Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Sci Rep. 2016 Sep 14;6:33072. doi: 10.1038/srep33072.
Liver injury is a common adverse effect of atorvastatin. This study aimed to investigate atorvastatin-induced hepatotoxicity in diabetic rats induced by high-fat diet combined with streptozotocin. The results showed that 40 mg/kg atorvastatin was lethal to diabetic rats, whose mean survival time was 6.2 days. Severe liver injury also occurred in diabetic rats treated with 10 mg/kg and 20 mg/kg atorvastatin. The in vitro results indicated that atorvastatin cytotoxicity in hepatocytes of diabetic rats was more severe than normal and high-fat diet feeding rats. Expressions and activities of hepatic Cyp3a and SLCO1B1 were increased in diabetic rats, which were highly correlated with hepatotoxicity. Antioxidants (glutathione and N-Acetylcysteine), Cyp3a inhibitor ketoconazole and SLCO1B1 inhibitor gemfibrozil suppressed cytotoxicity and ROS formation in primary hepatocytes of diabetic rats. In HepG2 cells, up-regulations of CYP3A4 and SLCO1B1 potentiated hepatotoxicity and ROS generation, whereas knockdowns of CYP3A4 and SLCO1B1 as well as CYP3A4/SLCO1B1 inhibitions showed the opposite effects. Phenobarbital pretreatment was used to induce hepatic Cyp3a and SLCO1B1 in rats. Phenobarbital aggravated atorvastatin-induced hepatotoxicity, while decreased plasma exposure of atorvastatin. All these findings demonstrated that the upregulations of hepatic Cyp3a and SLCO1B1 in diabetic rats potentiated atorvastatin-induced hepatotoxicity via increasing ROS formation.
肝损伤是阿托伐他汀的常见不良反应。本研究旨在探讨高脂饮食联合链脲佐菌素诱导的糖尿病大鼠中阿托伐他汀诱导的肝毒性。结果表明，40mg/kg 阿托伐他汀可使糖尿病大鼠致死，其平均存活时间为 6.2 天。10mg/kg 和 20mg/kg 阿托伐他汀治疗的糖尿病大鼠也发生严重肝损伤。体外结果表明，糖尿病大鼠肝细胞中阿托伐他汀的细胞毒性比正常和高脂饮食喂养的大鼠更为严重。糖尿病大鼠肝 CYP3A 和 SLCO1B1 的表达和活性增加，与肝毒性高度相关。抗氧化剂（谷胱甘肽和 N-乙酰半胱氨酸）、CYP3A 抑制剂酮康唑和 SLCO1B1 抑制剂吉非罗齐抑制了糖尿病大鼠原代肝细胞的细胞毒性和 ROS 形成。在 HepG2 细胞中，CYP3A4 和 SLCO1B1 的上调增强了肝毒性和 ROS 的产生，而 CYP3A4 和 SLCO1B1 的敲低以及 CYP3A4/SLCO1B1 的抑制则产生相反的效果。用苯巴比妥预处理大鼠诱导肝 CYP3A 和 SLCO1B1。苯巴比妥加重了阿托伐他汀诱导的肝毒性，同时降低了阿托伐他汀的血浆暴露量。所有这些发现表明，糖尿病大鼠肝 CYP3A 和 SLCO1B1 的上调通过增加 ROS 的形成增强了阿托伐他汀诱导的肝毒性。
