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PubMed1990

Prophylactic glutamine protects the intestinal mucosa from radiation injury.

Glutamine may be an essential dietary component, especially for the support of intestinal mucosal growth and function. This study evaluated the effects of a glutamine-enriched elemental diet, administered before whole-abdominal radiation on gut glutamine metabolism, mucosal morphometrics, and bacterial translocation. Rats were randomized to receive a nutritionally complete elemental diet that was glutamine-enriched or glutamine-free for 4 days. The animals were then subjected to a single dose of 1000 cGy x-radiation to the abdomen. After irradiation, all animals received the glutamine-free diet. Four days later the animals underwent laparotomy for sampling of arterial and portal venous blood, culture of mesenteric lymph nodes, and removal of the small intestine for microscopic examination. There was no difference in arterial glutamine or gut glutamine extraction between the two groups, but body weight loss was significantly diminished in the glutamine-fed rats. Rats receiving the glutamine-enriched elemental diet before radiation had a significant increase in jejunal villous number, villous height, and number of metaphase mitoses per crypt. Scanning electron microscopy confirmed the presence of an intact gut epithelium in eight of eight rats receiving prophylactic glutamine compared to one of eight animals in the glutamine-free group. Three of eight rats fed glutamine had culture positive mesenteric lymph nodes compared with five of seven rats receiving the glutamine-free diet. Glutamine exerts a protective effect on the small bowel mucosa by supporting crypt cell proliferation effect on accelerate healing of the acutely radiated bowel.

Animals↗
PubMed1995

Glutamine increases collagen gene transcription in cultured human fibroblasts.

We have previously shown that glutamine stimulates the synthesis of collagen in human dermal confluent fibroblast cultures (Bellon, G. et al. [1987] Biochim. Biophys. Acta, 930, 39-47). In this paper, we examine the effects of glutamine on collagen gene expression. A dose-dependent effect of glutamine on collagen synthesis was demonstrated from 0 to 0.25 mM followed by a plateau up to 10 mM glutamine. Depending on the cell population, collagen synthesis was increased by 1.3-to 2.3-fold. The mean increase in collagen and non-collagen protein synthesis was 63% and 18% respectively. Steady-state levels of alpha 1(I) and alpha 1(III) mRNAs, were measured by hybridizing total RNA to specific cDNA probes at high stringency. Glutamine increased the steady-state level of collagen alpha 1(I) and alpha 1(III) mRNAs in a dose-dependent manner. At 0.15 mM glutamine, collagen mRNAs were increased by 1.7-and 2.3-fold respectively. Nuclear run-off experiments at this concentration of glutamine indicated that the transcriptional activity was increased by 3.4-fold for the pro alpha 1(I) collagen gene. The effect of glutamine on gene transcription was also supported by the measurement of pro alpha 1(I) collagen mRNA half-life since glutamine did not affect its stability. Protein synthesis seemed to be required for the glutamine-dependent induction of collagen gene expression since cycloheximide suppressed the activation. The effect of glutamine appeared specific because analogues and/or derivatives of glutamine, such as acivicin, 6-diazo-5-oxo-L-norleucine, homoglutamine, ammonium chloride and glutamate did not replace glutamine. The influence of amino acid transport systems through plasma membrane was assessed by the use of 2(methylamino)-isobutyric acid and beta 2-aminobicyclo-(2.2.1)-heptane-2-carboxylic acid. The glutamine-dependent induction of collagen gene expression was found to be independent of transport system A but dependent on transport system L whose inhibition induced a decrease in pro alpha 1(I) collagen gene transcription by an unknown mechanism. Thus, glutamine, at physiological concentrations, indirectly regulates collagen gene expression.

Amino Acids↗
PubMed1986

Differences in long-term effects of L-glutamine and D-glucose on insulin release from rat pancreatic islets.

We have compared the effects of long-term exposure to L-glutamine or D-glucose on nutrient-induced insulin release from pancreatic islets of the rat. After 3 days of culture islets were finally tested in 1 h incubations for insulin responses to 16.7 mM of glucose, glutamine, leucine or a combination of leucine and glutamine. After culture at 11 mM glucose + 2 mM glutamine (A), glucose, leucine and glutamine stimulated release to a similar extent from islets. After culture at 1.7 mM glucose + 10 mM glutamine (B), only leucine stimulated insulin release. After culture at 11 mM glucose + 10 mM glutamine (C), both leucine and glutamine increased the insulin response. After culture at 1.7 mM glucose and 2 mM glutamine (D), only glutamine slightly stimulated release. After culture in high glutamine (B or C), a combination of leucine and glutamine significantly inhibited release as compared to leucine alone. A switch in culture media from B to A for 1 h prior to final incubations revived insulin release in response to glucose but not to glutamine. The reverse switch (A to B) abolished both subsequent glucose-and glutamine-induced insulin release. A switch from D to B revived an insulin response to leucine. Exposure of B-cells to 11 mM glucose during 30 min in another experimental system (perfused pancreas) induced a significant insulin response to subsequent stimulation with glutamine; this response was, however, only 17% of that to glucose per se observed in the same experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Increased glutamine consumption in small intestine epithelial cells during sepsis in rats.

