title: N-acetylcysteine prevents carbon tetrachloride-induced liver cirrhosis: role of liver transforming growth factor-beta and oxidative stress.
abstract: OBJECTIVE
  N-acetylcysteine (NAC) is an antioxidant, a precursor of reduced glutathione, and an inhibitor of the profibrotic cytokine liver transforming growth factor-beta (TGF-beta). Carbon tetrachloride (CCl4) cirrhosis is characterized by oxidative stress and fibrosis. Therefore, the aim of this work was to study the effect of NAC on experimental cirrhosis.
  
  
  METHODS
  CCl4 was chronically administered for 8 weeks along with 300 mg/kg of NAC orally once a day. Alkaline phosphatase, alanine aminotransferase, and gamma-glutamyltranspeptidase were measured in plasma. Hydroxyproline, glycogen, lipid peroxidation, glutathione were determined in liver samples by colorimetric methods. TGF-beta was evaluated by western blotting, and a histopathological analysis was performed.
  
  
  RESULTS
  Serum markers of liver damage increased by CCl4 intoxication (P<0.05), whereas cotreatment with NAC prevented these increases (P<0.05); glycogen was depleted in the cirrhotic group (P<0.05), but preserved by NAC (P<0.05). Lipid peroxidation increased and glutathione decreased by the administration of CCl4 (P<0.05), again NAC prevented both effects (P<0.05). Importantly, collagen increased by about seven-fold in the CCl4 group (P<0.05); administration of NAC preserved the normal levels of collagen (P<0.05). Biochemical determinations were corroborated by hematoxylin and eosin, and trichromic stains. Western blots revealed a four-fold increase in TGF-beta in the group receiving CCl4, NAC cotreatment abolished TGF-beta signal (P<0.05).
  
  
  CONCLUSIONS
  Our results strongly suggest that NAC prevents experimental cirrhosis by two mechanisms: by preventing oxidative stress and by downregulating the profibrogenic cytokine TGF-beta. As NAC is currently used in humans intoxicated with paracetamol, it can be tested in fibrotic or cirrhotic patients under controlled trials.
authors.affiliation: External Section of Pharmacology, Cinvestav-IPN, Mexico City, Mexico.
authors.forename: Marina
authors.initials: M
authors.lastname: Galicia-Moreno
authors.forename: Adriana
authors.initials: A
authors.lastname: Rodríguez-Rivera
authors.forename: Karina
authors.initials: K
authors.lastname: Reyes-Gordillo
authors.forename: José
authors.initials: J
authors.lastname: Segovia
authors.forename: Mineko
authors.initials: M
authors.lastname: Shibayama
authors.forename: Victor
authors.initials: V
authors.lastname: Tsutsumi
authors.forename: Paula
authors.initials: P
authors.lastname: Vergara
authors.forename: Mario G
authors.initials: MG
authors.lastname: Moreno
authors.forename: Pablo
authors.initials: P
authors.lastname: Muriel
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002251:Carbon Tetrachloride; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D016212:Transforming Growth Factor beta; D002251:Carbon Tetrachloride; D000111:Acetylcysteine