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 administered 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 extent of necrosis was noticeably less pronounced, as detected by the peak of serum aspartate aminotransferase activity. Depletion of hepatic glutathione (GSH) and the increase in malondialdehyde concentration as markers of oxidative stress, produced by thioacetamide metabolism, were significantly diminished. However, the activity of microsomal FAD monooxygenase, the system responsible for thioacetamide oxidation, did not show significant alterations. Antioxidant enzyme systems involved in the glutathione redox cycle, such as glutathione reductase and glutathione peroxidase activities, slightly decreased following aminoguanidine pretreatment. 3. Primary cultures of peritoneal macrophages from control rats, when incubated in the presence of serum collected following thioacetamide intoxication, showed a significant decrease in nitric oxide (NO) release at 24 h, that was more pronounced in the group pretreated with aminoguanidine. However, the sharp and progressive increase in macrophage NO release, when incubated in the presence of serum obtained at 48, 72 and 96 h, were increased by aminoguanidine-pretreatment. 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 aminoguanidine. 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 observed. 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 lipoperoxidation, but hepatocellular regeneration was apparently unaffected probably due to an enhanced mitogenic activity.
Instituto de Bioquímica (CSIC - UCM), Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
C
C
Díez-Fernández
N
N
Sanz
A M
AM
Alvarez
A
A
Zaragoza
M
M
Cascales
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011003:Ploidies; D051381:Rats; D017208:Rats, Wistar; D013853:Thioacetamide / Q000633:toxicity*; D013997:Time Factors
D002273:Carcinogens; D004791:Enzyme Inhibitors; D006146:Guanidines; D013853:Thioacetamide; D009569:Nitric Oxide; D008315:Malondialdehyde; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D005978:Glutathione; C004479:pimagedine