Our results suggest a potential hepatoprotective role of NAC in fulminant hepatic failure, mediated partially through the modulation of the intrinsic pathway of apoptosis.

Acute hepatic failure (AHF) is a severe liver injury accompanied by hepatic encephalopathy which causes multiorgan failure with an extremely high mortality rate, even if intensive care is provided. Management of severe AHF continues to be one of the most challenging problems in clinical medicine. Liver transplantation has been shown to be the most effective therapy, but the procedure is limited by shortage of donor organs. Although a number of clinical trials testing different liver assist devices are under way, these systems alone have no significant effect on patient survival and are only regarded as a useful approach to bridge patients with AHF to liver transplantation. As a result, reproducible experimental animal models resembling the clinical conditions are still needed. The three main approaches used to create an animal model for AHF are: surgical procedures, toxic liver injury and infective procedures. Most common models are based on surgical techniques (total/partial hepatectomy, complete/transient devascularization) or the use of hepatotoxic drugs (acetaminophen, galactosamine, thioacetamide, and others), and very few satisfactory viral models are available. We have recently developed a viral model of AHF by means of the inoculation of rabbits with the virus of rabbit hemorrhagic disease. This model displays biochemical and histological characteristics, and clinical features that resemble those in human AHF. In the present article an overview is given of the most widely used animal models of AHF, and their main advantages and disadvantages are reviewed.

This work was undertaken to investigate whether treatment with melatonin prevents oxidative stress and changes in the expression and activity of factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes in an animal model of fulminant hepatic failure of viral origin. Rabbits were experimentally infected with 2 x 10(4) hemagglutination units of a rabbit hemorrhagic disease virus (RHDV) isolate and received melatonin at two concentrations of 10 mg/kg and 20 mg/kg at 0, 12 and 24 hr postinfection. Blood transaminases, blood lactate dehydrogenase, liver concentration of thiobarbituric reactive acid substances and the liver oxidized to reduced glutathione ratio significantly increased at 36 hr postinfection in infected animals. Significant decreases were found in the mRNA levels and in the liver activities of Mn-superoxide dismutase, glutathione peroxidase and glutathione-S-transferase in infected rabbits. These effects were prevented by melatonin administration in a concentration-dependent manner. Melatonin treatment was not accompanied by changes in protein levels of Kelch-like ECH-associating protein 1 (Keap1) but resulted in an increased protein expression of Nrf2 in the cytoplasm and the nucleus, which was confirmed by the results of Nrf2 immunostaining. Nuclear extracts from livers of melatonin-treated rats displayed an enhanced antioxidant responsive element (ARE)-binding activity of Nrf2. Our results suggest a potential hepatoprotective role of melatonin in fulminant hepatic failure, partially mediated through the abrogation of oxidative stress and the prevention of the decreased activity of antioxidant enzymes via the Nrf2 pathways.

A theoretical calculation of the total nonaqueous exchangeable hydrogen in protein, carbohydrates, and fat in man has been made. It shows that of the total exchangeable hydrogen in the body 5.22% is located in biochemical components, soluble in body water, containing hydrogen that is exchangeable with the isotope. This value represents a maximum upward distortion of total body water measurements by isotope dilution, due to the maximum possible exchangeability in these molecular conformations. From comparative measurements reported in the literature it is clear that this maximum is not achieved during the short period of time during which tritium-dilution studies are performed. It is the authors' belief that the hard-to-exchange amide hydrogens described by Blout in the protein conformations account for this failure of the isotope to achieve complete exchange in the short time allowed.

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Total body water (TBW) determination by tritium space could be factitiously elevated by exchangeable H+ contained within water-soluble chemical configurations. Should this nonaqueous (molecular) exchangeable H+ turn out to be a large fraction of total exchangeable H+, TBW measurement by tritiated water (THO) dilution would display a systematic upward and non-random error. TBW was measured by THO dilution and subsequently by total body desiccation in 21 rats (weight 227+/-83 g, mean+/-SD). TBW was 71.38+/-2.4% by THO dilution and 70.20+/-1.5% by body desiccation. Analysis of variance of TBW vs. body weight showed a highly significant correlation both with desiccation (P less than 0.0005, r=-0.78) and dilution (P less than 0.03, r= -0.50). Convariance analysis of both methods showed no difference in slope (P greater than 0.9). There was a difference in variance (P less than 0.001) and means (P less than 0.03). Tritium space is 1.2% of body weight larger than TBW measured by desiccation. TBW measured by THO dilution gives a 1.71% overestimation of TBW as measured by desiccation. TBW measurement by THO dilution is accurate within less than 2% error. These findings have particular significance in the light of our theoretical model of the total nonaqueous exchangeable H+ in fat, protein, and carbodhydrate in the living vertebrate.

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