Oxymatrine Causes Hepatotoxicity by Promoting the Phosphorylation of JNK and Induction of Endoplasmic Reticulum Stress Mediated by ROS in LO2 Cells
Li-li Gu1,2, Zhe-lun Shen1,2, Yang-Lei Li1, Yi-Qi Bao1, and Hong Lu1,*
1College of Pharmaceutical science, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China, 2These
authors contributed equally to this work.
*Correspondence: luhong@zcmu.edu.cn
Received August 28, 2017; Revised December 23, 2017; Accepted January 16, 2018.; Published online May 10, 2018.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

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ABSTRACT
Oxymatrine (OMT) often used in treatment for chronic hepatitis B virus infection in clinic. However, OMT–induced liver injury has been reported. In this study, we aim to investigate the possible mechanism of OMT-induced hepatotoxicity in human normal liver cells (L02). Exposed cells to OMT, the cell viability were decreased and apoptosis rate increased, the intracellular markers of oxidative stress were changed. Simultaneously, OMT altered apoptotic related proteins levels, including Bcl-2, Bax and pro-caspase-8/-9/-3. In addition, OMT enhanced the protein levels of endoplasmic reticulum (ER) stress makers (GRP78/Bip, CHOP, cleaved-Caspase-4) and phosphorylation of c-Jun N-terminal kinase (p-JNK), as well as the mRNA levels of GRP78/Bip, CHOP, Caspase-4 and ER stress sensors (IREI, ATF6, PERK). Pre-treatment with Z-VADfmk, JNK inhibitor SP600125 and N-acetyl-l-cysteine (NAC), a ROS scavenger partly improved the survival rates and restored OMT-induced cellular damage, and reduced caspase-3 cleavage. SP600125 or NAC reduced OMT-induced p-JNK and NAC significantly lowered caspase-4. Furthermore, 4-PBA, the ER stress inhibitor, weakened inhibitory effect of OMT on cells, on the contrary, TM worsen. 4-PBA also reduced the levels of p-JNK and cleaved-caspase-3 proteins. Therefore, OMTinduced injury in L02 cells was related to ROS mediated p-JNK and ER stress induction, Antioxidant, inhibition of p-JNK or ER stress may be a feasible method to alleviate OMT-induced liver injury.
Keywords:
apoptosis, ER stress, hepatotoxicity, JNK, L02 cell, oxymatrine


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30 April 2018 Volume 41,
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