基于代谢组学结合生物信息学探讨热毒宁注射液与青霉素注射液联用致类过敏反应的潜在致敏原及作用机制  

Study on the potential allergen and mechanism of pseudo-allergic reactions induced by combined using of Reduning injection and penicillin G injection based on metabolomics and bioinformatics

作　　者：陈毓龙 翟优 王晓艳[2,3] 李伟霞[2,3] 张辉[2,3] 吴娅丽 杨柳青 陈小菲[2,3] 张书琦 牛璐 冯科冉 李琨 唐进法[2,3] 张明亮 CHEN Yu-long;ZHAI You;WANG Xiao-yan;LI Wei-xia;ZHANG Hui;WU Ya-li;YANG Liu-qing;CHEN Xiao-fei;ZHANG Shu-qi;NIU Lu;FENG Ke-ran;LI Kun;TANG Jin-fa;ZHANG Ming-liang(Henan University of Chinese Medicine,Zhengzhou 450046,China;Henan Province Engineering Research Center for Clinical Application,Evaluation and Transformation of Traditional Chinese Medicine,Henan Provincial Key Laboratory for Clinical Pharmacy of Traditional Chinese Medicine,Henan Province Engineering Research Center of Safety Evaluation and Risk Management of Traditional Chinese Medicine,Department of Pharmacy,the First Affiliated Hospital of Henan University of Chinese Medicinee,Zhengzhou 450000,China;Provincial and Ministerial Co-construction Collaborative Innovation Center for Prevention and Treatment of Respiratory Diseases with Traditional Chinese Medicine of Henan University of Chinese Medicine,Zhengzhou 450046,China)

机构地区：[1]河南中医药大学,河南郑州450046 [2]河南省中药临床应用,评价与转化工程研究中心,河南省中药临床药学中医药重点实验室,河南省中药安全评价与风险防控工程研究中心,河南中医药大学第一附属医院药学部,河南郑州450000 [3]河南中医药大学呼吸疾病中药防治省部共建协同创新中心,河南郑州450046

出　　处：《药学学报》2024年第2期382-394,共13页Acta Pharmaceutica Sinica

基　　金：河南省科技攻关课题(202102310185);河南省高校科技创新团队(23IRTSTHN026);河南省中医药拔尖人才培养项目(豫中医科教[2018]35号)。

摘　　要：本研究基于代谢组学结合生物信息学的策略分析热毒宁注射液与青霉素注射液联用引发类过敏反应(pseudo-allergic reactions,PARs)的潜在致敏原及作用机制。所有动物实验操作和福利均遵循河南中医药大学第一附属实验动物伦理与动物福利委员会要求(批号:YFYDW2020002)。基于UPLC-Q-TOF/MS技术结合UNIFI软件在热毒宁与青霉素混合注射液中共鉴定得到21种化合物。进一步基于分子对接技术筛选出其10种与类过敏原受体MrgprX2激动剂位点具有强烈结合活性的潜在致敏原。采用UPLC-Q-TOF/MS技术进行代谢组学分析发现花生四烯酸、磷脂酰胆碱、磷脂酰丝氨酸、前列腺素类以及白三烯类等34个内源性代谢物为热毒宁注射液与青霉素注射液联用引发PARs的差异代谢物。通过对“潜在致敏原-靶标-差异代谢物”交互网络分析获得二者联用时药液中的绿原酸类(绿原酸、新绿原酸、隐绿原酸、异绿原酸A等)以及β-内酰胺类致敏原可能主要通过调控PLD1、PLA2G12A和CYP1A1这三种上游信号靶标,主要激活花生四烯酸代谢通路,促使肥大细胞的脱颗粒,释放下游的内源性炎性介质,继而诱发PARs。Based on the strategy of metabolomics combined with bioinformatics,this study analyzed the potential allergens and mechanism of pseudo-allergic reactions(PARs)induced by the combined use of Reduning injection and penicillin G injection.All animal experiments and welfare are in accordance with the requirements of the First Affiliated Experimental Animal Ethics and Animal Welfare Committee of Henan University of Chinese Medicine(approval number:YFYDW2020002).Based on UPLC-Q-TOF/MS technology combined with UNIFI software,a total of 21 compounds were identified in Reduning and penicillin G mixed injection.Based on molecular docking technology,10 potential allergens with strong binding activity to MrgprX2 agonist sites were further screened.Metabolomics analysis using UPLC-Q-TOF/MS technology revealed that 34 differential metabolites such as arachidonic acid,phosphatidylcholine,phosphatidylserine,prostaglandins,and leukotrienes were endogenous differential metabolites of PARs caused by combined use of Reduning injection and penicillin G injection.Through the analysis of the"potential allergen-target-endogenous differential metabolite"interaction network,the chlorogenic acids(such as chlorogenic acid,neochlorogenic acid,cryptochlorogenic acid,and isochlorogenic acid A)andβ-lactam allergens in the combination of the two may be mainly regulated by PLD1,PLA2G12A and CYP1A1.The three upstream signal target proteins mainly activate the arachidonic acid metabolic pathway,promote the degranulation of mast cells,release downstream endogenous inflammatory mediators,and induce PARs.

关 键 词：中西药联用 类过敏反应 热毒宁注射液 注射用青霉素钠 代谢组学 生物信息学 

分 类 号：R917[医药卫生—药物分析学]