title: Protective effect of rosiglitazone against acetaminophen-induced acute liver injury is associated with down-regulation of hepatic NADPH oxidases.
abstract: The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism. The aim of the present study was to investigate the effects of rosiglitazone (RSG), a synthetic PPAR-γ agonist, on acetaminophen (APAP)-induced acute liver injury. Male CD-1 mice were injected with APAP (300mg/kg). Some mice were pretreated with RSG (20mg/kg) 48, 24 and 1h before APAP injection. As expected, RSG pretreatment alleviated APAP-induced acute liver injury. Moreover, RSG pretreatment attenuated APAP-induced hepatic cell death and improved the survival. Although it did not affect hepatic cytochrome P450 (CYP)2E1 expression, RSG pretreatment attenuated reduction of hepatic glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Rd) and glutathione S-transferase (GST) activities, inhibited upregulation of hepatic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-2 and NOX-4, and alleviated hepatic GSH depletion during APAP-induced acute liver injury. In addition, RSG pretreatment suppressed activation of hepatic nuclear factor kappa B (NF-κB) and extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling during APAP-induced acute liver injury. These results provide a novel mechanistic explanation for RSG-mediated protection against APAP-induced acute liver injury. The present results suggest that synthetic PPAR-γ agonists might be effective agents for preventing the progression of APAP-induced acute liver injury.
authors.affiliation: First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
authors.forename: Jun-Xian
authors.initials: JX
authors.lastname: Wang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Fu
authors.affiliation: First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
authors.forename: Da-Gang
authors.initials: DG
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
authors.forename: Bi-Wei
authors.initials: BW
authors.lastname: Wang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
authors.forename: Yuan-Hua
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Second Affiliated Hospital, Anhui Medical University, Hefei 230601, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: First Affiliated Hospital, Anhui Medical University, Hefei 230022, China. Electronic address: ayfychenxi@163.com.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China. Electronic address: xudex@126.com.
authors.forename: De-Xiang
authors.initials: DX
authors.lastname: Xu
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015536:Down-Regulation; D005978:Glutathione / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008297:Male; D008815:Mice, Inbred Strains; D019255:NADPH Oxidases / Q000235:genetics*; D047495:PPAR gamma / Q000819:agonists*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000082:Acetaminophen; D019255:NADPH Oxidases; D005978:Glutathione
keywords: Acetaminophen (APAP); Hepatotoxicity; NADPH oxidases; Peroxisome proliferator-activated receptor gamma (PPAR-γ); Rosiglitazone (RSG); Sterile inflammation