4种药物致小鼠肝脏毒性的基因表达谱聚类分析

目的在基因表达谱水平上观察红霉素、四环素、环磷酰胺、异环磷酰胺4种药物对Balb/c小鼠肝脏毒性效应。方法利用本室构建的小鼠毒理基因芯片和4种药物致Balb/c小鼠肝毒性动物模型,观察在药物作用不同时相点和剂量点上小鼠肝脏基因表达谱变化,结合层次聚类等手段对差异表达基因的生物学功能进行初步信息分析。结果共筛选出差异表达基因302个,其中282个参加了聚类分析。结果表明,环磷酰胺和异环磷酰胺组归为一类,红霉素和四环素归为另一类,不同时相和剂量组存在不同的聚类特征,一些差异表达基因在各药物组呈现共同上调或下调趋势。所有差异基因经genecards分析表明涉及脂肪代谢、蛋白质应激合成、抗氧化、炎症发生、细胞周期调控及药物代谢等多种生理功能。结论本研究揭示了与4种药物致Balb/c小鼠肝脏毒性相关的基因表达谱模式和特征基因群,为深入分析药物致小鼠肝毒性效应分子机制提供线索。

CLUSTERING ANALYSIS OF GENE EXPRESSION PROFILES IN MOUSE HEPATOTOXICITY INDUCED BY FOUR DRUGS

Objective To observe the toxic effect of erythromycin lactobionate,tetracycline hydrochloride,cyclophosphamide,and ifosfamide on Balb/c mouse liver using gene expression profiles.Methods The mouse toxicological microarray and animal models of four drugs-induced mouse hepatotoxicity established in our laboratory were used to observe the gene expression profiles at different doses and time points after treatment,and to analyze the differential expressed genes by hierarchical clustering and biologic information data-base.Results A total of 302 differential expressed genes were screened out.Clustering analysis showed that cyclophosphamide group and ifosfamide group were classified into one cluster,erythromycin lactobionate group and tetracycline hydrochloride group were classified into the other one,and different cluster characters were found to exist in various time point groups and dose groups.Moreover,some differential expressed genes revealed up-regulation or down-regulation together in the drug groups.Analysis of all differntial expressed genes in genecards showed that they are related to multiple physiolgical functions such as fat metabolism,protein synthesis in stress,antioxidation,inflammation,cell cycle regulation,and drug metabolism,etc.Conclusion The study revealed the gene expression profiles and characteristic genes related to hepatotoxicity in Balb/c mouse induced by four drugs,which may give clues to further studying the molecular mechanism of drug's hepatotoxicity.