PUBLICATION
Mechanism of isoniazid-induced hepatotoxicity in zebrafish larvae: Activation of ROS-mediated ERS, apoptosis and the Nrf2 pathway
- Authors
- Jia, Z.L., Cen, J., Wang, J.B., Zhang, F., Xia, Q., Wang, X., Chen, X.Q., Wang, R.C., Hsiao, C.D., Liu, K.C., Zhang, Y.
- ID
- ZDB-PUB-190422-22
- Date
- 2019
- Source
- Chemosphere 227: 541-550 (Journal)
- Registered Authors
- Hsiao, Chung-Der
- Keywords
- Apoptosis, ERS, Hepatotoxicity, Isoniazid, Nrf2, Zebrafish
- MeSH Terms
-
- Animals
- Antioxidants/metabolism
- Antitubercular Agents/toxicity
- Chemical and Drug Induced Liver Injury/etiology*
- Chemical and Drug Induced Liver Injury/genetics
- Chemical and Drug Induced Liver Injury/pathology
- Endoplasmic Reticulum Stress/drug effects*
- Endoplasmic Reticulum Stress/genetics
- Gene Expression Regulation
- Isoniazid/toxicity*
- Larva/drug effects
- Larva/metabolism*
- NF-E2-Related Factor 2/metabolism
- Oxidative Stress/physiology
- Reactive Oxygen Species*/adverse effects
- Signal Transduction
- Zebrafish/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 31004821 Full text @ Chemosphere
Citation
Jia, Z.L., Cen, J., Wang, J.B., Zhang, F., Xia, Q., Wang, X., Chen, X.Q., Wang, R.C., Hsiao, C.D., Liu, K.C., Zhang, Y. (2019) Mechanism of isoniazid-induced hepatotoxicity in zebrafish larvae: Activation of ROS-mediated ERS, apoptosis and the Nrf2 pathway. Chemosphere. 227:541-550.
Abstract
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 pparα 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping