Oxymatrine Causes Hepatotoxicity by Promoting the Phosphorylation of JNK and Induction of Endoplasmic Reticulum Stress Mediated by ROS in LO2 Cells

Li-li Gu; Zhe-lun Shen; Yang-Lei Li; Yi-Qi Bao; Hong Lu

doi:10.14348/molcells.2018.2180

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자료유형: 학술저널

저자정보: Li-li Gu (Zhejiang Chinese Medical University) Zhe-lun Shen (Zhejiang Chinese Medical University) Yang-Lei Li (Zhejiang Chinese Medical University) Yi-Qi Bao (Zhejiang Chinese Medical University) Hong Lu (Zhejiang Chinese Medical University)

저널정보: 한국분자세포생물학회 Molecules and Cells Molecules and Cells 제41권 제5호

발행연도: 2018.3

수록면: 401 - 412 (12page)

DOI: 10.14348/molcells.2018.2180

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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 was 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, and 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, and PERK). Pre-treatment with Z-VAD-fmk, 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, OMT-induced injury in L02 cells was related to ROS mediated p-JNK and ER stress induction. Antioxidant, by inhibition of p-JNK or ER stress, may be a feasible method to alleviate OMT-induced liver injury.

#apoptosis #ER stress #hepatotoxicity #JNK #L02 cell #oxymatrine

참고문헌 (43)

참고문헌 신청

Ashraf, N.U. / 2015 / Endoplasmic reticulum stress and Oxidative stress in the pathogenesis of Non-alcoholic fatty liver disease / Free Radic Res. 49:1405~1418

Bertolotti, A. / 2000 / Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response / Nat. Cell Biol. 2:326~332

Borkham-Kamphorst, E. / 2016 / CCN1/CYR61 overexpression in hepatic stellate cells induces ER stress-related apoptosis / Cell. Signal. 28:34~42

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Chughlay, M.F. / 2016 / N-acetylcysteine for non-paracetamol drug- induced liver injury: a systematic review / Br. J. Clin. Pharmacol. 81:1021~1029

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