PUBLICATION
L-FABP-deficiency provoked oxidative stress, inflammation and apoptosis-mediated hepatotoxicity induced by pyrazinamide on zebrafish larvae
- Authors
- Zhang, Y., Liu, K., Hassan, H.M., Guo, H., Ding, P., Han, L., He, Q., Chen, W., Hsiao, C.D., Zhang, L., Jiang, Z.
- ID
- ZDB-PUB-161007-26
- Date
- 2016
- Source
- Antimicrobial Agents and Chemotherapy 60(12): 7347-7356 (Journal)
- Registered Authors
- Hsiao, Chung-Der
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Antitubercular Agents/adverse effects
- Antitubercular Agents/pharmacology*
- Apoptosis/drug effects*
- Fatty Acid-Binding Proteins/metabolism*
- Green Fluorescent Proteins/genetics
- Hepatitis/pathology*
- Inflammation
- Larva/drug effects*
- Liver/drug effects
- Oxidative Stress
- PPAR alpha/metabolism
- Pyrazinamide/adverse effects
- Pyrazinamide/pharmacology*
- Reactive Oxygen Species/metabolism
- Transaminases/metabolism
- Transforming Growth Factor beta/biosynthesis
- Tumor Necrosis Factor-alpha/biosynthesis
- Zebrafish/genetics
- Zebrafish/physiology*
- PubMed
- 27697757 Full text @ Antimicrob. Agents Chemother.
Citation
Zhang, Y., Liu, K., Hassan, H.M., Guo, H., Ding, P., Han, L., He, Q., Chen, W., Hsiao, C.D., Zhang, L., Jiang, Z. (2016) L-FABP-deficiency provoked oxidative stress, inflammation and apoptosis-mediated hepatotoxicity induced by pyrazinamide on zebrafish larvae. Antimicrobial Agents and Chemotherapy. 60(12):7347-7356.
Abstract
Pyrazinamide (PZA) is an essential antitubercular drug, but still little is known about its hepatotoxicity potential. This study examined the effects of PZA exposure on zebrafish (Danio rerio) larvae and the mechanisms underlying its hepatotoxicity. The transgenic line of zebrafish larvae that expressed enhanced green fluorescent protein (EGFP) in the liver were incubated with 1, 2.5 and 5 mM of PZA from 72 hours post fertilization (hpf). Different endpoints such as mortality, morphology changes in size and shape of the liver, histological changes, transaminase analysis and apoptosis, markers of oxidative and genetic damage, as well as certain genes expression were selected to evaluate PZA-induced hepatotoxicity. Our results confirm the manner of PZA dose-dependent hepatotoxicity. PZA was found to induce marked injury on zebrafish larvae such as liver atrophy, transaminase elevation, oxidative stress and hepatocytes apoptosis. To further understand the mechanism behind PZA-induced hepatotoxicity, gene expression changes were determined in zebrafish larvae exposed to PZA for 72 hours post exposure (hpe). The results of this study demonstrated that PZA decreased liver fatty acid binding protein (L-FABP) expression and its target gene peroxisome proliferator activated receptor α (PPAR-α), and provoked more severe oxidative stress and hepatitis via up-regulation of inflammatory cytokines such as tumor necrosis factor α (TNF-α) and transforming growth factor β (TGF-β). These findings suggest that L-FABP-mediated PPAR-α down regulation would appear to be a hepatotoxic response resulting from zebrafish larvae liver cell apoptosis, and L-FABP can be used as a biomarker for early detection of PZA-induced liver damage in zebrafish larvae.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping