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PubMed1975

Factors regulating amino acid release from extrasplanchnic tissues in the rat. Interactions of alanine and glutamine.

1. Factors regulating the release of alanine and glutamine in vivo were investigated in starved rats by removing the liver from the circulation and monitoring blood metabolite changes for 30 min. 2. Alanine and glutamine were the predominant amino acids released into the circulation in this preparation. 3. Dichloroacetate, an activator of pyruvate dehydrogenase, inhibited net alanine release: it also interfered with the metabolism of the branched-chain amino acids valine, leucine and isoleucine. 4. L-Cycloserine, an inhibitor of alanine aminotransferase, decreased alanine accumulation by 80% after functional hepatectomy, whereas methionine sulphoximine, an inhibitor of glutamine synthetase, decreased glutamine accumulation by the same amount. 5. It was concluded that: (a) the alanine aminotransferase and the glutamine synthetase pathways respectively were responsible for 80% of the alanine and glutamine released into the circulation by the extrasplanchnic tissues, and extrahepatic proteolysis could account for a maximum of 20%; (b) alanine formation by the peripheral tissues was dependent on availability of pyruvate and not of glutamate; (c) glutamate availability could influence glutamine formation subject, possibly, to renal control.

Acetates↗
PubMed2002

Effect of starvation on glutamine ammoniagenesis and gluconeogenesis in isolated mouse kidney tubules.

It has been shown recently that glutamine is taken up by the mouse kidney in vivo. However, knowledge about the fate of this amino acid and the regulation of its metabolism in the mouse kidney remains poor. Given the physiological and pathophysiological importance of renal glutamine metabolism and the increasing use of genetically modified mice in biological research, we have conducted a study to characterize glutamine metabolism in the mouse kidney. Proximal tubules isolated from fed and 48 h-starved mice and then incubated with a physiological concentration of glutamine, removed this amino acid and produced ammonium ions at similar rates. In agreement with this observation, activities of the ammoniagenic enzymes, glutaminase and glutamate dehydrogenase, were not different in the renal cortex of fed and starved mice, but the glutamate dehydrogenase mRNA level was elevated 4.5-fold in the renal cortex from starved mice. In contrast, glucose production from glutamine was greatly stimulated whereas the glutamine carbon removed, that was presumably completely oxidized in tubules from fed mice, was virtually suppressed in tubules from starved animals. In accordance with the starvation-induced stimulation of glutamine gluconeogenesis, the activities and mRNA levels of glucose-6-phosphatase, and especially of phosphoenolpyruvate carboxykinase, but not of fructose-1,6-bisphosphatase, were increased in the renal cortex of starved mice. On the basis of our in vitro results, the elevated urinary excretion of ammonium ions observed in starved mice probably reflected an increased transport of these ions into the urine at the expense of those released into the renal veins rather than a stimulation of renal ammoniagenesis.

Adaptation, Biological↗
PubMed2005

Characteristics of glutamine metabolism in human precision-cut kidney slices: a 13C-NMR study.

The metabolism of glutamine, a physiological substrate of the human kidney, plays a major role in systemic acid-base homoeostasis. Not only because of the limited availability of human renal tissue but also in part due to the lack of adequate cellular models, the mechanisms regulating the renal metabolism of this amino acid in humans have been poorly characterized. Therefore given the renewed interest in their use, human precision-cut renal cortical slices were incubated in Krebs-Henseleit medium (118 mM NaCl, 4.7 mM KCl, 1.18 mM KH2PO4, 1.18 mM MgSO4*7H2O, 24.9 mM NaHCO3 and 2.5 mM CaCl2*2H2O) with 2 mM unlabelled or 13C-labelled glutamine residues. After incubation, substrate utilization and product formation were measured by enzymatic and NMR spectroscopic methods. Glutamate accumulation tended to plateau but glutamine removal and ammonia, alanine and lactate production as well as flux through GLDH (glutamate dehydrogenase) increased to various extents with time for up to 4 h of incubation indicating the metabolic viability of the slices. Valproate, a stimulator of renal glutamine metabolism, markedly and in a dose-dependent fashion increased ammonia production. With [3-13C]glutamine as a substrate, and in the absence and presence of valproate, [13C]glutamate, [13C]alanine and [13C]lactate accounted for 81 and 96%, 34 and 63%, 30 and 46% of the glutamate, alanine and lactate accumulations measured enzymatically respectively. The slices also metabolized glutamine and retained their reactivity to valproate during incubations lasting for up to 48 h. These results demonstrate that, although endogenous metabolism substantially operates in the presence of glutamine, human precision-cut renal cortical slices are metabolically viable and strongly respond to the ammoniagenic effect of valproate. Thus, this experimental model is suitable for metabolic and pharmaco-toxicological studies.

Ammonia↗
PubMed1983

Effect of acidosis on glutamine transport by isolated rat renal brush-border and basolateral-membrane vesicles.

Glutamine uptake was examined in isolated renal brush-border and basolateral-membrane vesicles from control and acidotic rats. In brush-border vesicles from acidotic animals, there was a significant increase in the initial rate of glutamine uptake compared with that in controls. Lowering the pH of the medium increased the initial rate of glutamine uptake in brush-border vesicles from acidotic, but not from control, rats. In brush-border vesicles from both groups of animals, two saturable transport systems mediated glutamine uptake. There was a 2-fold increase in the Vmax. of the low-affinity high-capacity system in the brush-border vesicles from the acidotic animals compared with that from control animals, with no alteration in the other kinetic parameters. There was no difference in glutamine uptake by the two saturable transport systems in basolateral vesicles from control and acidotic animals. Lowering the incubation-medium pH increased the uptake of glutamine by basolateral vesicles from both control and acidotic rats to a similar extent. The data indicate that during acidosis there are alterations in glutamine transport by both the basolateral and brush-border membrane which could enhance its uptake by the renal-tubule cell for use in ammoniagenesis.

Acidosis↗
PubMed1984

The oxidation of glutamine and glutamate in relation to anion transport in enterocyte mitochondria.

The oxidation of L-glutamate and L-glutamine by enterocyte mitochondria was supported by malate. The stimulation of the rate of oxidation of the two amino acids by small amounts of added malate was 93% and 76% respectively. This could not be accounted for by the oxidation of the small amounts of malate added. Amino-oxyacetate added initially inhibited malate-supported oxidation of L-glutamate by 81% and that of L-glutamine by 38%. The inhibition of L-glutamate oxidation was partially reversed by L-glutamine. The dicarboxylate-carrier inhibitor 2-phenylsuccinate inhibited the malate-supported oxidation of both amino acids, but appeared to be slightly stimulatory to L-glutamine oxidation when added initially. The inhibition of L-glutamate oxidation was reversed by L-glutamine. The mitochondrial uncoupler FCCP (carbonyl cyanide p-trifluoromethoxyphenylhydrazone) inhibited malate-supported oxidation of L-glutamate by 78% when added initially. The oxidation of L-glutamine was completely inhibited. However, the uncoupler stimulated the oxidation of both amino acids when added finally. Pyruvate inhibited aspartate synthesis when either of these amino acids was the main substrate, alanine being synthesized. There was no effect on O2 uptake. Mitochondria did not swell in KCl solution, but swelled rapidly in water. Mitochondrial swelling in potassium phosphate and potassium acetate solutions was activated by valinomycin and to a lesser extent by the further addition of FCCP. With potassium malate, swelling was mainly activated by phosphate. The swelling of enterocyte mitochondria in potassium glutamate was slow. In glutamine solution, mitochondrial swelling was greater and appeared to be enhanced by the initial presence of small amounts of phosphate.

Animals↗
PubMed1987

The maximal activity of phosphate-dependent glutaminase and glutamine metabolism in late-pregnant and peak-lactating rats.

The maximal activity of phosphate-dependent glutaminase was increased in the small intestine, decreased in the liver and unchanged in the kidney of late-pregnant rats. This was accompanied by increases in the size of both the small intestine and the liver. The maximal activity of phosphate-dependent glutaminase was increased in both the small intestine and liver but unchanged in the kidney of peak-lactating rats. Enterocytes isolated from late-pregnant or peak-lactating rats exhibited an enhanced rate of utilization of glutamine and production of glutamate, alanine and ammonia. Arteriovenous-difference measurements across the gut showed an increase in the net glutamine removed from the circulation in late-pregnant and peak-lactating rats, which was accompanied by enhanced rates of release of glutamate, alanine and ammonia. Arteriovenous-difference measurements for glutamine showed that both renal uptake and skeletal-muscle release of glutamine were not markedly changed during late pregnancy or peak lactation; but pregnant rats showed a hepatic release of the amino acid. It is concluded that, during late pregnancy and peak lactation, the adaptive changes in glutamine metabolism by the small intestine, kidneys and skeletal muscle of hindlimb are similar; however, the liver appears to release glutamine during late pregnancy, but to utilize glutamine during peak lactation.

