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糖尿病对乳腺癌耐药蛋白表达和功能的组织特异性损伤作用
引用本文:张璐璐,金实,李佳,段茹,刘晓东.糖尿病对乳腺癌耐药蛋白表达和功能的组织特异性损伤作用[J].中国药科大学学报,2011,42(6):544-550.
作者姓名:张璐璐  金实  李佳  段茹  刘晓东
作者单位:中国药科大学药物代谢动力学重点实验室;中国药科大学药物代谢动力学重点实验室;中国药科大学药物代谢动力学重点实验室;中国药科大学药物代谢动力学重点实验室;中国药科大学药物代谢动力学重点实验室
基金项目:国家自然科学基金资助项目(No.81072693)
摘    要:首先从在体水平研究糖尿病能否导致大鼠皮层、海马、肝、肠黏膜和肾中乳腺癌耐药蛋白(BCRP)的功能和表达发生改变以及胰岛素治疗能否逆转糖尿病引起的这种改变;进一步通过体外Caco-2和HepG-2细胞模型研究糖尿病血清中是否存在异常成分影响BCRP的功能和表达。通过单次给予链脲菌素(65mg/kg,ip)诱导糖尿病模型,三磷酸腺苷结合转运蛋白G超家族成员2(ABCG2)/BCRP的表达分别由QT-PCR和Western blot实验测定,体外通过测定Caco-2和HepG-2细胞中哌唑嗪的摄取研究BCRP的功能改变。在体QT-PCR分析结果表明:5周和8周糖尿病大鼠的皮层、肝和肠黏膜中,ABCG2的表达均显著降低,而在海马和肾中其表达却显著增加。Western blot实验结果在大部分组织中与QT-PCR结果相一致。离体实验结果表明在Caco-2和HepG-2细胞中,高胰岛素和高血糖均可以抑制BCRP的功能。由此证明糖尿病对ABCG2/BCRP的表达和功能具有组织特异性的损伤作用,并且在大鼠肝和肠黏膜中,BCRP功能的改变可能是由高血糖水平引起的。

关 键 词:糖尿病  乳腺癌耐药蛋白  组织特异性  表达和功能  哌唑嗪

Tissue-specific damage in expression and function of breast cancer resistance protein in streptozotocin-induced diabetic rats
ZHANG Lu-lu,JIN Shi,LI Ji,DUAN Ru and LIU Xiao-dong.Tissue-specific damage in expression and function of breast cancer resistance protein in streptozotocin-induced diabetic rats[J].Journal of China Pharmaceutical University,2011,42(6):544-550.
Authors:ZHANG Lu-lu  JIN Shi  LI Ji  DUAN Ru and LIU Xiao-dong
Institution:ZHANG Lu-lu,JIN Shi,LI Jia,DUAN Ru,LIU Xiao-dong Key Laboratory of Drug Metabolism and Pharmacokinetics,China Pharmaceutical University,Nanjing 210009,China
Abstract:The purpose of the study was to investigate whether diabetes mellitus would alter breast cancer resistance protein (BCRP) expression and function in the cerebral cortex,hippocampus,liver,intestinal mucosa and kidney of rat and whether insulin treatment would reverse the alteration caused by diabetes.Abnormal factors in diabetic blood serum altering the expression and function of BCRP were investigated using Caco-2 and HepG-2 cells.Diabetic rats were induced by an intraperitoneal administration of 55 mg/kg of streptozotocin.ATP-binding cassette transporter G2(ABCG2)/BCRP mRNA and protein expression levels in the indicated tissues were evaluated by quantitative real time polymerase chain reaction (QT-PCR) analysis and Western blot,respectively.BCRP functional activities were estimated by the uptake of prazosin in Caco-2 and HepG-2 cells.QT-PCR analysis revealed that ABCG2 mRNA levels were significantly decreased in cerebral cortex,liver and intestinal mucosa,but were dramatically increased in hippocampus and kidney of 5- and 8-week diabetic rats.Western blot results were in accordance with the alterations of ABCG2 mRNA levels in most tissues.Uptake assay results demonstrated that high insulin and high glucose may cause the down-regulation of BCRP in Caco-2 and HepG-2 cells.The results demonstrated that diabetes damaged the ABCG2/BCRP expression and function in a tissue-specific manner;and in rat liver and intestinal mucosa,the alteration of BCRP under diabetic condition may be caused by high glucose level.
Keywords:diabetes mellitus  breast cancer resistance protein  tissue-specificity  expression and function  prazosin
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