title: The protective potential of metformin against acetaminophen-induced hepatotoxicity in BALB/C mice.
abstract: BACKGROUND
  Acetaminophen overdose is regarded to a common cause of acute liver failure. The hepatotoxicity leads to mitochondrial oxidative stress and subsequent necrotic hepatocellular death.
  
  
  OBJECTIVE
  This study examines the protective effect of metformin on acetaminophen-induced oxidative stress, inflammation and subsequent hepatotoxicity in mice.
  
  
  METHODS
  Male BALB/c mice were orally administered to acetaminophen (250 mg/kg/d) for a 7-day period. The mice received metformin (100 and 200 mg/kg/d, p.o.) for 21 days. To evaluate acetaminophen-induced oxidative stress, liver tissue level of malodialdehyde (MDA), end product of membrane lipid peroxidation, and activities of superoxide dismutase (SOD) and glutathione (GSH) were measured. Histological analysis and measurement of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were performed. Moreover, tissue concentrations of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), along with, C-reactive protein (CRP) were assessed.
  
  
  RESULTS
  Acetaminophen caused focal hepatocyte necrosis, inflammation and fatty degeneration, as well as increased tissue levels of AST, ALT, ALP and MDA, and also decreased GSH and SOD activities. Moreover, IL-6, TNF-α and CRP levels were increased following acetaminophen hepatotoxicity. Metformin (200 mg/kg/d) significantly normalized MDA, SOD and GSH levels (p < 0.001), and exerted a hepatoprotective effect by significant decreasing ALT, AST and ALP concentrations (p < 0.001). The tissue levels of IL-6, TNF-α and CRP were markedly decreased by 21-day treatment with metformin (200 mg/kg/d) (p < 0.001).
  
  
  CONCLUSIONS
  The results suggest metformin protects hepatocytes against acute acetaminophen toxicity. Metformin is indicated to diminish oxidative stress, proinflammatory cytokines, and hepatocyte necrosis.
authors.affiliation: a Department of Pharmacology, School of Medicine , Tehran University of Medical Sciences , Tehran , Iran.|b Experimental Medicine Research Center, Tehran University of Medical Sciences , Tehran , Iran.|c Department of Toxicology-Pharmacology, Faculty of Pharmacy , Gilan University of Medical Sciences , Rasht , Iran.
authors.forename: Seyed Soheil
authors.initials: SS
authors.lastname: Saeedi Saravi
authors.affiliation: a Department of Pharmacology, School of Medicine , Tehran University of Medical Sciences , Tehran , Iran.|d Department of Pharmacology and Toxicology, Faculty of Pharmacy , Lorestan University of Medical Sciences , Khorramabad , Iran.
authors.forename: Amin
authors.initials: A
authors.lastname: Hasanvand
authors.affiliation: e Department of Neuroscience and Addiction, School of Advanced Technologies in Medicine , Tehran University of Medical Sciences , Tehran , Iran.
authors.forename: Kourosh
authors.initials: K
authors.lastname: Shahkarami
authors.affiliation: a Department of Pharmacology, School of Medicine , Tehran University of Medical Sciences , Tehran , Iran.|b Experimental Medicine Research Center, Tehran University of Medical Sciences , Tehran , Iran.
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D020011:Protective Agents / Q000627:therapeutic use; D011897:Random Allocation
chemical_list: D018712:Analgesics, Non-Narcotic; D007004:Hypoglycemic Agents; D020011:Protective Agents; D000082:Acetaminophen; D008687:Metformin
keywords: Cytokine; hepatocellular necrosis; hepatocyte