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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 liver injury induced by antituberculosis drugs combined with simvastatin and the possible mechanism of liver injury. Methods: 80 SD rats of 8 weeks old with SPF grade were divided into 4 groups: control group (blank), simvastatin group, isoniazid + rifampicin + pyrazinamide (HRZ) group and the combination group (simvastatin + HRZ); according to the dose of human-mouse drug, the rats were given the corresponding drugs by intragastric administration, rats were killed at 10, 35 and 55 d after administration, Before sacrifice, the indexes of hepatic function such as total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT) (ALP). The immunohistochemical staining of CYP3A4 and CYP2E1 was performed to observe the protein expression of CYP3A4 and CYP2E1 in the liver. Finally, the liver tissues were sectioned and the hepatocyte sub-microstructure and organelle were observed under different magnification electron microscope. The damage situation. Results: The serum TBIL, DBIL and IBIL in the combination group and the simvastatin group were significantly different from those in the control group on day 10, day 35 and day 55 (P <0.05) Immunohistochemical staining of CYP3A4 and CYP2E1 showed positive expression at different time points after treatment, but less in control group and simvastatin group. Sub-microscopic observation of hepatocytes revealed the proliferation of smooth endoplasmic reticulum, swelling of mitochondria, Drop accumulation, bile duct obstruction. Conclusion: Combined use of antituberculosis drugs and simvastatin aggravates the liver injury in rats. With the extension of time, the liver injury is further aggravated. Cholestatic liver injury is predominant, especially in rats. It is speculated that aggravation of liver injury may be associated with drug Combined use of CYP3A4 and CYP2E1 induced expression to speed up the production of toxic substances and some drugs hinder bilirubin, bile acid excretion.