The hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea protect rats against thioacetamide-induced fulminant hepatic failure

Background/Aims: Reactive oxygen species, proinflammatory cytokines, glutat hione depletion and nitric oxide have all been implicated in the pathogenes is of fulminant hepatic failure. The aim of the present study was to examin e the respective roles of these factors in the pathogenesis of thioacetamid e-induced fulminant hepatic failure in rats. Methods: Fulminant hepatic failure was induced by 3 consecutive intraperito neal injections of thioacetamide (400 mg/kg) at 24-h intervals. Rats were p retreated with one of the following agents: the free radical scavengers dim ethylsulfoxide (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 mu g/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 thi oacetamide 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 t reatment groups (p<0.001). Liver histology and the survival rate in these r ats were not adversely affected by thioacetamide administration (p<0.001), while in all the other treatment groups those parameters were similar to co ntrol rats with fulminant hepatic failure. Furthermore, dimethylsulfoxide a meliorated liver damage and improved survival even when its administration was initiated 8 and 16 h after the first thioacetamide injection. The hepat ic concentration of methanesulfinic acid, which is produced after direct in teraction of dimethylsulfoxide with hydroxyl radicals, was increased five-f old in rats treated with thioacetamide+dimethylsulfoxide (p<0.001), suggest ing 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 t he mortality rate were higher than in the control group, treated with thioa cetamide only. Conclusions: In thioacetamide-induced fulminant hepatic failure, the hydrox yl radical scavengers dimethylsulfoxide and dimethylthiourea prevent liver injury, Neither N-acetylcysteine nor antagonists of tumor necrosis factor-a lpha are protective in this rat model. Inhibition of nitric oxide formation aggravates liver damage and reduces the survival of rats with thioacetamid e-induced liver damage.