摘要
目的利用已发表的丙戊酸钠(VPA)处理的大鼠原代肝细胞的基因芯片原始数据,深入分析VPA对肝细胞生物过程/通路的干扰作用,为VPA毒性机制的深入研究提供参考。方法将NCBI的GEO(Gene Expression Omnibus)数据库中,VPA处理的大鼠肝原代细胞样本的数据GSE40338取出,采用GCBI在线平台分析,样本数据分为VPA处理组(实验组)和蒸馏水处理组(对照组),进行差异基因分析,功能分析及信号通路分析。结果基因芯片分析结果显示,不同剂量和不同时间VPA处理,肝细胞的基因调控变化不同,进一步分析提示VPA干扰了的生物过程(biological process)、代谢(metabolism)和发育(development)等过程。与发育相关的通路主要包括血管新生(vasculogenesis)、胚胎发育(embryonic development)、神经发育(neural development)及器官发育(organ development),其中器官发育和神经发育的富集度为最高。结论体外肝细胞基因组学分析表明,除代谢外,VPA可以干扰多种生物学过程,包括干扰发育相关的生物功能网络,提示其可能具有器官发育和神经发育毒性,与体内动物实验的致畸效应和神经管发育毒性相一致。本研究表明对基因芯片数据的生物网络/过程的深入分析对预测药物毒性和理解作用机制具有重要价值。
Objective To investigate the interference of sodium valproate（VPA） on hepatocyte bioprocessing/pathways by using published original data of rat hepatocyte-derived gene microarrays and to provide a basis for further studies on the mechanism of VPA toxicity. Methods Data of GSE40338 from VPA-treated rat primary hepatocytes in NCBI database was analyzed by GCBI online platform. The data was divided into control group and experimental group for differential gene analysis, Gene Ontology analysis and pathway analysis. Results Gene microarray analysis showed that different doses and incubation times of VPA treatment induced different gene regulations on hepatocytes.Further analyses suggest that VPA might interfer with the processes of biological processes, metabolism, development and etc. Pathways associated with development mainly include vasculogenesis, embryonic development, neurodevelopment and organ development. And the enrichments of organ development and neurodevelopment were much stronger than others. Conclusion Genomic analysis of hepatocytes in vitro indicates that in addition to metabolism, VPA can interfere with a variety of biological processes, including disruption of developmental bio-functional networks, implying that it is associated with organ developmental and neurodevelopmental toxicities. This study indicates that in-depth analysis of bio-networks/processes of gene microarray data is of important value in predicting toxicity of a drug and understanding its mechanism.
出处
《中国药物警戒》
2017年第12期705-710,共6页
Chinese Journal of Pharmacovigilance
基金
新药创制重大专项(2012ZX09301001-006):基于人源化动物模型和肝脏生物功能网络的药物肝毒性预测关键新技术
国家自然科学基金(81573162):整合生物标志物与临床表型以精确预测子痫前期发病风险
关键词
丙戊酸钠
肝原代细胞
基因组学
生物功能
毒性预测
sodium valproate
primary hepatocytes
genomics
biological function
prediction of toxicity
