高剂量阿托伐他汀对肝损伤小鼠胆汁酸代谢的影响及其机制

INFLUENCE OF HIGH-DOSE ATORVASTATIN ON BILE ACID METABOLISM IN MICE WITH LIVER INJURY AND RELATED MECHANISM

目的探讨高剂量阿托伐他汀对肝损伤小鼠胆汁酸代谢的影响及其机制。方法选取SPF级雄性C57BL/6小鼠40只,随机分为生理盐水组(A组)及阿托伐他汀低、中、高剂量组(B、C、D组),每组10只。分别用生理盐水及10、20、30 mg/kg阿托伐他汀灌胃30 d后,取各组小鼠眼眶血,比较各组小鼠血清总胆汁酸(TBA)、内毒素(ET)、天冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)表达水平;取各组小鼠部分肝脏组织,HE染色后观察肝脏组织病理变化情况,并采用PCR方法检测肝组织中胆汁酸代谢相关基因尼酯衍生物X受体(FXR)基因及多药耐药相关蛋白2(MRP2)基因的表达。结果D组小鼠肝组织可见轻微肿大样改变、散在炎症细胞浸润和羽毛样变性情况。与其他组相比,D组小鼠血清TBA、ET、AST、ALT水平均显著升高(P<0.05);与A组相比,C、D组小鼠肝组织中FXR、MRP2基因相对表达量显著降低(P<0.05);与B组相比,D组小鼠肝组织中FXR、MRP2基因相对表达量显著降低(P<0.05)。结论阿托伐他汀可诱导小鼠血清TBA水平升高,并且导致肝组织中胆汁酸代谢下游相关基因FXR、MRP2表达改变,大剂量给药导致的肝组织胆汁酸代谢异常可能是阿托伐他汀肝脏毒性的主要原因之一。

Objective To investigate the influence of high-dose atorvastatin on bile acid metabolism in mice with liver injury and its mechanism.Methods A total of 40 specific pathogen-free male C57BL/6 mice were randomly divided into normal saline group(group A)and low-,middle-,and high-dose atorvastatin groups(groups B,C,and D,respectively),with 10 mice in each group.After 30 days of intragastric administration of normal saline and atorvastatin at a dose of 10,20,and 30 mg/kg,respectively,orbital blood was collected from the mice in each group,and these groups were compared in terms of the serum levels of total bile acid(TBA),endotoxin(ET),aspartate aminotransferase(AST),and alanine aminotransferase(ALT);after liver tissue samples were collected,HE staining was performed to observe the pathological changes of liver tissue,and PCR was used to measure the mRNA expression levels of the bile acid metabolism-related genes farnesoid X receptor(FXR)and multidrug resis-tance-associated protein 2(MRP 2)in liver tissue.Results The mice in group D had slight swelling,sporadic inflammatory cell infiltration,and feather-like degeneration in liver tissue.Compared with the other groups,group D had significant increases in the serum levels of TBA,ET,AST,and ALT(P<0.05).Compared with group A,groups C and D had significant reductions in the relative mRNA expression levels of FXR and MRP 2 in liver tissue(P<0.05),and compared with group B,group D had significant reductions in the relative mRNA expression levels of FXR and MRP 2 in liver tissue(P<0.05).Conclusion Atorvastatin can induce the increase in serum TBA level in mice and lead to changes in the expression of the downstream FXR and MRP 2 genes associated with bile acid metabolism in liver tissue,and abnormal bile acid metabolism in liver tissue caused by high-dose administration may be one of the main causes of atorvastatin hepatotoxicity.