The enhanced atorvastatin hepatotoxicity in diabetic rats was partly attributed to the upregulated hepatic Cyp3a and SLCO1B1.
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.
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Nan
N
Shu
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Mengyue
M
Hu
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Zhaoli
Z
Ling
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Peihua
P
Liu
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Fan
F
Wang
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Ping
P
Xu
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Zeyu
Z
Zhong
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Binbin
B
Sun
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Mian
M
Zhang
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Feng
F
Li
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Qiushi
Q
Xie
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Xiaodong
X
Liu
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Li
L
Liu
D000818:Animals; D000069059:Atorvastatin / Q000009:adverse effects* / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D027381:Liver-Specific Organic Anion Transporter 1 / Q000096:biosynthesis*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
D027381:Liver-Specific Organic Anion Transporter 1; D017382:Reactive Oxygen Species; D000069059:Atorvastatin; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A