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目的:比较氟他胺及其活性代谢产物2-羟基氟他胺对原代培养大鼠肝细胞毒性及对CYP1A2 mRNA的影响.方法:分离大鼠肝细胞,原代培养4h,台酚蓝拒染法检测肝细胞活力.氟他胺和2-羟基氟他胺在培养液中浓度分别为10、20和50mg/L.肝细胞毒性检测包括台酚蓝拒染法,乳酸脱氢酶(LDH)释放量,谷丙转氨酶(AST)和谷草转氨酶(ALT)释放百分比,谷胱甘肽(GSH)含量.同时采用Northern blot方法进一步研究两药对CYP1A2 mRNA的影响.结果:药物作用8h后,氟他胺三个剂量组和2-羟基氟他胺50mg/L组出现肝细胞损伤,表现为ALT和AST释放百分比增加,GSH含量下降.氟他胺三个剂量组使CYP1A2 mRNA水平分别升高2,5和7.5倍,而2-羟基氟他胺仅在50mg/L时使CYP1A2mRNA水平升高3.5倍.结论:氟他胺对原代培养大鼠肝细胞的毒性大于其活性代谢物2-羟基氟他胺,且明显增加CYP1A2 mRNA水平.
OBJECTIVE: To compare the toxicity of 2-hydroxyflutamide and 2-hydroxyflutamide on the hepatocyte cytotoxicity and its effect on CYP1A2 mRNA in primary cultured rat.Methods: Rat hepatocytes were isolated and cultured in primary culture for 4 h, Fluorescence staining was used to detect the viability of liver cells, and the concentrations of flutamide and 2-hydroxyflutamide in the culture medium were 10, 20 and 50 mg / L, respectively.The detection of hepatotoxicity included Trypan blue exclusion, lactate dehydrogenase (LDH ), The release of alanine aminotransferase (AST) and aspartate aminotransferase (ALT) and the content of glutathione (GSH) were determined.Meanwhile, the effects of the two drugs on CYP1A2 mRNA were further studied by Northern blot.Results: Flutamide three dose group and 2-hydroxyflutamide 50mg / L group of liver cell injury, the performance of the ALT and AST release percentage increased, decreased GSH content. Flutamide three dose group CYP1A2 mRNA levels were increased 2, 5 and 7.5 times, respectively, while CYP1A2 mRNA level increased by 3.5 times when 2-hydroxyflutamide only 50mg / L. Conclusion: Flutamide is more toxic to primary cultured rat hepatocytes than its active metabolite 2- Hydroxyflutamide, and significantly increased CYP1A2 mRNA levels.