hPPARα转基因小鼠在吉非罗齐临床前药效学评价中的应用

Application of human PPARα transegenic mice in preclinical pharmacodynamic evaluation for gemfibrozil

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。

Objective： To explore the feasibility of preclinical pharmacodynamic evaluation for PP drugs with h PPARα transgenic mice. Methods： High fat fodder was fed to h PPAR transgenic mice for 6 weeks to build a high fat model. The mice with high fat fodder were assigned to 2 groups according to the content of TG and CHO in serum（ n = 8 mice in each group） and treated with oral dd H2 O or gemfibrozil for 4 weeks. Additional 8 h PPARαtransgenic mice fed with conventional fodder were selected as control group. The body weight was recorded and blood biochemical indixes were examined. Furthermore the expression of human PPAR gene in h PPARα transgenic mice was detected at the termination of the study. Results： The contents of TG,CHO and LDL-C in serum of h PPAR transgenic mice significantly increased 6 weeks after feeding with high fat fodder. No abnormality was found in body weight 4 weeks after gemfibrozil treatment. The biochemical examination showed that the contents of GLU,CHO,TG,and LDL-C in serum significantly increased in mice with high fat fodder compared with those of control mice. The contents of CHO,TG and LDL-C significantly decreased and the content of HDL-C significantly increased in gemfibrozil group compared with those of high fat fodder alone group. No abnormality was found for variables of liver and kidney function. The tissue distribution results revealed that human PPAR gene was expressed at higher level in heart,liver and kidney in human PPAR transgenic mice. Conclusion： h PPARα transgenic mice can be served as a useful model for preclinical pharmacodynamic evaluation for PP drugs.