title: Liver Fatty Acid Binding Protein Deficiency Provokes Oxidative Stress, Inflammation, and Apoptosis-Mediated Hepatotoxicity Induced by Pyrazinamide in Zebrafish Larvae.
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.
authors.affiliation: Biology Institute of Shandong Academy of Sciences, Jinan, People's Republic of China.|Key Laboratory for Drug Screening Technology of Shandong Academy of Sciences, Jinan, People's Republic of China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Biology Institute of Shandong Academy of Sciences, Jinan, People's Republic of China.|Key Laboratory for Drug Screening Technology of Shandong Academy of Sciences, Jinan, People's Republic of China.|Key Laboratory for Biosensor of Shandong Province, Jinan, People's Republic of China.
authors.forename: Kechun
authors.initials: K
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, People's Republic of China.|Department of Pharmacology, Faculty of Pharmacy, University of Gezira, Wad-Medani, Sudan.
authors.forename: Hozeifa M
authors.initials: HM
authors.lastname: Hassan
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Guo
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Ding
authors.affiliation: Biology Institute of Shandong Academy of Sciences, Jinan, People's Republic of China.|Key Laboratory for Drug Screening Technology of Shandong Academy of Sciences, Jinan, People's Republic of China.
authors.forename: Liwen
authors.initials: L
authors.lastname: Han
authors.affiliation: Biology Institute of Shandong Academy of Sciences, Jinan, People's Republic of China.|Key Laboratory for Drug Screening Technology of Shandong Academy of Sciences, Jinan, People's Republic of China.
authors.forename: Qiuxia
authors.initials: Q
authors.lastname: He
authors.affiliation: Biology Institute of Shandong Academy of Sciences, Jinan, People's Republic of China.
authors.forename: Weiyun
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li, Taiwan.
authors.forename: Chung-Der
authors.initials: CD
authors.lastname: Hsiao
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, People's Republic of China.|Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing, People's Republic of China.
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, People's Republic of China beaglejiang@cpu.edu.cn.|Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing, People's Republic of China.
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Jiang
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000995:Antitubercular Agents / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006505:Hepatitis / Q000473:pathology*; D007249:Inflammation; D007814:Larva / Q000187:drug effects*; D008099:Liver / Q000187:drug effects; D018384:Oxidative Stress; D047493:PPAR alpha / Q000378:metabolism; D011718:Pyrazinamide / Q000009:adverse effects / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000637:Transaminases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015027:Zebrafish / Q000235:genetics / Q000502:physiology*
chemical_list: D000995:Antitubercular Agents; D050556:Fatty Acid-Binding Proteins; D047493:PPAR alpha; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D011718:Pyrazinamide; D000637:Transaminases