洛伐他汀联合异烟肼、利福平、吡嗪酰胺致大鼠肝损伤的实验研究

Experimental study of liver injury caused by lovastatin combined with isoniazid,rifampicin and pyrazinamide in rats

目的探讨洛伐他汀联合异烟肼(H)、利福平(R)、吡嗪酰胺(Z)(联用简称为HRZ)致大鼠肝损伤的特点。方法 SPF级8周龄SD大鼠80只,雌雄各半,采用随机数字表法随机分为四组:空白对照组、洛伐他汀组、HRZ组、洛伐他汀+HRZ组,按人-鼠间药物剂量换算,分别给予相应药物灌胃,于10、35、55 d分别处死大鼠,采集标本行肝功能生化指标、肝病理学检测及电镜观察。结果在给药10、35、55 d时,与空白对照组比较,洛伐他汀+HRZ组肝功能生化指标均明显升高,总胆红素(TBil)、直接胆红素(DBil)、间接胆红素(IBil)升高,差异有统计学意义,而天冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)、碱性磷酸酶(ALP)升高,差异无统计学意义,且随着给药时间点延长,洛伐他汀+HRZ组肝损伤并未呈进行性增加;与洛伐他汀组、HRZ组两两比较时,仅AST在给药55 d时洛伐他汀组与HRZ组比较差异有统计学意义,其他各组在各时间点两两比较均差异无统计学意义;以上结果与病理、电镜观察结果一致。结论洛伐他汀联合HRZ后短时间内即可能出现肝损伤,以胆汁淤积型肝损伤为主;且随着给药时间延长,洛伐他汀联合HRZ所致肝损伤可能存在适应性现象,联合组并未比洛伐他汀单用或HRZ单用更容易导致肝损伤。

ObjectiveTo investigate the characteristics of liver injury caused by lovastatin combined with isoniazid(HRZ)in rats.MethodsEighty SD rats were assigned into four groups by using a random number table:blank control group,lovastatin group,HRZ group,lovastatin+HRZ group.Half of the rats were male,and half were female.According to the drug dose conversion between human and mouse,the rats were given the corresponding intragastric drug administration respectively.The rats were killed at the end of10days,35days and55days respectively.The liver biochemical indicators,liver pathological examination and electron microscopic observation were detected by the collection of specimens.ResultsCompared with the blank control group,the liver biochemical indicators of the rats in the lovastatin+HRZ group were significantly higher than those in the control group at10days,35days and55days.The differences of total bilirubin(TBil),direct bilirubin(DBil)and indirect bilirubin(IBil)were statistically significant.The differences in AST,ALT and ALP were not statistically significant.And with the prolongation of administration time,the liver injury in lovastatin+HRZ group did not show progressive increase.By pairwise comparison with lovastatin group and HRZ group,there were no significant differences between the groups at each time point,except for the statistically significant difference in AST at55days between lovastatin group and HRZ group.The above results were consistent with the pathological and electron microscopy results.ConclusionsThe liverinjury may occur in a short time when lovastatin was used with HRZ,and the liver injury was caused mainly by cholestasis.However,with the extension of the time point,the liver injury may be adaptive.Compared with lovastatin alone or HRZ alone,the joint group did not lead to liver injury more easily.