0180.
[39] Esfahani M, Mehri F. Homeostatic changes of trace elements in diazinon toxicity in rat model: The beneficial role of resveratrol[J]. Toxicol Rep, 2024, 13:101719-101719. https://doi.org/10.1016/j.toxrep.2024.101719.
[40] Miranda CA, Beretta EM, Ferreira LA, et al. Role of biotransformation in the diazinon-induced toxicity in HepG2 cells and antioxidant protection by tetrahydrocurcumin[J]. Toxicol Rep, 2022, 10:32-39. https://doi.org/10.1016/j.toxrep.2022.12.005.
[41] Enan EE, El-Sebae AH, Enan OH, et al. In-vivointeraction of some organophosphorus insecticides with different biochemical targets in white rats[J]. J Environ Sci Health B, 1982, 17(5):549-570. https://doi.org/10.1080/ 03601238209372341.
[42] Morteza Z, Mousavi SB, Baghestani MA, et al. An assessment of agricultural pesticide use in Iran, 2012-2014[J]. J Environ Health Sci Eng, 2017, 15:10-10. https://doi.org/ 10.1186/s40201-017-0272-4.
[43] Delorenzi Schons D, Leite GaA. Malathion or diazinon exposure and male reproductive toxicity: a systematic review of studies performed with rodents[J]. Crit Rev Toxicol, 2023, 53(8):506-520. https://doi.org/10.1080/10408444.2023.2270494.
[44] Herrera EG, Bonini A, Vivaldi F, et al. A Biosensor for the Detection of Acetylcholine and Diazinon[J]. Annu Int Conf IEEE Eng Med Biol Soc, 2019, 2019:1159-1162. https://doi.org/10.1109/EMBC.2019.8856959.
[45] Cheng Y, Chen J, Shi Y, et al. MAPK Signaling Pathway in Oral Squamous Cell Carcinoma: Biological Function and Targeted Therapy[J]. Cancers (Basel), 2022, 14(19):4625. https://doi.org/10.3390/cancers14194625.
[46] Shi A, Liu L, Li S, et al. Natural products targeting the MAPK-signaling pathway in cancer: overview[J]. J Cancer Res Clin Oncol, 2024, 150(1):6-6. https://doi.org/10.1007/s00432-023-05572-7.
[47] Wei J, Liu R, Hu X, et al. MAPK signaling pathway-targeted
marine compounds in cancer therapy[J]. J Cancer Res Clin Oncol, 2021, 147(1):3-22. https://doi.org/10.1007/s00432-020-03460-y.
[48] Lee YJ, Kim WR, Park EG, et al. Exploring the Key Signaling Pathways and ncRNAs in Colorectal Cancer[J]. Int J Mol Sci, 2024, 25(8):4548. https://doi.org/10.3390/ijms25084548.
[49] Zou X, Blank M. Targeting p38 MAP kinase signaling in cancer through post-translational modifications[J]. Cancer Lett, 2017, 384:19-26. https://doi.org/10.1016/j.canlet.2016.10.008.
[50] Feulefack J, Khan A, Forastiere F, et al. Parental Pesticide Exposure and Childhood Brain Cancer: A Systematic Review and Meta-Analysis Confirming the IARC/WHO Monographs on Some Organophosphate Insecticides and Herbicides[J]. Children (Basel), 2021, 8(12):1096. https://doi.org/10.3390/children8121096.
[51] Li J, Sun Y, Bi H. Exploring molecular mechanisms of diazinon toxicity in HT22 hippocampal neurons through integrated miRNA and mRNA profiling[J]. Comput Biol Med, 2024, 182:109091-109091. https://doi.org/10.1016/j.compbiomed.2024.109091.
[52] Sadighara P, Mahmudiono T, Marufi N, et al. Residues of carcinogenic pesticides in food: a systematic review[J]. Rev Environ Health, 2023, 39(4):659-666. https://doi.org/10.1515/reveh-2022-0253.
[53] Li H, Song F, Duan L-R, et al. Paeonol and danshensu combination attenuates apoptosis in myocardial infarcted rats by inhibiting oxidative stress: Roles of Nrf2/HO-1 and PI3K/Akt pathway[J]. Sci Rep, 2016, 6:23693-23693. https://doi.org/10.1038/srep23693.
[54] Li X, He P, Wang X-L, et al. Sulfiredoxin-1 enhances cardiac progenitor cell survival against oxidative stress via the upregulation of the ERK/NRF2 signal pathway[J]. Free Radic Biol Med, 2018, 123:8-19. https://doi.org/10.1016/j.freeradbiomed.2018.05.060.