Animals↗
PubMed1987

Stimulation of glycogen synthesis and lipogenesis by glutamine in isolated rat hepatocytes.

Glutamine stimulated glycogen synthesis and lactate production in hepatocytes from overnight-fasted normal and diabetic rats. The effect, which was half-maximal with about 3 mM-glutamine, depended on glucose concentration and was maximal below 10 mM-glucose. beta-2-Aminobicyclo[2.2.1.]heptane-2-carboxylic acid, an analogue of leucine, stimulated glutaminase flux, but inhibited the stimulation of glycogen synthesis by glutamine. Various purine analogues and inhibitors of purine synthesis were found to inhibit glycogen synthesis from glucose, but they did not abolish the stimulatory effect of glutamine on glycogen synthesis. The correlation between the rate of glycogen synthesis and synthase activity suggested that the stimulation of glycogen synthesis by glutamine depended solely on the activation of glycogen synthase. This activation of synthase was not due to a change in total synthase, nor was it caused by a faster inactivation of glycogen phosphorylase, as was the case after glucose. It could, however, result from a stimulation of synthase phosphatase, since, after the addition of 1 nM-glucagon or 10 nM-vasopressin, glutamine did not interfere with the inactivation of synthase, but did promote its subsequent re-activation. Glutamine was also found to inhibit ketone-body production and to stimulate lipogenesis.

Animals↗
PubMed1989

Rates of utilization of glucose, glutamine and oleate and formation of end-products by mouse peritoneal macrophages in culture.

1. The metabolism of mouse thioglycollate-elicited peritoneal macrophages was studied in culture for up to 96 h. 2. The rates of glycolysis, lactate formation and glutamine utilization were approximately linear with time for at least 80 h of culture. 3. The rates of glucose and glutamine utilization by cultured macrophages were approx. 500 and 90 nmol/h per mg of protein respectively. This rate of glucose utilization is at least 50% greater than that previously reported for macrophages during 60 min incubation in a shaking flask; and it is now increased by addition of glutamine to the culture medium. The rate of glutamine utilization in culture is similar to that previously reported for macrophages during 60 min incubation. The major end-product of glucose metabolism is lactate, and those of glutamine metabolism are CO2, glutamate, ammonia and alanine. 4. Oleate was utilized by these cells: 14C from [14C]oleate was incorporated into CO2 and cellular lipid. The highest rate of oleate utilization was observed when both glucose and glutamine were present in the culture medium. The presence of oleate in the culture medium did not affect the rates of utilization of either glucose or glutamine. Of the [14C]oleate incorporated into lipid, approx. 80% was incorporated into triacylglycerol and only 18% into phospholipid. 5. The turnover rate for the total ATP content of the macrophage in culture is about 10 times per minute: the value for the perfused isolated maximally working rat heart is 22. This indicates a high metabolic rate for macrophages, and consequently emphasizes the importance of the provision of fuels for their function in an immune response.

Adenosine Triphosphate↗
PubMed1990

Effects of hyperthyroidism and hypothyroidism on glutamine metabolism by skeletal muscle of the rat.

1. The effects of hyperthyroidism and hypothyroidism on the concentrations of glutamine and other amino acids in the muscle and plasma and on the rates of glutamine and alanine release from incubated isolated stripped soleus muscle of the rat were investigated. 2. Hyperthyroidism decreased the concentration of glutamine in soleus muscle but was without effect on that in the gastrocnemius muscle or in the plasma. Hyperthyroidism also increased markedly the rate of release of glutamine from the incubated soleus muscle. 3. Hypothyroidism decreased the concentrations of glutamine in the gastrocnemius muscle and plasma but was without effect on that in soleus muscle. Hypothyroidism also decreased markedly the rate of glutamine release from the incubated soleus muscle. 4. Thyroid status was found to have marked effects on the rate of glutamine release by skeletal muscle per se, and may be important in the control of this process in both physiological and pathological conditions.

