PPARα转基因小鼠在药物毒性评价中的应用

Application of PPARα transgenic mice in the evaluation of drug toxicity

目的研究PPARα转基因小鼠在评价PPARα激动剂类药物毒性时,是否比传统动物更敏感。方法8周龄PPARα转基因小鼠(Tg)和C57BL/6J小鼠(WT),雌雄各半,分别随机分成3组,氯贝丁酯高剂量组(400 mg/kg)、氯贝丁酯低剂量组(300 mg/kg)、溶媒对照组(10%羧甲基纤维素钠)。连续灌胃一个月,给药结束后检测血生化指标、心肝肾脏器系数及病理改变,并观察动物的一般生长情况。结果 1血生化:Tg♂高、低剂量组肌酐(CREA)、天门冬氨酸氨基转移酶(AST)分别显著高于各对应的野生型对照组(P<0.01,P<0.05)。2脏器系数:Tg高、低剂量组肾脏系数与Tg溶媒对照组比较均有显著增加(P<0.01,P<0.05)。3组织病理:Tg各剂量组肝脏、肾脏病理损伤较WT各剂量组更严重。结论 PPARα转基因小鼠评价PPARα激动剂药物肝脏毒性和肾脏毒性时比常规C57BL/6J野生小鼠更敏感,是一个新的动物模型。

Objective To explore whether PPARα transgenic mice are more sensitive animal models in the evaluation of toxicity of PPARα agonists. Methods Twenty-eight 8-week old PPARα transgenic mice( Tg) and 28 C57 BL /6J mice( WT) with half males and half females were randomly divided into high dose group( 400 mg / kg of clofibrate),low dose group( 30 mg / kg of clofibrate) and solvent control group( 10% sodium carboxymethyl cellulose). The time of gavage administration lasted 28 days. The blood biochemistry,organ coefficient and pathological changes of the heart,liver,kidney were tested after the drug administration. The growth of mice was also recorded. Results 1Blood biochemistry: Compared with the WT male administration group,in the Tg male administration group,the levels of blood creatinine( CREA)and aspartate aminotransferase( AST) were markedly increased( P < 0. 01,P < 0. 05). 2 Organ coefficient: Compared with the Tg control group,the kidney coefficients of Tg administration group were significantly increased( P < 0. 01,P <0. 05). 3Histopathology: Compared with the WT administration group,the pathological damages of liver and kidney were more serious in the Tg administration group. Conclusions Compared with C57 BL /6J mouse,PPARα transgenic mice are more sensitive in evaluation of hepatotoxicity and nephrotoxicity of PPARα agonists. It is a new animal model.