title: Protective effects of allopurinol against acute liver damage and cirrhosis induced by carbon tetrachloride: modulation of NF-κB, cytokine production and oxidative stress.
abstract: BACKGROUND
  The aim of this work was to evaluate the hepatoprotective ability of allopurinol to prevent the liver injury induced by carbon tetrachloride (CCl(4)).
  
  
  METHODS
  Acute liver damage was induced with CCl(4) (4g/kg, by gavage); allopurinol (50mg/kg, by gavage) was given 1h before and 1h after CCl(4) intoxication and two daily doses for the previous three days. Cirrhosis was established by CCl(4) administration (0.4g/kg, i. p. three times a week, eight weeks); allopurinol was administered (100mg/kg, by gavage, daily) during the long-term of CCl(4) treatment. Alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GTP), xanthine oxidase (XO), lipid peroxidation, reduced and oxidized glutathione (GSH, GSSG, respectively), hydroxyproline and histopathologycal analysis were performed. Nuclear factor-κB (NF-κB), pro-inflammatory and anti-inflammatory cytokines, transforming growth factor-β (TGF-β) and metalloproteinase-13 (MMP-13) were analyzed by Western blots.
  
  
  RESULTS
  Acute injury increased ALT and γ-GTP activities, additionally enhanced NF-κB nuclear translocation and cytokines production such as tumor necrosis factor-α, interleukine-1β, and interleukine-6. Allopurinol partially prevented these effects, while increased interleukine-10. Acute and chronic CCl(4) treatments altered the levels of XO activity, lipid peroxidation, and GSH/GSSG ratio, while these remained within normal range with allopurinol administration. Necrosis, fibrosis and TGF-β production induced in chronic injury were partially prevented by allopurinol, interestingly, this drug induced MMP-13 activity.
  
  
  CONCLUSIONS
  Allopurinol possesses antioxidant, anti-inflammatory and antifibrotic properties, probably by its capacity to reduce NF-κB nuclear translocation and TGF-β expression, as well as to induce MMP-13. General significance Allopurinol might be effective treatment of liver diseases.
authors: Departamento de Farmacología, Cinvestav-IPN, Apdo. Postal 14-740, México 07000, DF México. laldaba@cinvestav.mx
authors: Liseth R
authors: LR
authors: Aldaba-Muruato
authors: Mario G
authors: MG
authors: Moreno
authors: Mineko
authors: M
authors: Shibayama
authors: Víctor
authors: V
authors: Tsutsumi
authors: Pablo
authors: P
authors: Muriel
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002251:Carbon Tetrachloride; D002457:Cell Extracts; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis*; D005978:Glutathione / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008103:Liver Cirrhosis / Q000097:blood / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014969:Xanthine Oxidase / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: D002457:Cell Extracts; D016207:Cytokines; D016328:NF-kappa B; D020011:Protective Agents; D000493:Allopurinol; D002251:Carbon Tetrachloride; D014969:Xanthine Oxidase; D005723:gamma-Glutamyltransferase; D000410:Alanine Transaminase; D053509:Matrix Metalloproteinase 13; D005978:Glutathione