Alanine↗
PubMed1992

Glutamine is a good substrate for glycogen synthesis in isolated hepatocytes from 72 h-starved rats, but not from 24 h- or 48 h-starved rats.

In isolated hepatocytes from 24 h-starved rats, no glycogen synthesis was observed in the presence of glutamine. By contrast, glutamine was the best gluconeogenic substrate to induce glycogen synthesis in isolated hepatocytes from 72 h-starved rats. The effect of glutamine on glycogen synthesis was not accompanied by parallel changes in glucose or lactate production. Glutamine activated glycogen synthase independently of the starvation period; however, the extent of synthase activation was 2-fold higher in isolated hepatocytes from 72 h-starved rats than in hepatocytes from 24 h-starved rats. This increase in synthase activation was associated with increased cell swelling. The rate of glutamine transport was not significantly different in hepatocytes from 24 h- and 72 h-starved rats. By contrast, the intracellular glutamate concentration was 1.5-fold higher after 3 days of starvation in hepatocytes incubated with 5 mM-glutamine. We propose that glutamine may play a key role in the glycogen synthesis observed in vivo after 3 days of starvation.

Animals↗
PubMed1994

Glutamine synthesis from glucose and ammonium chloride by guinea-pig kidney tubules.

1. At a physiological concentration (5 mM), glucose was found to be metabolized by isolated kidney cortex tubules prepared from fed guinea pigs. 2. The release of 14CO2 from [U-14C]glucose indicated that oxidation of the glucose carbon skeleton represented about 50% of the glucose removed; significant amounts of lactate and glutamine also accumulated. 3. Addition of 0.1-10 mM NH4Cl led to a dose-dependent stimulation of glucose metabolism which was accompanied by a large increase in lactate and glutamine accumulation and, to a lesser extent, in glucose oxidation. 4. Comparison of the release of 14CO2 from [1-14C]- and [6-14C]glucose indicates that, in both the absence and the presence of NH4Cl, the pentose phosphate shunt was only a minor pathway of glucose metabolism. 5. The central role of pyruvate carboxylase in the conversion of glucose carbon into glutamine carbon was demonstrated by using a bicarbonate-free medium and measuring the fixation of 14CO2 from [14C]bicarbonate, which was recovered mostly at C-1 of glutamine plus glutamate. 6. The NH4Cl-induced stimulation of glucose removal was secondary not only to increased glutamine synthesis, as shown by the effect of methionine sulphoximine, an inhibitor of glutamine synthetase, but also to the stimulation of phosphofructokinase activity by NH4Cl. 7. Renal arterio-venous difference measurements revealed that, in vivo, the guinea-pig kidney removed glucose from the circulating blood, which suggests that glucose carbon may contribute to the carbon skeleton of the glutamine released by this organ.

Ammonium Chloride↗
PubMed1995

Glutamine transport by vesicles isolated from tumour-cell mitochondrial inner membrane.

Mitochondrial-inner-membrane vesicles, isolated from Ehrlich ascites carcinoma cells by titration with detergents, accumulated L-glutamine by a very efficient transport system. The vesicles lack any phosphate-activated glutaminase activity, allowing measurement of transport rates without interference by L-glutamine metabolism. The time course of the transport was linear for the first 60 s, reaching a steady state after 120 min. L-Glutamine transport showed co-operativity, with a Hill coefficient of 2.2; the kinetic parameters S0.5 and Vmax had values of 5 mM and 26 nmol/30 s per mg of protein respectively. The pH-dependence curve showed a bell shape, with a pH optimum about 8.0. The uptake of L-glutamine was not affected by the presence of a 50-fold molar excess of D-glutamine, L-cysteine, L-histidine, L-alanine, L-serine and L-leucine, whereas L-glutamate behaved as a poor inhibitor. The structural analogue L-glutamate gamma-hydroxamate (5mM) inhibited the net uptake by 68%; interestingly, other analogues (6-diazo-5-oxo-L-norleucine, acivicin and L-glutamate gamma-hydrazide) were ineffective. The impermeant thiol reagent p-chloromercuriphenylsulphonic acid (0.5mM) completely abolished the mitochondrial L-glutamine uptake; in contrast, other thiol reagents (mersalyl and N-ethylmaleimide) did not significantly affect the transport. These data confirm the existence of a specific transport system with high capacity for L-glutamine in the mitochondrial inner membrane, a step preceding the highly operative glutaminolysis in tumour cells.

