Glutaredoxin-1 alleviates acetaminophen-induced liver injury by decreasing its toxic metabolites  

作　　者：Ying Xu Yan Xia Qinhui Liu Xiandan Jing Qin Tang Jinhang Zhang Qingyi Jia Zijing Zhang Jiahui Li Jiahao Chen Yimin Xiong Yanping Li Jinhan He 

机构地区：[1]Department of Pharmacy,Institute of Metabolic Diseases and Pharmacotherapy,West China Hospital,Sichuan University,Chengdu,610041,China

出　　处：《Journal of Pharmaceutical Analysis》2023年第12期1548-1561,共14页药物分析学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Grant Nos.:82025007,81930020,and 82170874);China Postdoctoral Science Foundation(Grant No.:2022M710099).

摘　　要：Excessive N-acetyl-p-benzoquinone imine(NAPQI)formation is a starting event that triggers oxidative stress and subsequent hepatocyte necrosis in acetaminophen(APAP)overdose caused acute liver failure(ALF).S-glutathionylation is a reversible redox post-translational modification and a prospective mechanism of APAP hepatotoxicity.Glutaredoxin-1(Glrx1),a glutathione-specific thioltransferase,is a primary enzyme to catalyze deglutathionylation.The objective of this study was to explored whether and how Glrx1 is associated with the development of ALF induced by APAP.The Glrx1 knockout mice(Glrx1^(-/-))and liver-specific overexpression of Glrx1(AAV8-Glrx1)mice were produced and underwent APAPinduced ALF.Pirfenidone(PFD),a potential inducer of Glrx1,was administrated preceding APAP to assess its protective effects.Our results revealed that the hepatic total protein S-glutathionylation(PSSG)increased and the Glrx1 level reduced in mice after APAP toxicity.Glrx1^(-/-)mice were more sensitive to APAP overdose,with higher oxidative stress and more toxic metabolites of APAP.This was attributed to Glrx1 deficiency increasing the total hepatic PSSG and the S-glutathionylation of cytochrome p4503a11(Cyp3a11),which likely increased the activity of Cyp3a11.Conversely,AAV8-Glrx1 mice were defended against liver damage caused by APAP overdose by inhibiting the S-glutathionylation and activity of Cyp3a11,which reduced the toxic metabolites of APAP and oxidative stress.PFD precede administration upregulated Glrx1 expression and alleviated APAP-induced ALF by decreasing oxidative stress.We have identified the function of Glrx1 mediated PSSG in liver injury caused by APAP overdose.Increasing Glrx1 expression may be investigated for the medical treatment of APAP-caused hepatic injury.

关 键 词：Glutaredoxin-1 S-GLUTATHIONYLATION ACETAMINOPHEN Toxic metabolites Cyp3a11 

分 类 号：R575[医药卫生—消化系统] R96[医药卫生—内科学]