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Dietary treatment of tyrosinemia type I: importance of methionine restriction.

A patient with tyrosinemia type I was treated with formula 3200 AB. This dietary approach lowered the elevated plasma phenylalanine and tyrosine levels but failed to eliminate the hypermethioninemia and the concomitant clinical abnormalities of ascites and other abnormal liver functions. Strict control of dietary intake of methionine, as well as phenylalanine and tyrosine, by a synthetic amino acid mixture or by a combination with formula 3200 AB maintained all plasma amino acids within the normal limits, permitted normal physical growth, and eliminated all hepatic and renal abnormalities. We suggest that restriction of only phenylalanine and tyrosine is inadequate in treating tyrosinemia type I during the acute phase. In such cases, the dietitian should use 3200 AB formula with caution until the acute phase of the disease subsides and plasma methionine levels return to normal.

4-Hydroxyphenylpyruvate Dioxygenase↗

Alternative models for analyses of liver and mammary transorgan metabolite extraction data.

Alternative models for analyses of liver and mammary transorgan data were formulated and fitted to liver and mammary data sets respectively. The models considered metabolite inputs to and effluxes from an extracellular pool. In general, fits were greatly improved over previous efforts using other models (Miller et al. 1991a; Hanigan et al. 1992; Wray-Cahen et al. 1997). Errors of prediction were generally less than 15% for liver and less than 20% for mammary glands. With the possible exception of glutamine for the udder, all metabolites exhibited linear responses to extracellular concentrations within the observed ranges of inputs. However, prediction biases were evident for beta-hydroxybutyrate, acetate, and propionate by liver and for arginine, histidine, citrulline and glycerol by mammary tissue. These biases were hypothesized to be caused by the existence of additional regulatory complexity. With the exception of histidine, parameter estimates for essential amino acid removal by liver were 2-3-fold lower than for mammary gland. Infusion of an amino acid mixture into the mesenteric vein did not alter parameter estimates for removal of amino acids by the liver. Treatment of cows with bovine somatotropin resulted in changes in mammary parameter estimates for aspartate, glutamate, leucine, phenylalanine, glucose, and glycerol.

Amino Acids↗

Nitrogen retention of young men who consumed selection patterns of essential amino acids at a constant nitrogen intake.

Six patterns of essential amino acids were devised to represent different sources or combinations of protein based on a daily intake of 6.0 g of nitrogen from these sources. In each diet, cereals furnished 70% and a specially designed amino acid mixture 30% of the total nitrogen. Nitrogen retention of young men who consumed amino acids equivalent to combinations of rice and soy or egg and potato did not differ from the pattern of egg, and these patterns were superior to a combination of rice and wheat; egg also was superior to corn plus beans and wheat plus milk. Relative amounts and proportions of essential amino acids could be modified without depressing nitrogen retention until one amino acid became limiting or the pattern became imbalanced. Therefore, more than one pattern of amino acids should be recognized as useful for adult human subjects; both minimal and total amounts of essential amino acids need to be considered.

Adult↗

Plasma proline kinetics and concentrations in young men in response to dietary proline deprivation.

This study examined plasma proline concentration flux, oxidation, and endogenous biosynthesis in five healthy young men given three isocaloric, isonitrogenous diets for 1 wk [a complete egg-pattern amino acid diet (diet 1), an amino acid mixture devoid of proline (diet 2), and a diet composed solely of indispensable amino acids (diet 3)]. At the end of each dietary period, a 360-min postabsorptive, primed, continuous stable-isotope-tracer infusion of L-[1-13C]proline and L-[methyl-2H3]leucine was performed in all subjects. Plasma proline concentrations declined by 22% on diet 2 (p less than 0.02) and by 29% on diet 3 (p less than 0.01). No statistically significant (p greater than 0.2) changes were observed for proline oxidation, endogenous biosynthesis, or flux. The data suggest that the absence of proline in the human diet does not trigger changes in proline dynamics during the postabsorptive state. The metabolic significance of the reduction of plasma proline concentrations requires elucidation.

Adult↗

Utilization of amino acids by the isolated perfused sheep liver.

To test Elwyn's suggestion [1970], that high concentrations of amino acids supplied to the liver from the hepatic artery do not stimulate protein synthesis, substrates containing amino acids have been infused into either the hepatic artery or portal vein of isolated sheep livers. The livers received highly oxygenated blood from the hepatic artery and partly deoxygenated blood from the portal vein. There were no significant differences in amino acid uptake (81 +/- 4% of input), urea output (69 +/- 6% of uptake) or 'protein synthesis' as assessed by N accumulation in the liver. Amino acids were actively extracted from the plasma by both routes of infusion and , when the concentrations simul-ted those occurring in the portal vein of fed sheep, the uptake was very similar to that in vivo. When an amino acid mixture based on that absorbed in dogs was infused, the extraction of individual amino acids was similar except for a negligible uptake of valine, leucine and isoleucine. In these experiments protein synthesis was also very low.

Alanine↗

Conversion of 14C-galactose into amino acids in tissue culture cells and its inhibition by manganese.

The incorporation of 14C-galactose into primary AGMK-cells was studied in the presence and absence of Mn2+. The transport of galactose into the cells is not influenced by Mn2+. 1 mM MnCl2 inhibits the incorporation of galactose into acid-precipitable material up to 50% after 6 hours incubation. In the absence of Mn2+ a substantial amount of galactose is converted to glucose, which is mainly metabolized into aspartic acid and serine. The conversion of galactose into glucose is inhibited by the addition of Mn2+. However, Mn2+ does not influence the activity of the UDP-galactose-4'-epimerase in vitro. Using the SDS-polyacrylamide electrophoresis the labelling of protein bands is similar with 14C-galactose or a 14C-amino acid mixture, respectively. In the presence of Mn2+ the incorporation of both galactose or amino acids is inhibited: With amino acids the inhibition is observed in all protein bands, whereas with galactose some bands remain unaffected. It is concluded that these are galactoproteins.

Amino Acids↗

[The effect of parenteral administration of amino acids and their mixtures the secretory activity of the stomach].

Experiments on dogs with gastric fistula after Basov and Pavlov pouch demonstrated that introduction into the blood by the drip method of solutions of L-amino acids and their mixtures tends to induce gastric secretion. This effect is produced by nonessential acids somewhat more intensively than by essential ones. A complete mixture of amino acids yields the least secretory effect. Among individual amino acids under study, taken in isomolar quantities, the most intensive gastric secretion induce glycin, alanine and proline. The least active in this respect proved to be lysine.

Alanine↗

Dissociation between plasma and brain amino acid profiles and short-term food intake in the rat.

The relationship between plasma and brain amino acids and short-term food intake after administration of albumin, or its constituent amino acids, was examined. Rats given protein (0.85 g chicken egg albumin) or an amino acid mixture patterned after egg albumin reduced their food intake during 1 h of feeding beginning 30 min after gavage. Similarly, when given separately, the essential (EAA) and nonessential amino acid (NEAA) fractions of egg albumin caused comparable decreases in food intake. As the dose increased from 0.5 to 1.5 g the duration of anorexia prolonged to 12 h. Little change occurred in plasma amino acids at 30 and 60 min after albumin at 0.85 g, although many increased by 25-50% at 60 min after 1.5 g. Marked changes in plasma occurred after gavage with the total mixture of constituent free amino acids and after either EAA or NEAA fractions. Brain amino acid concentrations were little affected by albumin and did not show consistent changes after the amino acid treatments. Thus the reductions in food intake after ingestion of albumin or of its constituent amino acids were not predicted from the resulting changes in either plasma or brain concentrations of amino acids.

Administration, Oral↗

The effects of tyrosine depletion in normal healthy volunteers: implications for unipolar depression.

RATIONALE: In recent years, there has been a growing interest in the role of dopamine (DA) both in the pathogenesis of unipolar depression and in motivated behaviour. The innovative technique of acute tyrosine depletion presents an opportunity to characterise further its function in these domains. OBJECTIVE: The present study examined the physiological, subjective and cognitive effects of acute tyrosine depletion in healthy volunteers. METHODS: A double-blind, placebo-controlled, parallel group design was employed. Half of the participants ingested a balanced amino-acid mixture (BAL) and the other half received an identical mixture except that tyrosine and phenylalanine were absent (TYR-free). Plasma amino acid concentrations and subjective ratings were monitored at both baseline (T(0)) and 5 h following consumption (T(5)) of the mixtures. A comprehensive neuropsychological test battery was also administered at T(5). RESULTS: Relative to the BAL group, the reduction in TYR availability to the brain was more marked in the TYR-free group. Employment of psychological rating scales revealed that, compared with the BAL group, the TYR-free group became less content and more apathetic. For the affective go/no-go task, whilst the BAL group exhibited a happy latency bias, the TYR-free group demonstrated a sad latency bias. Furthermore, in the decision-making task, the rate at which the TYR-free group increased their bets in response to more likely outcomes was lower than that of the BAL group. Taken together, these neuropsychological findings strikingly paralleled those reported in previous investigations of unipolar depression. The experimental groups could not be differentiated on any of the other neuropsychological measures, including more classical assessments of fronto-executive function. CONCLUSION: These findings are consistent with the hypothesis that dopaminergic factors are particularly involved in disrupted affect/reward-based processing characteristic of clinical depression.

Adult↗

Lipoprotein lipid and protein synthesis in experimental nephrosis and plasmapheresis: II. Perfused rat liver.

Livers from rats with experimental hypoproteinemia induced by aminonucleoside-nephrosis or plasmapheresis were perfused with a [14C]-labeled amino acid mixture at physiological concentration. Compared to control rats, a significantly increased incorporation of the amino acid label was found in the apolipoproteins of the ultracentrifugally separated very low and high density lipoproteins (VLDL, HDL), and into albumin secreted into the perfusate. However, no increase in the amino acid-derived lable was detected in VLDL-or HDL-borne lipids in nephrosis or plasmapheresis. Perfusion with U-[14C]leucine as a lipogenesis precursor at < 10 times higher than physiological concentration resulted in 5-fold increase in the label incorporation into perfusate proteins in nephrosis but only in a slightly significant increase in perfusate lipids. In contrast, the incorporation of a preformed fatty acid, 9,10-[3H] oleate into VLDL and HDL lipids increased 3- to 4-fold in nephrosis. Both with leucine and oleate as precursors, the increments in the label appearing in perfusate proteins or lipids, respectively, were markedly greater than the increases in hepatic tissue proteins or lipids. The results indicate that amino acids are preferentially directed by the liver into the synthesis of circulating apolipoproteins and albumin in hypoproteinemia and do not seem to constitute an important precursor of the liporpotein lipids. The increased production of apolipoproteins is associated with an increased incorporation of preformed fatty acids into lipoprotein lipids in addition to the previously reported stimulation of hepatic de novo lipid synthesis from recursors other than amino acids.

Animals↗

Differential p70S6k and 4E-BP1 regulation by insulin and amino acids in vascular endothelial and smooth muscle cells.

Differential stimulation of vascular endothelial and smooth muscle cells proliferation is responsible for atherosclerotic lesions. Amino acids and insulin modulate p70S6k and 4E-BP1 activity, regulating cell growth and proliferation. We hypothesised that nutritional (amino acids) and hormonal (insulin) signals differently modulate protein anabolism in human vascular endothelial (HUVEC) and smooth muscle (HVSMC) cells. We evaluated p70S6kinase and 4E-BP1 phosphorylation in the two cell types, grown in amino acid-free medium with or without insulin (INS, 100 nM) or/and amino acids mixture (AA, 3 mM) and with the selective addition or deprivation of branched chain amino acids (BCAA, 0.5 mM). INS stimulated p70S6k and 4E-BP1 phosphorylation transiently in HUVEC and persistently in HVSMC. AA and INS+AA stimulated p70S6k and 4E-BP1 phosphorylation persistently in HUVEC and HVSMC. AA, but not BCAA alone or BCAA-deprived AA, induced p70S6k phosphorylation in HUVEC. BCAA deprivation decreased the p70S6k phosphorylation induced by AA with or without insulin in HVSMC. These results show that anabolic stimuli modulate p70S6k and 4E-BP1 activity differently in the two vascular cell types, suggesting that insulin stimulates protein synthesis for a longer time in HUSMC than in HUVEC. We speculate that hyperinsulinaemia frequently associated with atherosclerosis could induce a selective HVSMC proliferation.

Adaptor Proteins, Signal Transducing↗

Effects of protein-deprivation on the regeneration of rat liver after partial hepatectomy.

Rats maintained on a protein-free diet for 3 days have an altered time course of hepatic DNA synthesis during liver regeneration. The delay in DNA synthesis is eliminated by the administration of casein hydrolysate (given as late as 6h after partial hepatectomy), but not by glucose or incomplete amino acid mixtures. Despite the change in the timing of DNA synthesis, the increases in hepatic amino acid pools, which take place at the earliest stages of the regenerative process, occur in a normal pattern in the regenerating liver of rats fed the protein-free diet. Protein-deprived rats have increased protein synthesis and decreased rates of protein degradation in the liver in response to partial hepatectomy, but these adaptations do not prevent a lag in protein accumulation and low protein/RNA ratios. The regenerating livers of these animals show a deficit in the accumulation of cytoplasmic polyadenylated mRNA as well as a smaller proportion of free polyribosomes. It is suggested that the deficit in free polyribosomes found in the regenerating liver of protein-deprived rats might be a consequence of the slow accumulation of mRNA species coding for intracellular proteins.

Amino Acids↗

Lysine kinetics at graded lysine intakes in young men.

Healthy young men participated in a study designed to explore the effects of decreasing dietary lysine content on plasma amino acid concentrations and lysine kinetics, studied with L-[1-13C]lysine as tracer. Diets provided adequate energy and the equivalent (N X 6.25) of 0.8 g protein kg-1.day-1 as a synthetic L-amino acid mixture simulating egg protein. Lysine intake was reduced every 7 days. Changes in plasma amino acids suggested that effects characteristic of a dietary lysine inadequacy were prevented by consuming more than 32 mg lysine.kg-1 day-1. Primed, continuous intravenous infusions of L-[1-13C]lysine, at the end of each diet period while subjects were in the fed state, showed that as dietary lysine was reduced, 13C enrichment increased in plasma lysine and decreased in expired CO2. It was estimated that lysine oxidation exceeded, by 4.4 mg kg-1 day-1, the lysine intake of 20 mg kg-1.day-1 indicating that the lysine required for body protein maintenance would probably exceed this latter value. These results are discussed in relation to the physiological requirement in adults for lysine, currently accepted to be met by an intake of 12 mg kg-1.day-1. which is assumed to be the upper range of the lysine requirement for this population group.

Adolescent↗

Long-term effects of histidine depletion on whole-body protein metabolism in healthy adults.

The essentiality of histidine in healthy adults is a controversial topic. To study the potential metabolic effects of a lack of exogenous histidine, four healthy adults consumed a histidine-free diet, with adequate energy and 1.0 g/(kg. d) of an L-amino acid mixture for 48 d. Protein metabolism was monitored every 4 d by using indicator amino acid (L-[1-(13)C]phenylalanine) oxidation (in four subjects) and [(15)N]glycine (in one subject). Urine samples (24-h) were collected for measurement of urea, total nitrogen, creatinine, 3-methylhistidine (3-MH), histidine and beta-alanine. Albumin, transferrin and hematologic concentrations were measured on d 0, 24 and 48. Urinary excretion of nitrogen, urea, creatinine and 3-MH were not affected by the histidine-free diet. However, there was a significant (P < 0.001) linear decline (24-28%) in whole-body protein turnover. Significant (P < 0.05) decreases in albumin (12%), transferrin (17%) and hemoglobin (Hb) (11%) concentrations occurred slowly over the histidine depletion period. The urinary excretion of beta-alanine (an index of carnosine catabolism) generally increased in the smallest subject during the consumption of histidine-free diet. This study demonstrates that a lack of histidine in the diet for a prolonged period resulted in an accommodation of protein turnover and phenylalanine oxidation, measured by the (13)C-phenylalanine indicator amino acid. The extensive metabolic accommodation, together with decreases in Hb, albumin and transferrin during histidine depletion, leaves unresolved the issue of whether histidine is a dietary essential amino acid in healthy adults.

Adult↗

Effect of individual amino acids on plasma cholesterol level in rats fed a high cholesterol diet.

The effect of individual amino acids added to a cholesterol containing casein diet on the plasma cholesterol level of rats was systematically investigated with objective of confirming the possibility that specific amino acids are responsible for the regulation of plasma cholesterol level by dietary proteins. Half the amino acids tested were effective to some degree in influencing the plasma cholesterol level when amino acids were added singly to the diet at a 5% level. However, only sulfur containing amino acids had significant effects when added to the diet at a 1% level; Met enhanced and Cys reduced the plasma cholesterol level. In addition, the results of an experiment with amino acid mixture diets with different Met, Cys, and/or Gly contents indicated the importance of sulfur amino acids and also of Gly in plasma cholesterol regulation. The results obtained here support the notion that the plasma cholesterol level of rats can be influenced by specific amino acids or amino acid compositions of dietary proteins, at least under the experimental conditions used.

Amino Acids↗

Branched chain amino acid administration and metabolism during starvation, injury, and infection.

Branched chain amino acids were administered intragastrically in a septic-fractured rat model to determine the degree and mechanism of their protein-sparing ability. The septic injury model was first shown to produce a metabolic response characterized by hyperglycemia, reduced ketonemia and increased nitrogen loss. Branched chain amino acids were then administered either alone or as 25% or 50% (w/w) of a complete crystalline amino acid solution. L-(U-14C)-tyrosine was added to the diet to estimate protein synthesis in individual tissues. Branched chain amino acids, when given alone, spared total body nitrogen as compared with fasting by increasing the fractional synthesis of both mixed liver and muscle protein. Although the two complete amino acid mixtures produced similar nitrogen preservation and muscle synthesis in the septic animals, the crystalline amino acid diet containing 50% branched chain amino acids resulted in the greatest preservation of total liver nitrogen and the highest fractional synthetic rate. The effect of branched chain amino acids would not appear to be explained by their nitrogen content alone, and in starvation with injury and infection, increased intakes may have potential benefit. Clinical trials in starved, injured man appear to be indicated.

Amino Acids, Branched-Chain↗

A hypothesis on the pathogenesis of pterygiums.

All true pterygiums are attracted to a specific site at the corneoscleral junction along the 3 to 9 o'clock meridian. The pathogenesis of a pinguecula-pterygium is postulated to be due to a noninfected inflammation at the junction of the conjunctival blood vessels and Bowman's membrane where the autolytic process of inflammation results in a protein degradation amino acid mixture which has the ability of attracting conjunctival blood vessels on the cornea. This amino acid mix is hypothesized to contain a pterygium angiogenesis factor.

Aged↗

Prebiotic syntheses of vitamin coenzymes: II. Pantoic acid, pantothenic acid, and the composition of coenzyme A.

Pantoic acid can by synthesized in good prebiotic yield from isobutyraldehyde or alpha-ketoisovaleric acid + H2CO + HCN. Isobutyraldehyde is the Strecker precursor to valine and alpha-ketoisovaleric acid is the valine transamination product. Mg2+ and Ca2+ as well as several transition metals are catalysts for the alpha-ketoisovaleric acid reaction. Pantothenic acid is produced from pantoyl lactone (easily formed from pantoic acid) and the relatively high concentrations of beta-alanine that would be formed on drying prebiotic amino acid mixtures. There is no selectivity for this reaction over glycine, alanine, or gamma-amino butyric acid. The components of coenzyme A are discussed in terms of ease of prebiotic formation and stability and are shown to be plausible choices, but many other compounds are possible. The gamma-OH of pantoic acid needs to be capped to prevent decomposition of pantothenic acid. These results suggest that coenzyme A function was important in the earliest metabolic pathways and that the coenzyme A precursor contained most of the components of the present coenzyme.

4-Butyrolactone↗