Amino Acids↗
PubMed1995

Dependence of in vivo glutamine synthetase activity on ammonia concentration in rat brain studied by 1H - 15N heteronuclear multiple-quantum coherence-transfer NMR.

The dependence of the in vivo rate of glutamine synthesis on the substrate ammonia concentration was studied in rat brain by 1H-15N heteronuclear multiple-quantum coherence-transfer NMR in combination with biochemical techniques. In vivo rates were measured at various steady-state blood and brain ammonia concentrations within the ranges 0.4-0.55 mumol/g and 0.86-0.98 mumol/g respectively, after low-rate intravenous 15NH4+ infusion (isotope chase). The rate of glutamine synthesis at steady state was determined from the change in brain [5-15N]glutamine levels during isotope chase, observed selectively through the amide proton by NMR, and 15N enrichments of brain glutamine and of blood and brain ammonia measured byN gas chromatography-MS. The in vivo rate (v) was 3.3-4.5 mumol/h per g of brain at blood ammonia concentrations (s) of 0.40-0.55 mumol/g. A linear increase of 1/v with 1/s permitted estimation of the in vivo glutamine synthetase (GS) activity at a physiological blood ammonia concentration to be 0.4-2.1 mumol/h per g. The observed ammonia-dependence strongly suggests that, under physiological conditions, in vivo GS activity is kinetically limited by sub-optimal in situ concentrations of ammonia as well as glutamate and ATP. Comparison of the observed in vivo GS activity with the reported in vivo rates of glutaminase and of gamma-aminobutyrate (GABA) synthesis suggests that, under mildly hyperammonaemic conditions, glutamine is synthesized at a sufficiently high rate to serve as a precursor of GABA, but glutaminase-catalysed hydrolysis of glutamine is too slow to be the sole provider of glutamate used for GABA synthesis.

Adenosine Triphosphate↗
PubMed1998

Identification and purification of the reconstitutively active glutamine carrier from rat kidney mitochondria.

The glutamine carrier from rat kidney mitochondria, solubilized in dodecyl octaoxyethylene ether (C12E8) and partly purified on hydroxyapatite, was identified and completely purified by Celite chromatography. On SDS/PAGE, the purified glutamine carrier consisted of a single protein band with an apparent molecular mass of 41.5 kDa. When reconstituted into liposomes, the glutamine carrier catalysed both the unidirectional flux of glutamine and the glutamine/glutamine countertransport, which were completely inhibitable by a mixture of pyridoxal 5'-phosphate and N-ethylmaleimide. The carrier protein was purified 474-fold with a recovery of 58% and a protein yield of 0.12% with respect to the mitochondrial extract. The glutamine carrier-mediated transport is quite specific for l-glutamine. l-Asparagine is the only other amino acid that is efficiently transported by the reconstituted carrier protein. d-Glutamine, l-glutamate and l-aspartate are very poor substrates. The transport activity was inhibited by several thiol-group and amino-group reagents.

Animals↗
PubMed1982

Glutamine production rate and its contribution to urinary ammonia in normal man.

1. Glutamine [15N]amide was infused at a steady rate of 33.34 mumol/h into seven male adult volunteers who were in the fed state and normal acid-base status. 2. Plasma glutamine amide N enrichment and urinary ammonia N enrichment rose to a constant rate within 3 h. 3. The glutamine production rate was 51.8 +/- 7.9 mmol/h. 4. The total ammonia excretion rate was 0.87 mmol/h. Of this excreted ammonia 62.6 +/- 9% was derived from the amide N atom of glutamine. 5. The excreted glutamine amide N (0.53 mmol/h) was only 1% of the glutamine production. If half the ammonia formed by the kidney is excreted in urine and half liberated into the renal vein in subjects with normal acid-base status [E. E. Owen & R. R. Robinson (1963) Journal of Clinical Investigation, 42, 263-276], then the kidney accounts for only 2% of glutamine disposal. 6. Whole body protein turnover, measured from the urinary [15N]ammonia enrichment, was 30.3 +/- 7.7 g of N/day (2.8 g of protein day-1 kg-1).

Adult↗
PubMed1985

Glutamine synthesis in the perfused rat kidney and in isolated rat cortical tubules: regulation by pH.

The possible involvement of renal glutamine synthesis in the regulation of ammoniagenesis during metabolic acidosis has been investigated. Using an isotope dilution technique glutamine synthesis has been demonstrated in the intact perfused rat kidney, despite zero net balance for glutamine in this preparation. Inhibition of glutamine synthesis resulted in increased ammonia production in isolated cortical tubules. The rates of these processes were comparable. We conclude that recycling of nitrogen through glutamine synthesis and glutamine hydrolysis could play a quantitatively significant role in the control of ammonia excretion by the kidney, particularly in acute acidosis where the fall in pH seems to inhibit glutamine synthesis.

Ammonia↗
PubMed1987

Renal ammoniagenesis following glutamine loading in intact dogs during acute metabolic acid-base perturbations.

Adaptation of renal ammoniagenesis during acute metabolic acidosis in intact dogs may be nonexistent or, at least, markedly less than in chronic acidosis. This contrasts to adaptation in acute respiratory acidosis, where levels similar to those attained in chronic acidosis occur within hours. Accordingly, the inability to discern marked changes in acute metabolic acidosis compared with acute respiratory acidosis has been attributed to decreased glomerular filtration rate and renal blood flow seen frequently in the former. In our studies, we found early changes in ammoniagenesis and glutamine metabolism during acute metabolic acidosis, but not of the magnitude seen in chronic acidosis, even considering the changes in renal blood flow (RBF) and glomerular filtration rate (GFR). Exogenous glutamine loading allowed us to discover that the qualitative changes in glutamine metabolism during acute metabolic acidosis differed from control but fell short of those seen in chronic metabolic a acidosis. We also examined glutamine metabolism when renal ammoniagenic adaptation was acutely inhibited in chronically acidotic dogs. Infusing NaHCO3 into chronically acidotic dogs decreased renal ammonia production significantly (247 mumol min-1 100 ml-1 GFR vs 148 mumol min-1 100 ml-1 GFR: P less than 0.001) and glutamine extraction (111.8 mumol min-1 100 ml-1 GFR vs 90.9 mumol min-1 100 ml-1 GFR: P less than 0.02). The qualitative changes in renal glutamine metabolism in both studies suggest that alterations in deamination of glutamate formed from glutamine are responsible, at least in part, for adaptation to acute acid-base perturbations. Compared with respiratory acidosis, adaptation to metabolic acidosis is progressive and prolonged.

Acid-Base Imbalance↗
PubMed2002

Glutamine plays a role in superoxide production and the expression of p47phox, p22phox and gp91phox in rat neutrophils.

The effect of glutamine on the activity of the NADPH oxidase complex from rat neutrophils was investigated. Superoxide anion (O(2)(-)) production was assessed: (1) by scintillation counting by using lucigenin, and (2) by reduction of cytochrome c over 10 min. The effects of glutamine and PMA on the expression of the NADPH oxidase components p22( phox ), gp91( phox ) and p47( phox ) were also determined. Glutamine at 1 and 2 mM increased O(2)(-) generation in the presence of PMA by 100% and 74% respectively, in neutrophils maintained previously for 3 h in medium deprived of this amino acid. DON (6-diazo-5-oxo-L-norleucine), an inhibitor of phosphate-dependent glutaminase and thus of glutamine metabolism, caused a significant decrease in O(2)(-) production by neutrophils stimulated with PMA both in the absence (44%) and in the presence (66%) of glutamine. PMA markedly increased the expression of gp91( phox ), p22( phox ) and p47( phox ) mRNAs. Glutamine (2 mM) increased the expression of these three proteins both in the absence and in the presence of PMA. We postulate that glutamine leads to O(2)(-) production in neutrophils, probably via the generation of ATP and regulation of the expression of components of NADPH oxidase.

Animals↗