The effects of tumor necrosis factor-α (TNF-α; cachectin) and lipopolysaccharide of Salmonella enteritidis (LPS; endotoxin) on leucine metabolism in rats were evaluated in the whole body using intravenous infusion ofl-[1-14C]leucine and in isolated perfused liver (IPL) using the single-pass perfusion technique with α-keto[1-14C]isocaproate as a tracer for measurement of ketoisocaproic acid (KIC) oxidation, and the recirculation technique for measurement of hepatic amino acid exchanges. The data obtained in TNF-α and LPS groups were compared with those obtained in controls. Both TNF-α and LPS treatment induced an increase of whole body leucine turnover, oxidation, and clearance. As the result of a higher increase of leucine oxidation than of incorporation into the pool of body proteins, the fractional oxidation of leucine was increased. The fractional rate of protein synthesis increased significantly in the spleen (both in TNF-α and LPS rats), in blood plasma, liver, colon, kidneys, gastrocnemius muscle (in LPS rats), and in lungs (TNF-α-treated rats), whereas it decreased in the jejunum (LPS rats). In IPL of TNF-α- and LPS-treated rats a decrease of KIC oxidation and higher uptake of branched-chain amino acids (BCAA; valine, leucine, and isoleucine) were observed when compared with control animals. We hypothesize that the negative consequences of increased whole body proteolysis and of increased oxidation of BCAA induced by TNF-α and/or LPS are reduced by decreased activity of hepatic branched-chain ketoacid dehydrogenase that can help resupply BCAA to the body.

IV administration of alanine or glutamine improves protein balance and decreases leucine oxidized fraction in postabsorptive state and in endotoxemia. Decreased proteolysis is the main cause of decreased plasma BCAA levels after AG treatment.

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The mechanism by which glutamine produces a favorable effect in the treatment of sepsis, injury, burns and abdominal irradiation is not completely understood. The main aim of this study was to evaluate the effect of alanyl-glutamine (AlaGln) administration on the metabolism of proteins in irradiated rats. The rats were exposed to whole-body irradiation (8Gy) and then fed intragastrically with a mixture of glucose and amino acids either with AlaGln or without AlaGln. At 48 hours after irradiation, parameters of whole-body protein metabolism and DNA synthesis in intestinal mucosa were investigated using a primed, continuous infusion of [1-14C]leucine and [3H]thymidine. In addition, we evaluated the effect of irradiation and AlaGln on gut morphology, blood count and amino acid concentrations in blood plasma and skeletal muscle. Control rats were not irradiated but were given identical treatment. An increase in whole-body leucine oxidation, and insignificant changes in whole-body proteolysis and in protein synthesis were observed after irradiation. In irradiated rats we observed a decrease in muscle glutamine concentration, a decrease in protein synthesis in jejunum, colon and heart, and an increase in synthesis of proteins of blood plasma and spleen. Morphological examination and measurement of DNA synthesis failed to demonstrate any favorable effect of AlaGln supplementation on irradiated gut. However, administration of AlaGln resulted in a decrease in whole-body proteolysis and leucine oxidation which caused an increase in the fraction of leucine incorporated into the pool of body proteins. We conclude that the data obtained demonstrate that irradiation induces metabolic derangement associated with increased oxidation of essential branched-chain amino acids (valine, leucine and isoleucine) and that these disturbances can be ameliorated by administration of AlaGln.

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1. The changes in contents of DNA and total protein in the liver of the rats exposed to low level sarin by inhalation at 3, 6 and 12 months following the exposure were studied. The influence of sarin on the DNA and protein metabolism in liver was determinated by the measurements of incorporation of tritiated thymidine into DNA, the concentration of DNA and total protein. 2. Our results show that not only symptomatic level 3 but also asymptomatic levels 1 and 2 of sarin are able to significantly decrease the incorporation of radiolabelled thymidine without changing total concentrations of DNA as well as protein at three months following sarin exposure. On the other hand, the significant decrease in total contents of DNA and protein in liver without the changes in the incorporation of tritiated thymidine was determined in liver six months following sarin exposure. Practically no significant changes in the metabolism of DNA and protein were observed at 12 months following sarin exposure. 3. Thus, not only clinically manifested intoxication but also low-level, asymptomatic exposure to nerve agents such as sarin is able to influence the metabolism of nucleic acids as well as proteins even several months following the exposure.