title: The hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea protect rats against thioacetamide-induced fulminant hepatic failure.
abstract: OBJECTIVE
  Reactive oxygen species, proinflammatory cytokines, glutathione depletion and nitric oxide have all been implicated in the pathogenesis of fulminant hepatic failure. The aim of the present study was to examine the respective roles of these factors in the pathogenesis of thioacetamide-induced fulminant hepatic failure in rats.
  
  
  METHODS
  Fulminant hepatic failure was induced by 3 consecutive intraperitoneal injections of thioacetamide (400 mg/kg) at 24-h intervals. Rats were pretreated with one of the following agents: the free radical scavengers dimethylsulfoxide (4 g/kg every 6 h) or dimethylthiourea (200 mg/kg every 12 h), the glutathione donor, N-acetylcysteine (130 or 200 mg/kg every 6 h), or the anti-tumor necrosis factor-alpha agents pentoxifylline (100 and 200 mg/kg) and soluble tumor necrosis factor receptor (100 or 1000 microg/rat). The nitric oxide synthase inhibitor N-mono-methyl arginine ester (L-NAME, 0.1 mg/ml) was administered in the drinking water, starting 7 days prior to thioacetamide administration.
  
  
  RESULTS
  Serum levels of liver enzymes, blood ammonia and prothrombin time and the stage of hepatic encephalopathy were significantly improved in rats treated with dimethylsulfoxide or dimethylthiourea compared to the other treatment groups (p<0.001). Liver histology and the survival rate in these rats were not adversely affected by thioacetamide administration (p<0.001), while in all the other treatment groups those parameters were similar to control rats with fulminant hepatic failure. Furthermore, dimethylsulfoxide ameliorated liver damage and improved survival even when its administration was initiated 8 and 16 h after the first thioacetamide injection. The hepatic concentration of methanesulfinic acid, which is produced after direct interaction of dimethylsulfoxide with hydroxyl radicals, was increased five-fold in rats treated with thioacetamide+dimethylsulfoxide (p<0.001), suggesting a role for hydroxyl radical scavenging in the protection from fulminant hepatic failure in this model. In the group of thioacetamide-treated rats that were pretreated with L-NAME, liver enzymes, blood ammonia levels and the mortality rate were higher than in the control group, treated with thioacetamide only.
  
  
  CONCLUSIONS
  In thioacetamide-induced fulminant hepatic failure, the hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea prevent liver injury. Neither N-acetylcysteine nor antagonists of tumor necrosis factor-alpha are protective in this rat model. Inhibition of nitric oxide formation aggravates liver damage and reduces the survival of rats with thioacetamide-induced liver damage.
authors.affiliation: Department of Gastroenterology, The E. Wolfson Medical Center, Holon, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Bruck
authors.forename: H
authors.initials: H
authors.lastname: Aeed
authors.forename: H
authors.initials: H
authors.lastname: Shirin
authors.forename: Z
authors.initials: Z
authors.lastname: Matas
authors.forename: L
authors.initials: L
authors.lastname: Zaidel
authors.forename: Y
authors.initials: Y
authors.lastname: Avni
authors.forename: Z
authors.initials: Z
authors.lastname: Halpern
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006501:Hepatic Encephalopathy / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D017665:Hydroxyl Radical; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D010431:Pentoxifylline / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013853:Thioacetamide / Q000633:toxicity*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016166:Free Radical Scavengers; D013853:Thioacetamide; D017665:Hydroxyl Radical; C038983:1,3-dimethylthiourea; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D013890:Thiourea; D010431:Pentoxifylline; D019331:NG-Nitroarginine Methyl Ester; D004121:Dimethyl Sulfoxide