摘要
目的通过对肾脏基因的差异表达研究,对大鼠口服大黄总蒽醌肾脏毒性作用靶点提供科学推论。方法SD大鼠大黄总蒽醌4 500 mg.kg-1.d-1灌胃给药13周,选用大鼠全基因组芯片检测肾脏基因差异表达,使用荧光定量PCR手段对10条关键基因进行了差异表达确认。实验分为给药组和正常组(n=4),对基因芯片检测结果进行按生理通路聚类分析。结果研究发现有143条基因在给药组中发生上调,101条基因发生了下调。上调的基因中与糖脂代谢相关的有29条,免疫相关的有13条,肾脏解毒功能相关的有15条,与细胞周期调控、信号传导、内分泌调节相关的有24条,未知功能的有26条;下调的基因中与糖脂代谢相关的有12条,免疫相关的有11条,细胞周期调控、信号传导相关的有20条,肾功能相关的有25条,功能未知的为39条。结论大黄总蒽醌给药组基因芯片分析结果显示,caspase3和p53通路并不是造成细胞凋亡的主要原因。研究发现,p38 MAPK通路中,MAPK激酶6可能是某种程度上造成细胞损伤的原因。细胞周期调节相关通路研究表明,周期蛋白D1和周期素依赖性蛋白激酶1的下调可能是造成真核细胞周期调控受阻,进而产生增殖抑制作用的原因。
OBJECTIVE To provide evidence for the study of the nephrotoxicological targets after oral administration of total rubarb anthraquinones （TRAs） in SD rats. METHODS SD rats were administrated with TRAs per os once daily for 13 weeks at a dose of 4 500 mg . kg^-1 . d^-1 body weight. Oligonucleotide microarrays Rat Genome 230 2.0 A （Affymetrix, USA） were used to determine the kidney gene differentia/ expression rates and the key functional gene variations were confirmed by real-time PCR methodology. Each group consisted of four samples. The gene expression data was clustered according to biological pathways. RESULTS The obtained results showed that 143 genes revealed up-regulation and 101 genes showed down-regulation. Among the up-regulated groups, 29 genes were related to glycolipide metabolism, 13 to immunity, 15 to detoxification in kidney,24 to regulation of cell cycles, endocrine and signal transduction, other 26 genes remained unknown functions. Among the down-regulated group, 12 genes were related to glycolipid metabolism, 11 to immunity ,20 to regulation of cell cycles and signal transduction,25 to kidney functions ,39 remained unknown functions. CONCLUSION In TRAs treated group,caspase 3 and p53 pathways obviously did not lead to the apoptosis of cells according to microarray results. Concerning p38 MAPK pathway, expression of MAPK kinase6 was found down-regulated, which related to the cell injury to some extent. In cell cycle regulation pathway, down-regulation of cyclin D1, cyclin-dependent kinase 1 （ CDK-1 ） maybe play a key role in the blockage control of the eukaryotic cell cycle.
出处
《中国药学杂志》
CAS
CSCD
北大核心
2008年第1期7-11,共5页
Chinese Pharmaceutical Journal
基金
国家“十五”滚动项目(2004AA2Z3785)
国家“十五”攻关项目(2004BA721A14)
国家中医药管理局中医药科学技术研究专项(国中医药科2004ZX00)
关键词
大黄总蒽醌
基因芯片
肾毒性
total rhubarb anthraquinones
gene microarray
nephrotoxicity
