PUBLICATION
Hepatotoxicity induced by Isoniazid/Lipopolysaccharide through ERS-, autophagy- and apoptosis pathway in zebrafish
- Authors
- Zhang, Y., Cen, J., Jia, Z., Hsiao, C.D., Xia, Q., Wang, X., Chen, X., Wang, R., Jiang, Z., Zhang, L., Liu, K.
- ID
- ZDB-PUB-190313-2
- Date
- 2019
- Source
- Antimicrobial Agents and Chemotherapy 63(5): (Journal)
- Registered Authors
- Hsiao, Chung-Der
- Keywords
- none
- MeSH Terms
-
- Alanine Transaminase/metabolism
- Animals
- Antitubercular Agents/adverse effects*
- Apoptosis/drug effects
- Aspartate Aminotransferases/metabolism
- Endoplasmic Reticulum Stress/drug effects*
- Female
- Isoniazid/adverse effects*
- Lipopolysaccharides/toxicity*
- Liver/drug effects
- Liver/enzymology
- Male
- Oxidative Stress/drug effects
- Reactive Oxygen Species/metabolism
- Zebrafish
- PubMed
- 30858204 Full text @ Antimicrob. Agents Chemother.
Citation
Zhang, Y., Cen, J., Jia, Z., Hsiao, C.D., Xia, Q., Wang, X., Chen, X., Wang, R., Jiang, Z., Zhang, L., Liu, K. (2019) Hepatotoxicity induced by Isoniazid/Lipopolysaccharide through ERS-, autophagy- and apoptosis pathway in zebrafish. Antimicrobial Agents and Chemotherapy. 63(5):.
Abstract
Isoniazid (INH) is a first-line antituberculosis drug. The incidence of adverse reactions accompanied by inflammation in the liver during drug administration to tuberculosis patients is high and severely affects clinical treatment. To better understanding the mechanism of hepatotoxicity induced by INH under the inflammatory state, we compared the differences in hepatotoxicity from INH between normal and inflammatory zebrafish to elucidate the hepatotoxic mechanism using different endpoints such as mortality, malformation, inflammatory effects, liver morphology, histological changes, transaminase analysis and certain genes expression. The results showed that the toxic effect of INH in inflammatory zebrafish was more obvious than that in normal zebrafish, liver areas were significantly decreased measured by lfabp reporter fluorescence and intensity, and ALT and AST levels were significantly increased. HE staining and electron microscopy showed that hepatocyte injury was more obvious in the inflammatory state. In the inflammatory state, INH significantly increased the expression levels of ERS-related factors (GRP78, ATF6, PERK, IRE1, XBP1s, GRP94, and CHOP), autophagy-related factors (Beclin1, LC3, Atg3, and Atg12), and apoptosis-related factors (Caspase-3, Caspase-8, Caspase-9, Bax, P53, and Cyt) in larvae. Correlational analyses indicated that the transcription levels of the inflammatory factors IL-1b, TNF-β, COX-2, and TNF-β were strongly positively correlated with ALT and AST. Furthermore, ERS inhibitor sodium 4-phenylbutyrate (4-PBA) could ameliorate the hepatotoxicity of INH-LPS in zebrafish larvae. These results indicated that INH hepatotoxicity was enhanced in the inflammatory state. ERS and its mediated autophagy and apoptosis pathways might be involved in INH-induced liver injury promoted by inflammation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping