Glutaric aciduria; a "new" disorder of amino acid metabolism.
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1. The effect of exogenous cortisone on concentration of free amino acids in serum, skeletal muscle, kidney, small intestine and liver was studied. 2. The amino acid pool in serum, skeletal muscle and small intestine decreased significantly. 3. Glutamine synthesis increased significantly in skeletal muscle. 4. Levels of branched amino acids increased in serum and small intestine. 5. Levels of alanine increased in kidney and liver.
Tolerance to an intravenous nutrient infusion containing amino acids, glucose and insulin was assessed in 12 adult patients with clinical and biochemical evidence of liver failure. In six individuals, fasting plasma amino acid patterns and turnover rates were measured by a constant intravenous infusion of [1-14C]leucine tracer. In the remaining patients the same measurements were made after a 10 h intravenous infusion of a 'standard' commercial mixture of amino acids (3.4 g/h), dextrose (20 g/h) and insulin (1.6 units/h). On the second day, conditions were crossed over and measurements were repeated. With the exception of glycine, the infusion of the amino acid-containing solution failed to significantly increase plasma amino acid content. Plasma leucine flux measurements indicated that the explanation involved a reduction in input of amino acids derived from the breakdown of body proteins rather than an increased uptake of amino acids into protein; i.e., the rate of liberation of leucine from protein decreased by an average of 2.4 mmol/h (P less than 0.05) whilst intake only added 1.6 mmol/h. No consistent changes in encephalopathy were observed. In conclusion, the infusion of the amino acid solution together with glucose and insulin resulted in improved nutritional intake and had no deleterious short-term effects on encephalopathy. However, judging from the plasma amino acid concentrations, the composition of the commercial mixture could be improved by reducing the glycine content.
Concentrations of free amino acids were measured in human milk and arterial blood from lactating women after an overnight fast or after a controlled breakfast. The concentrations of many free amino acids in milk (except L-tyrosine, L-aspartate, L-asparagine, L-glutamate and L-glutamine) were lower after an overnight fast than after breakfast. Similarly, the arterial concentrations of amino acids were lower except for L-asparagine, L-alanine, L-tyrosine and L-phenylalanine. Net uptake of amino acids by the mammary gland of the lactating rat was significantly lower after starvation for 6 or 24 h than in the fed state because the arteriovenous differences of amino acids and the blood flow were significantly lowered. Starvation produced a significant decrease of 2-amino-[1-14C]isobutyric acid uptake by isolated acini from lactating rat. These results show that short-term starvation decreases the amino acid supply and transport in mammary gland as well as the free amino acid concentration in milk.
Acute administration of ethanol increased the cerebrocortical amino acids derived through the tricarboxylic acid cycle except for GABA and decreased the plasma alanine, valine, isoleucine, leucine, and phenylalanine whereas chronic administration of ethanol caused no significant changes in the cerebrocortical amino acids and increased the plasma glutamic acid, glutamine, glycine, and ornithine, with decreases in taurine and phenylalanine. Result of this experiment suggests that the CNS-depressant effect of ethanol is related to changes in the GABA system and increased uptake by the brain of the branched-chain amino acids while the development of tolerance to ethanol is associated with cellular adaptation in the CNS.
We studied the responses of NH3 and amino acids (AA) to prolonged exercise (3 h) in trained (Tr; n = 6) and untrained (Utr; n = 6) men. Each subject exercised the knee extensor muscles of one leg at 60% of maximum capacity. Thigh blood flow and femoral arteriovenous differences (0, 30, 60, 120, 150, and 180 min) as well as muscle biopsies (0, 120, and 180 min) were taken for NH3 and AA measurements. In both groups, muscle Glu decreased (P < 0.05) and Asp increased (P < 0.05), but the intramuscular AA pool, including the essential AA, remained constant despite a total AA efflux of 22.4 +/- 8.3 and 24.4 +/- 6.8 mmol/kg wet wt in Tr and Utr, respectively. Tr had greater (P < 0.05) muscle Tau, Phe, Ala, and Glu. Both groups had a large Glu uptake and effluxes of NH3, Gln, and Ala as well as essential AA. The latter implies that there was a net protein catabolism. The efflux of NH3 and Gln was much greater than that expected from AMP deamination, suggesting that deamination of AA was occurring. Many of the AA responses use Glu, and Tr maintained the intramuscular Glu pool at a higher concentration (P < 0.05), implying that they derived more Glu from protein catabolism and/or AA transaminations. Under these conditions, prolonged dynamic knee extensor exercise is associated with a large release of alpha-amino moieties both as NH3 and as Gln as well as a net protein catabolism; these responses are similar in Tr and Utr.
Burn injury induces time-dependent variations in plasma amino acids, ie, an initial hyperaminoacidemia reflecting proteolysis in the wound areas, a decrease in gluconeogenic amino acids a consequence of excessive utilization in the liver, and a progressive return to normal. There is also a durable hyperphenylalaninemia, reflecting increased protein turnover and specific alterations of sulfur amino acids. In burned rats, the same general pattern is observed, except that glycine rather than alanine and glutamine exhibits the largest variations. Improvements in nutritional support with regard to the amino acid composition of diets are envisaged.
Fulminant hepatitis shows characteristic imbalance of amino acid levels; increased aromatic amino acid (AAA) and methionine. Elevated plasma AAA may cause hepatic encephalopathy and BCAA-enriched amino acids solution (BCAAs). Glucagon-Insulin (G-I) therapy and artificial liver support system have been proposed to correct the imbalance of amino acids. BCAAs and G-I therapy correct the aberrant amino acid patterns and artificial liver support system, including plasma pheresis, and charcoal haemoperfusion has also been used to reduce plasma amino acids levels. While imbalance of amino acids level in fulminant hepatitis is a result of acute necrosis of a large proportion of hepatocytes, careful and sufficient management of the disease is essential to normalize amino acid profiles.
The effects of norepinephrine (NE) on hepatic amino acid exchanges were studied in the isolated perfused rat liver using a recirculating system with a medium containing amino acids at twice physiologic concentrations. Norepinephrine induced a significant decrease (25%) in portal blood flow at a concentration of 2 ng/ml (10(-8) M). The hormone also increased total hepatic amino acid uptake, essentially through a switch from glutamine release to net uptake. There was no modification in free intracellular amino acids, but glycogen was slightly decreased, and glucose production was increased. Taken as a whole, these results suggest that NE modulates hepatic protein balance.
The free amino acid pool of blood of man exposed to 120-day head-down tilt (at -4 degrees) was examined. Beginning with bed rest day 28 and till the end of the study, the amino acid pool increased. The increase involved most free amino acids which was produced by a decline of anabolic and stimulation of catabolic processes during hypokinesia.
Recent investigations from our and other laboratories indicate that glycogen is a carbon-chain precursor in muscle for the synthesis of TCA cycle intermediates and glutamine. During intense exercise and in conditions of a relative lack of energy (hypoxia, trauma, sepsis) the metabolism of branched-chain amino acids (BCAA) is accelerated in muscle. In the primary BCAA aminotransferase reaction 2-oxoglutarate is used as amino-group acceptor (putting a carbon-drain on the TCA cycle) under formation of glutamate. Glutamate will subsequently react with ammonia, generated in the AMP deaminase reaction or by deamination of amino acids, under formation of glutamine in a reaction catalysed by glutamine synthetase (glutamate + ammonia + ATP--> glutamine + ADP). Muscle glycogen stores may be smaller or less available at high altitude. It is hypothesized that this will lead to premature fatigue (due to both a lack of fuel and of TCA cycle carbon-precursor) and to a reduction in the synthesis rate of glutamine. A chronic reduction in the synthesis rate of glutamine during a long term stay at high altitude on its turn may lead to gut atrophy, bacterial translocation, endotoxemia, muscle protein catabolism and a weakened immune status.
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