Inhibition of mitochondrial complex I by rotenone protects against acetaminophen-induced liver injury

American Journal of Translational Research

Peipei Wang¹  Hu Hua²  Jiaqi Liu³  Xuhua Ge⁴ 

[1]Department of Emergency, Childrens Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, P. R. China

[2]Department of Nephrology, Childrens Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, P. R. China

[3]Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, P. R. China

[4]Nanjing Key Laboratory of Pediatrics, Childrens Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, P. R. China

关键词: Rotenone;    acetaminophen;    hepatotoxicity;    mitochondria;    inflammation;   

DOI  :  

学科分类：医学（综合）

来源: e-Century Publishing Corporation

【 摘 要 】

Acetaminophen (APAP) is widely used as an antipyretic analgesic in clinic. However, overdose-related severe liver injury is a major concern of this drug. Recently, accumulating evidence indicated an important role of mitochondrial abnormality in the pathogenesis of APAP hepatoxicity. Thus, the present investigation was undertaken to evaluate the effect of mitochondrial complex I inhibition by rotenone on APAP hepatoxicity. In this study, male BALB/c mice were pretreated with 250 ppm of rotenone in food for 3 days, then the animals were intraperitoneally injected with 300 mg/kg APAP. After 24 h APAP administration, animals developed severe liver injury as shown by the remarkable elevation of ALT and AST and hepatic centrilobular necrosis in line with the reduced liver GSH content. Strikingly, rotenone treatment markedly attenuated liver injury as shown by the improved liver enzyme release and liver morphology and enhanced liver GSH content. Meanwhile, rotenone ameliorated mitochondrial abnormality, inflammatory response and oxidative stress. Moreover, the downregulation of NOX4, a documented protector against APAP hepatotoxicity, was significantly restored by rotenone. However, mitochondrial complex III inhibitor AZOX failed to protect liver against APAP-induced injury. Together, these results suggested that inhibition of mitochondrial complex I but not mitochondrial complex III played a potent role in protecting against APAP hepatotoxicity.

【 授权许可】

CC BY-NC