应用比较毒理基因组学数据库解析棉酚对动物机体的毒性作用机制  

Analysis of the mechanism of gossypol toxicity in animals using comparative toxicogenomics database

作　　者：孔伟帅 刘娟 邓中原 刘岩 KONG Wei-shuai;LIU Juan;DENG Zhong-yuan;LIU Yan(College of life sciences,Zhengzhou University,Zhengzhou Henan 450001,China;Beijing Center for Disease Control and Prevention,Beijing Key Laboratory of Traceability Technology for Food Poisoning Diagnosis,Beijing 100013,China;School of Agricultural Sciences,Zhengzhou University,Zhengzhou Henan 450001,China)

机构地区：[1]郑州大学生命科学学院,河南郑州450001 [2]北京市疾病预防控制中心,食品中毒诊断溯源技术北京市重点实验室,北京100013 [3]郑州大学农学院,河南郑州450001

出　　处：《毒理学杂志》2023年第2期121-127,136,共8页Journal of Toxicology

基　　金：郑州大学全国大学生创新创业训练计划资助项目(2021cxcy178);棉花生物学国家重点实验室开放课题(CB2020A06);北京市自然科学基金(7224356)。

摘　　要：目的 利用生物信息学方法分析棉酚(gossypol)及其衍生物醋酸棉酚(gossypol acetic acid)诱导的差异基因和涉及的信号通路,解析棉酚对动物机体的毒性作用机制,为开发减毒棉酚类新药物提供思路。方法 利用比较毒理基因组学数据库(Comparative Toxicogenomic Database, CTD)筛选棉酚及其衍生物(醋酸棉酚)诱导的差异基因,分析两者诱导的共同差异基因、差异基因间相互作用网络、差异基因的KEGG通路,利用网络毒理学方法对分析结果进行验证。结果 CTD筛选得到棉酚及其衍生物(醋酸棉酚)诱导的差异基因115个,两者共同诱导的差异基因2个。基因相互作用网络分析与KEGG分析得出在差异基因中,CYCS、CASP3和BCL2L1有较多交互基因,介导多种细胞凋亡通路。以神经毒性为例,网络毒理学验证得出棉酚及其衍生物通过诱导CYCS、CASP3和BCL2L1等差异基因的表达引起对机体的毒作用。结论 本次基于2022年2月更新的CTD所开展的生物信息学分析得出,棉酚类物质的毒性作用主要是通过线粒体依赖性细胞凋亡途径实现的,即棉酚及其衍生物诱导Bcl-2基因家族表达下调、Caspase基因家族表达上调进而促进细胞凋亡从而起到毒性作用。Objective To analyze the differential genes and pathways induced by gossypol and its derivative gossypol acetic acid using bioinformatics method,and to figure out the toxic mechanism of gossypol on animals and provide ideas for developing new gossypol drugs with low toxicity.Methods The Comparative Toxicogenomics Database(CTD)was used to screen the differential genes induced by gossypol and its derivative(gossypol acetic acid).The common differential genes induced by gossypol and gossypol acetic acid,the gene interaction network and the KEGG pathways of differential genes were analyzed.The method of network toxicology were used to verify the analysis result.Results A total of 115 differential genes induced by gossypol and its derivative(gossypol acetic acid)were obtained from the database including 2 common differential genes induced by both.Gene interaction network analysis and KEGG analysis showed that among the differential genes,CYCS,CASP3 and BCL2LI had a lager number of interacting genes,which mediated multiple apoptosis pathways.Taking neurotoxicity as an example,the network toxicological validation showed that the toxicity of gossypol and its derivative on bodies was induced by affecting the expression of CYCS,CASP3,BCL2LI and other differential genes.Conclusion The bioinformatics analysis based on the Comparative Toxicogenomics Database updated in February 2022 shows that the toxicity of gossypol is mainly achieved through the mitochondria-dependent apoptosis pathway.Gossypol and its derivatives promote cell apoptosis to lead the its toxic effect by inducing the down-regulation of Bcl-2 gene family and the up-regulation of Caspase gene family.

关 键 词：棉酚 醋酸棉酚 比较毒理基因组学数据库 Caspase 线粒体依赖性细胞凋亡通路 

分 类 号：R99[医药卫生—毒理学] R114[医药卫生—药学]