基于系统生物学的药物毒理学研究进展  

Research progress in drug toxicology based on systems biology

作　　者：楼宜嘉[1] 

机构地区：[1]浙江大学药学院药理毒理与生化药学研究所,浙江杭州310058

出　　处：《中国药理学与毒理学杂志》2012年第4期476-481,共6页Chinese Journal of Pharmacology and Toxicology

基　　金：国家自然科学基金资助项目(81173135);国家自然科学基金资助项目(30973600);浙江省自然科学基金重点资助项目(LZ12H31001)~~

摘　　要：近年来涉及系统生物学的毒理学研究已日渐兴起,在整体性、动态性、网络调控性的内涵下,关注外来物质对机体的损伤评估与预测。药物与生物大分子作用涉及机体网络系统的巨大复杂性,使得对药物毒性作用机制的理解难度也有所增加。应用计算与实验系统生物学,药物毒理学研究在生物组织扩大到多重尺度网络分析,并由此说明治疗作用和不良反应。系统毒理学依靠实验"组学"技术,在大量可变因素中能测量多重变化,通常在全基因组水平建立网络分析药物作用。组学技术由于将个体基因组状态联系到所用药物的治疗效能和毒性反应,通常在全基因组水平建立分析药物毒性的网络系统。通路与网络分析相结合,毒理效应与毒代动力学模型,和基因多态性知识,将发展为预测毒性作用的模型。基于诸如美国食品药品管理局不良事件报告系统网络分析,可建立初步了解分子水平的药物靶点相互作用,导致器官和各级水平不良反应表型过程的远端效应。系统生物学的集成数据设计分子及相互之间作为一个网络行为,如动力学模拟,代谢调控,鲁棒性和流量分析,确实有助于理解网络介导的毒性及药物毒理学。The research of toxicology based on systems biology has come into vogue. Systems toxicology analyses rely on experimental ＇omics＇ technologies that are capable of measuring changes in large numbers of variables, often at a genome-wide level, to build networks for analyzing drug toxic action. A major use of ＇omics＇ technologies is to relate the genomic status of an individual to the therapeutic efficacy of a drug of interest. Combining pathway and network analyses, toxicokinetic and toxicodynamic models, and a knowledge of polymorphisms in the genome will enable the development of predictive models of therapeutic toxic efficacy, Network analyses based on publicly available databases such as the U.S. Food and Drug Administration＇s Adverse Event Reporting System allow us to develop an initial understanding of the context within which molecular-level drug-target interactions can lead to distal effectors in a process that results in adverse phenotypes at the organ and organism levels. This review focuses on recent advancements in the application of genomic and genetic data to drug safety and highlights recent successes and current knowledge gaps in the following areas： ① the discovery of toxicity biomarkers and identification of compounds that are predicted to cause toxicity, ② the identification of susceptible individuals, and ③ integration of various ＇omics＇ datasets to improve understanding of toxicity mechanisms within a biological system.

关 键 词：系统生物学 药物毒理学 生物标记物 易感个体 

分 类 号：R96[医药卫生—药理学]