Oxymatrine ameliorates agomelatine-induced hepatocyte injury through promoting proteasome-mediated CHOP degradation

[Display omitted] The novel antidepressant drug agomelatine has been observed to cause adverse effect of hepatotoxicity in clinical applications. This study was designed to explore protective agents and investigated the underlying mechanism on L02 cells. L02 cells were treated with agomelatine and o...

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Published in:Biomedicine & pharmacotherapy 2019-06, Vol.114, p.108784, Article 108784
Main Authors: Jia, Yina, Long, Sen, Jiang, Nan, Shan, Zhe, Lu, Yingmei, Han, Feng, Yu, Jianqiang, Feng, Lili
Format: Article
Language:English
Subjects:
Acetamides - pharmacology
Agomelatine
Alkaloids - pharmacology
Apoptosis - drug effects
Cell Line
CHOP degradation
ER stress
Hepatocyte injury
Hepatocytes - drug effects
Hepatocytes - metabolism
Humans
Oxymatrine
Proteasome Endopeptidase Complex - drug effects
Proteasome Endopeptidase Complex - metabolism
Protective Agents - pharmacology
Quinolizines - pharmacology
Signal Transduction - drug effects
Transcription Factor CHOP - metabolism
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Summary:[Display omitted] The novel antidepressant drug agomelatine has been observed to cause adverse effect of hepatotoxicity in clinical applications. This study was designed to explore protective agents and investigated the underlying mechanism on L02 cells. L02 cells were treated with agomelatine and oxymatrine (OMT) and cell apoptosis were analyzed through flow cytometric analysis, CCK-8 assay and TUNEL assay. In a separate experiment, the expressions of ER stress-related proteins were determined by western blot. In addition, MG132, chloroquine (CQ) and bafilomycinA1(BafA1) were used to investigate the potential pathway participating in CHOP degradation. OMT significantly rescued agomelatine-induced hepatocyte apoptosis. Agomelatine treatment resulted in accumulation of CHOP protein in L02 cells, and this phenomenon could be significantly reduced by OMT, whereas abolished by MG132 treatment. We have demonstrated for the first time that OMT ameliorates the hepatocyte toxicity induced by agomelatine through decreasing CHOP on protein level. The underlying mechanism was proved to involve the molecular events that OMT promotes CHOP degradation via proteasome pathway. Overall, these results suggest that using OMT in combination with agomelatine may provide a safety strategy for clinical depression treatment.
ISSN:0753-3322
1950-6007
DOI:10.1016/j.biopha.2019.108784