4.7 Article

Mechanism of isoniazid-induced hepatotoxicity in zebrafish larvae: Activation of ROS-mediated ERS, apoptosis and the Nrf2 pathway

期刊

CHEMOSPHERE
卷 227, 期 -, 页码 541-550

出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.chemosphere.2019.04.026

关键词

Isoniazid; Zebrafish; Hepatotoxicity; ERS; Apoptosis; Nrf2

资金

  1. National Natural Science Foundation of China [81703624, 31800287]
  2. Training plan for young backbone teachers in Colleges and universities in Henan
  3. Natural Science Foundation of Shandong Province [ZR2015YL010, ZR2016YL009]
  4. Key Research & Development Plan of Shandong Province [2017YYSP032]

向作者/读者索取更多资源

Isoniazid (INH) is a first-line anti-tuberculosis drug. INH has been detected in surface waters which may create a risk to aquatic organisms. In this study, the hepatotoxicity of INH was elucidated using zebrafish. The liver morphology, transaminase level, redox-related enzyme activity, reactive oxygen species (ROS) content and mRNA levels of liver injury-related genes were measured. The results showed that INH (4, 6 mM) significantly caused liver atrophy and increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in zebrafish. INH (6 mM) led to decreased catalase (CAT) activity, glutathione peroxidase (GPx) activity and glutathione (GSH) content but increased ROS and malondialdehyde (MDA) levels. Moreover, INH (6 mM) decreased expression levels of miR-122 and ppar alpha but increased mRNA levels of ap-1 and c-jun. Furthermore, mRNA levels of factors related to endoplasmic reticulum stress (ERS) (grp78, atf6, perk, ire1, xbp1s and chop), apoptosis (bax, cyt, caspase-3, caspase-8 and caspase-9) and the Nrf2 signalling pathway (nrf2, ho-1, nqo1, gclm and gclc) were significantly upregulated. INH may act on hepatotoxicity in zebrafish by increasing ROS content, which weakens the antioxidant capacity, leading to ERS, cell apoptosis and liver injury. In addition, the Nrf2 signalling pathway is activated as a stress compensation mechanism during INH-induced liver injury, but it is not sufficient to counteract INH-induced hepatotoxicity. (C) 2019 Elsevier Ltd. All rights reserved.

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