Chlorpromazine protects against acetaminophen-induced liver injury in mice by modulating autophagy and c-Jun N-terminal kinase activation  

作　　者：Yuan Li Hong-Min Ni Hartmut Jaeschke Wen-Xing Ding 

机构地区：[1]Department of Pharmacology,Toxicology and Therapeutics,The University of Kansas Medical Center,Kansas City,KS,USA

出　　处：《Liver Research》2019年第1期65-74,共10页肝脏研究（英文）

基　　金：This research was funded by the USA NIH R01 AA 020518,R01 DK 102142,U01 AA 024733,P20 GM 103549(COBRE),and P30 GM 118247(COBRE)。

摘　　要：Background and aim:Overdose of acetaminophen(APAP)leads to liver injury,which is one of the most common causes of liver failure in the United States.We previously demonstrated that pharmacological activation of autophagy protects against APAP-induced liver injury in mice via removal of damaged mitochondria and APAP-adducts(APAP-ADs).Using an image-based high-throughput screening for autophagy modulators,we recently identified that chlorpromazine(CPZ),a dopamine inhibitor used for anti-schizophrenia,is a potent autophagy inducer in vitro.Therefore,the aim of the present study is to determine whether CPZ may protect against APAP-induced liver injury via inducing autophagy.Methods:Wild type C57BL/6J mice were injected with APAP to induce liver injury.CPZ was administrated either at the same time with APAP(co-treatment)or 2 h later after APAP administration(post-treat-ment).Hemotoxyline and eosin(H&E)staining of liver histology,terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling(TUNEL)staining of necrotic cell death as well as serum levels of alanine aminotransferase(ALT)were used to monitor liver injury.Results:We found that CPZ markedly protected against APAP-induced liver injury as demonstrated by decreased serum levels of ALT,liver necrotic areas as well as TUNEL-positive cells in mice that were either co-treated or post-treated with CPZ.Mechanistically,we observed that CPZ increased the number of autolysosomes and decreased APAP-induced c-Jun N-terminal kinase activation without affecting the metabolic activation of APAP.Pharmacological inhibition of autophagy by chloroquine partially weak-ened the protective effects of CPZ against APAP-induced liver injury.Conclusions:Our results indicate that CPZ ameliorates APAP-induced liver injury partially via activating hepatic autophagy and inhibiting JNK activation.

关 键 词：Chlorpromazine(CPZ) Acetaminophen(APAP) Drug-induced liver injury NECROSIS Autolysosome HEPATOTOXICITY Glutathione(GSH) Oxidant stress 

分 类 号：R57[医药卫生—消化系统]