Chlorpromazine protects against acetaminophen-induced liver injury in mice by modulating autophagy and c-Jun N-terminal kinase activation
10.1016/j.livres.2019.01.004
- Author:
Li YUAN
1
;
Ni HONG-MIN
;
Jaeschke HARTMUT
;
Ding WEN-XING
Author Information
1. Department of Pharmacology
- Keywords:
Chlorpromazine(CPZ);
Acetaminophen(APAP);
Drug-induced liver injury;
Necrosis;
Autolysosome;
Hepatotoxicity;
Glutathione(GSH);
Oxidant stress
- From:
Liver Research
2019;3(1):65-74
- CountryChina
- Language:Chinese
-
Abstract:
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.
