INFLUENCE OF AMINOGUANIDINE ON PARAMETERS OF LIVER-INJURY AND REGENERATION INDUCED IN RATS BY A NECROGENIC DOSE OF THIOACETAMIDE

1 When aminoguanidine, a nucleophilic hydrazine compound, was administ ered to rats (50 mg kg(-1) body wt) 30 min before a necrogenic dose of thioacetamide (500 mg kg(-1) body wt), significant changes related to liver injury and hepatocellular regeneration were observed. 2 The ext ent of necrosis was noticeably less pronounced, as detected by the pea k of serum aspartate aminotransferase activity. Depletion of hepatic g lutathione (GSH) and the increase in malondialdehyde concentration as markers of oxidative stress, produced by thioacetamide metabolism, wer e significantly diminished. However, the activity of microsomal FAD mo nooxygenase, the system responsible for thioacetamide oxidation, did n ot show significant alterations. Antioxidant enzyme systems involved i n the glutathione redox cycle, such as glutathione reductase and gluta thione peroxidase activities, slightly decreased following aminoguanid ine pretreatment. 3 Primary cultures of peritoneal macrophages from co ntrol rats, when incubated in the presence of serum collected followin g thioacetamide intoxication, showed a significant decrease in nitric oxide (NO) release at 24 h, that was more pronounced in the group pret reated with aminoguanidine. However, the sharp and progressive increas e in macrophage NO release, when incubated in the presence of serum ob tained at 48, 72 and 96 h, were increased by aminoguanidine-pretreatme nt. 4 The cell population involved in DNA synthesis sharply increased in both groups at 48 h of intoxication, although the values at 0, 24, 72 and 96 h were markedly higher in the group pre-treated with aminogu anidine. Polyploidy at 72 and 96 h of intoxication was delayed by the effect of aminoguanidine and a progressive increase in the hypodiploid hepatocyte population, which reached 16% of the total at 96 h, was ob served. 5 These results indicate that a single dose of aminoguanidine before thioacetamide administration, markedly diminished the severity of the liver injury by decreasing oxidative stress and lipoperoxidatio n, but hepatocellular regeneration was apparently unaffected probably due to an enhanced mitogenic activity.