In:
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 60, No. 12 ( 2016-12), p. 7347-7356
Abstract:
Pyrazinamide (PZA) is an essential antitubercular drug, but little is still known about its hepatotoxicity potential. This study examined the effects of PZA exposure on zebrafish ( Danio rerio ) larvae and the mechanisms underlying its hepatotoxicity. A transgenic line of zebrafish larvae that expressed enhanced green fluorescent protein (EGFP) in the liver was incubated with 1, 2.5, and 5 mM PZA from 72 h postfertilization (hpf). Different endpoints such as mortality, morphology changes in the size and shape of the liver, histological changes, transaminase analysis and apoptosis, markers of oxidative and genetic damage, as well as the expression of certain genes were selected to evaluate PZA-induced hepatotoxicity. Our results confirm the manner of PZA dose-dependent hepatotoxicity. PZA was found to induce marked injury in zebrafish larvae, such as liver atrophy, elevations of transaminase levels, oxidative stress, and hepatocyte apoptosis. To further understand the mechanism behind PZA-induced hepatotoxicity, changes in gene expression levels in zebrafish larvae exposed to PZA for 72 h postexposure (hpe) were determined. The results of this study demonstrated that PZA decreased the expression levels of liver fatty acid binding protein (L-FABP) and its target gene, peroxisome proliferator-activated receptor α (PPAR-α), and provoked more severe oxidative stress and hepatitis via the upregulation of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and transforming growth factor β (TGF-β). These findings suggest that L-FABP-mediated PPAR-α downregulation appears to be a hepatotoxic response resulting from zebrafish larva liver cell apoptosis, and L-FABP can be used as a biomarker for the early detection of PZA-induced liver damage in zebrafish larvae.
Type of Medium:
Online Resource
ISSN:
0066-4804
,
1098-6596
DOI:
10.1128/AAC.01693-16
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2016
detail.hit.zdb_id:
1496156-8
detail.hit.zdb_id:
217602-6
SSG:
12
SSG:
15,3
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