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目的:研究用人过氧化物酶体增殖物激活受体α(h PPARα)转基因小鼠对过氧化物酶体增殖剂(PP)药物进行临床前药效学评价的可行性。方法:用高脂饲料喂养h PPARα转基因小鼠6周,建立h PPARα转基因小鼠高脂模型。根据模型小鼠血清甘油三酯(TG)和总胆固醇(CHO)含量,将动物随机分为模型组和给药组,8只/组,另选择8只基础饲料喂养的h PPARα转基因小鼠作为对照组。模型组和给药组小鼠分别灌胃(ig)纯化水和吉非罗齐4周。给药结束称量动物体重,取血进行血液生化学检查,并检测人PPARα基因在转基因小鼠体内的组织表达。结果:给予高脂饲料6周,h PPARα转基因小鼠血清TG、CHO、低密度脂蛋白胆固醇(LDL-C)含量明显升高。给予吉非罗齐4周,动物体重未见异常;血液生化学检查结果显示:模型组小鼠血清葡萄糖(GLU),CHO,TG,LDL-C含量与对照组相比显著升高,给药组小鼠血清CHO,TG,LDL-C含量与模型组相比显著降低,高密度脂蛋白胆固醇(HDL-C)含量与模型组相比显著升高,其他肝肾功能指标各组之间均未见显著性差异。组织分布结果显示:人PPARα基因在h PPARα转基因小鼠的心、肝、肾组织中呈高水平表达。结论:h PPARα转基因动物可以作为PP药物临床前药效学评价较为理想的动物模型。
AIM: To investigate the feasibility of preclinical pharmacodynamic evaluation of peroxisome proliferator (PP) drugs in human peroxisome proliferator - activated receptor α (h PPARα) transgenic mice. Methods: The h PPARα transgenic mice were fed with high fat diet for 6 weeks, and the hyperlipemia model of h PPARα transgenic mice was established. According to the model of serum triglyceride (TG) and total cholesterol (CHO) content, the animals were randomly divided into model group and the administration group, 8 / group, and the other eight basic feed-fed h PPARα transgenic mice as Control group. Mice in the model group and the administration group were respectively gavage (ig) purified water and gemfibrozil for 4 weeks. The animals were weighed at the end of the administration, blood biochemical tests were performed, and the tissue expression of the human PPARα gene in the transgenic mice was examined. Results: The levels of serum TG, CHO and low density lipoprotein cholesterol (LDL-C) in hPPARα transgenic mice were significantly increased after 6 weeks of high fat diet. The results of blood biochemistry showed that the levels of GLU, CHO, TG and LDL-C in the model group were significantly higher than those in the control group Compared with model group, the levels of serum CHO, TG and LDL-C in serum of mice in model group decreased significantly, and the content of high density lipoprotein cholesterol (HDL-C) increased significantly compared with model group No significant difference was found. Tissue distribution results showed that human PPARα gene was highly expressed in heart, liver and kidney of h PPARα transgenic mice. Conclusion: h PPARα transgenic animals can be used as PP animal pre-clinical pharmacodynamic evaluation of the ideal animal model.