title: Pyrazinamide induced hepatic injury in rats through inhibiting the PPARα pathway.
abstract: Pyrazinamide (PZA) causes serious hepatotoxicity, but little is known about the exact mechanism by which PZA induced liver injury. The peroxisome proliferator-activated receptors alpha (PPARα) is highly expressed in the liver and modulates the intracellular lipidmetabolism. So far, the role of PPARα in the hepatotoxicity of PZA is unknown. In the present study, we described the hepatotoxic effects of PZA and the role of PPARα and its target genes in the downstream pathway including L-Fabp, Lpl, Cpt-1b, Acaa1, Apo-A1 and Me1 in this process. We found PZA induced the liver lipid metabolism disorder and PPARα expressionwas down-regulated which had a significant inverse correlation with liver injury degree. These changeswere ameliorated by fenofibrate, the co-treatment that acts as a PPARα agonist. In contrast, short-termstarvation significantly aggravated the severity of PZA-induced liver injury. In conclusion, this study demonstrated the critical role played by PPARα in PZA-induced hepatotoxicity and provided a better understanding of the molecular mechanisms underlying PZA-induced liver injury. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.|Biology Institute of Shandong Academy of Sciences, 19 Keyuan Road, Lixia District, Jinan, 250014, Shandong Province, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Guo
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, 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, 210009, China.
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Ding
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Yijing
authors.initials: Y
authors.lastname: Su
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Song
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.|Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.|Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China. lyzhang@cpu.edu.cn.|Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China. lyzhang@cpu.edu.cn.|Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China. lyzhang@cpu.edu.cn.
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China. beaglejiang@cpu.edu.cn.|Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing, 210009, China. beaglejiang@cpu.edu.cn.
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D015536:Down-Regulation; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D047493:PPAR alpha / Q000037:antagonists & inhibitors* / Q000235:genetics; D011718:Pyrazinamide / Q000633:toxicity*; D017208:Rats, Wistar
chemical_list: D000995:Antitubercular Agents; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D011718:Pyrazinamide; D011345:Fenofibrate
keywords: PPARα; PZA; fenofibrate; hepatotoxicity; lipid metabolic disorder; starvation