Influence of aminoguanidine on parameters of liver injury and regeneration induced in rats by a necrogenic dose of thioacetamide

Abstract

1 When aminoguanidine, a nucleophilic hydrazine compound, was administered to rats (50 mg kg 71 body wt) 30 min before a necrogenic dose of thioacetamide (500 mg kg 71 body wt), signi®cant 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 signi®cantly diminished. However, the activity of microsomal FAD monooxygenase, the system responsible for thioacetamide oxidation, did not show signi®cant 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 signi®cant 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 e ect 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 una ected probably due to an enhanced mitogenic activity.

Hepatocyte Ploidy in Regenerating Livers after Partial Hepatectomy, Drug-Induced Necrosis, and Cirrhosis

“…We found that this was associated with a marked decrease in the number of viable hepatocytes isolated from those livers, as also observed by Diez-Fernandez et al [52] in TA-treated rats. As previously described by Chanda and Mehendale [56] and Theocharis et al [57] after sublethal TA injection, we found a return to basal aminotransferase values 7-12 days after sublethal injection of both TA and GalN.…”

“…Oxidative injury may play a key role in polyploidy following PH, given the fact that hepatic polyploidization was decreased in partially hepatectomized transgenic mice overexpressing antioxidants such as glutathione peroxidase and copper-zinc superoxide dismutase [51]. Similarly, treatment with aminoguanidine, which attenuates oxidative stress, has been shown to decrease polyploidy Gandillet/Alexandre/Royer/Cinqualbre/ Jaeck/Richert [52]. We observed a transitory increase in serum aminotransferase values which returned to basal levels within 7-12 days and found that the distribution of hepatocyte ploidy was equivalent to that of controls 21 days after PH.…”

Aminoguanidine impedes human pancreatic tumor growth and metastasis development in nude mice

“…The same effect on these enzymes was observed in diabetic rats [29] and on superoxide dismutases in doxorubicin treated rats [30] . GPx activity was slightly decreased after AG treatment in a model of liver injury in rat [31] . Chronic treatment with AG might cause a disruption of the cellular redox balance due to its capacity to scavenge oxidant reactive species [32] and to inhibit NO synthesis.…”

Nitric Oxide and Allyl Alcohol Induced Hepatotoxicity

“…It is generally accepted that NO is an important regulator in the hepatotoxicity of many chemicals [4,5,6]. However, the role of NO in the development of liver necrosis is still not fully known and demands further studies.…”

“…NO produced by eNOS plays important role in liver microcirculation. It has been shown that aminoguanidine, a relatively selective inhibitor of iNOS, protected against acetaminopheninduced hepatotoxicity [4], as well as thioacetamideinduced hepatotoxicity [5]. Another study concluded that iNOS plays an important role in liver cirrhosis following CCl 4 intoxication to rats [6].…”