摘要
目的:研究抗结核药与辛伐他汀联用致肝损伤的特征及发生肝损伤的可能机制。方法:取SPF级8周龄SD大鼠80只,♂♀各半;将其随机分为4组,即对照组(空白)、辛伐他汀组、异烟肼+利福平+吡嗪酰胺(HRZ)组和联用药组(辛伐他汀+HRZ);按人-鼠间药物剂量换算,分别给予大鼠相应药物灌胃给药,于给药后10,35和55 d处死大鼠,处死前取股动脉血检测肝功能各指标如总胆红素(TBIL)、直接胆红素(DBIL)、间接胆红素(IBIL)、谷草转氨酶(AST)、谷丙转氨酶(ALT)和碱性磷酸酶(ALP);制作CYP3A4及CYP2E1免疫组化染色,观察CYP3A4及CYP2E1在肝脏的蛋白表达情况,最后做肝组织切片并于不同倍数电镜下观察肝细胞亚显微结构和细胞器(organelle)的损伤情况。结果:联用药组和辛伐他汀组血清TBIL、DBIL及IBIL在第10天,第35天和第55天时与对照组比较其差异有统计学意义(P<0.05);联用药组、HRZ组CYP3A4和CYP2E1免疫组化在用药后不同时间段均呈现阳性表达物,对照组及辛伐他汀组阳性表达物较少;肝细胞亚显微结构观察示滑面内质网增生、线粒体肿胀、脂滴堆积、胆管阻塞等。结论:抗结核药与辛伐他汀联用加重大鼠肝脏损伤,且随着时间延长,肝损伤进一步加重,以胆汁淤积型肝损伤为主,尤其是♀大鼠;推测肝损伤加重可能与药物联用后诱导CYP3A4及CYP2E1表达,加速毒性物质产生以及部分药物阻碍胆红素、胆汁酸排泄有关。
Objective： To study the characteristics of simvastatin combined with HRZ induced liver injury and the possible mechanism of liver injury. Methods： We randomly divided 80 eight-week-old SD rats into four groups： control group, simvastatin group, HRZ （INH＋RFP＋PZA） group and simvastatin＋HRZ group（half male and female in each group）. Based on the human-mouse drug dose conversion, they were given corresponding drugs by garage. The rats were killed at the 10th day, 20th day and 40th day. Before killed them, we used blood from Femoral artery to detect liver function index： total bilirubin （TBIL）, direct bilirubin （DB1L）, indirect bilirubin （IB/L） and aspartate aminotransferase （AST）, alanine aminotransferase （ALT）, alkaline phosphatase （ALP）; immunohistochemical staining were made to observe the protein expression of CYP3A4 and CYP2EI in liver. Finally, we made liver tissue sections to observe the microscopic structure of liver cells under the Electron microscope of different multiples. Results： There were significant differences of TBIL, DBIL and IBIL when comparing control group with combined therapy group and single drug group in 10th day. 20th day and 40th day. Alter treatment in different time periods, CYP3A4. CYP2E1 imrnunohistochemical showed positive expression in combined therapy group and hrz group, while the control group and simvastatin group positive expression was less. Finally, we observed hyperplasia of smooth endoplasmic reticulum, mitochondria swelling, fat accumulation and bile duct obstruction from the Liver cell sub microstructurc. Conclusion： Sinlvastatin＋ HRZ aggravate liver injury, with the time prolonged, the liver injury was further aggravated. Liver injury is mainly based on cholestasis, especially in female rats. We hypothesized that the liver injury might be associated with the induction of CYP3A4 and CYP2E1 expression after drug combination, and accelerated the production of toxic substances. Furthermore, Some of the drugs that block the bile acid and bilirubin excretion are also one of the reasons.
出处
《抗感染药学》
2016年第4期729-735,共7页
Anti-infection Pharmacy
基金
昆明市卫计委基金课题(编号:20120103)