BACKGROUND: Previous reports have emphasized increased intestinal glutamine consumption during sepsis. This may be of clinical significance as glutamine is a (and perhaps the) physiologic fuel for the intestine. A problem remains, however, as glutaminase, the major enzyme for the degradation of glutamine, is decreased rather than increased in sepsis. This implies an alteration in the metabolic fate of glutamine in sepsis, which may be of clinical significance. METHODS: We determined the effect of sepsis on glutamine metabolism in mucosa of small intestine. Sepsis was induced in rats by cecal ligation and puncture. Control rats were sham-operated. After 16 hours, glutamine consumption was measured in isolated enterocytes, and glutaminase, glutamine synthetase, and glutamine transaminase activities and DNA synthesis were determined in mucosa. RESULTS: Glutamine consumption was increased during sepsis in enterocytes from the tips of the villi and was unchanged in enterocytes from the midportions of the villi and the crypts. As previously shown, mucosal glutaminase activity was reduced. However, glutamine synthetase and glutamine transaminase activities were stimulated in septic rats, suggesting an increase in metabolism of glutamine via alternate pathways. DNA synthesis was increased during sepsis, especially in crypt cells. CONCLUSIONS: Increased or unchanged glutamine consumption in enterocytes from septic rats, despite reduced glutaminase activity, appears to reflect increased activity of other enzyme systems and/or increased utilization of the amino acid for DNA and protein synthesis. Since other aspects of glutamine metabolism may also be deranged in sepsis, a continual enteral supply of glutamine to the intestinal lumen during sepsis may be clinically useful.

Animals↗
PubMed2001

Glutamine supplementation in cancer patients.

OBJECTIVES: Three series of studies investigated whether 1) glutamine deficiency occurs in tumor-bearing rats, 2) glutamine supplementation improves protein metabolism during chemotherapy in tumor-bearing rats, and 3) oral glutamine supplement improves systemic immune and gut-barrier function in patients with esophageal cancer receiving radiochemotherapy. METHODS: In the animal studies, AH109A hepatoma cells or Yoshida sarcoma cells were inoculated into male Donryu rats to induce tumors. Glutamine production was measured by U-14C-glutamine infusion and the conversion of arginine to glutamine was measured by infusion of U-14C-arginine. The effect of glutamine on protein metabolism was investigated by 1-14C-leucine infusion. In the clinical study, 13 patients with esophageal cancer were randomized into two groups, control and glutamine supplemented (30 g/d), for 4 wk. RESULTS: Glutamine levels in plasma and skeletal muscle were decreased in tumor-bearing rats, although glutamine production and the conversion of arginine to glutamine were increased. Glutamine-supplemented total parenteral nutrition reduced whole-body protein breakdown rate during chemotherapy in tumor-bearing rats. Oral supplementation of glutamine to the patients with esophageal cancer enhanced lymphocyte mitogenic function and reduced permeability of the gut during radiochemotherapy. CONCLUSIONS: Glutamine depletion in host tissues occurs in tumor-bearing rats. Glutamine supplementation can attenuate loss of protein in the muscle in tumor-bearing animals and protect immune and gut-barrier function during radiochemotherapy in patients with advanced cancer.

Animals↗
PubMed1997

Effect of a glutamine-enriched diet on small bowel allograft during immunosuppressive therapy.

The effect of an orally administered glutamine-enriched elemental diet was examined following orthotopic small bowel allotransplantation using Brown Norway rats as donors and Lewis rats as recipients. The recipients was treated with FK 506 and randomized to receive glutamine-free elemental enteral diet solution (glutamine-free group), glutamine-enriched elemental diet solution containing 7500 mg of glutamine per 100 g diet (glutamine-enriched group) or standard chow (chow group) ad libitum for 7 d. There were no histological changes due to resection. Weight loss in the glutamine-enriched group was significantly less than that of the chow group. Both plasma glutamine levels and the ratio of glutamine to total amino acids in the homogenate of the graft mucosa of the glutamine-enriched group were significantly higher than those of the glutamine-fee group. Villous height and crypt depth were significantly decreased in the glutamine-free group. The BrdU labeling index in the graft epithelium and alkaline phosphatase activity in the homogenate of the graft mucosa of the glutamine-enriched group were significantly higher than those of the glutamine-free group. Therefore, orally administered glutamine-enriched elemental diet appears to promote the regeneration and differentiation of the graft mucosa following small bowel allotransplantation.

Aging↗
PubMed1989

Functional hepatocyte heterogeneity. Vascular 2-oxoglutarate is almost exclusively taken up by perivenous, glutamine-synthetase-containing hepatocytes.

1. In isolated perfused rat liver maximal rates of 2-[1-14C]oxoglutarate uptake were about 0.4 mumol.g-1 .min-1; half-maximal rates of 2-[14C]oxoglutarate uptake were observed with influent concentrations of about 100 microM. 2-[14C]Oxoglutarate uptake by the liver was not affected by the direction of perfusion, but was decreased by about 80-90% when Na+ in the perfusion fluid was substituted by choline+, suggesting a Na+-dependence of hepatic 2-oxoglutarate uptake. In the absence of added ammonia, [14C]oxoglutarate uptake by the liver was about twice the net oxoglutarate uptake, indicating a simultaneous release of unlabeled oxoglutarate from perfused rat liver. 2. 14C-Labeled metabolites derived from [1-14C]oxoglutarate and recovered in the effluent perfusate were 14CO2 and 14C-labeled glutamate and glutamine; they accounted for 85-100% of the radiolabel taken up by the liver. 14CO2 was the major product (more than 70%) from [1-14C]oxoglutarate taken up the liver, provided glutamine synthesis was either inhibited by methionine sulfoximine or the endogenous rate of glutamine production was below 40 nmol.g-1.min-1. 3. Stimulation of glutamine synthesis by ammonia did not affect [14C]oxoglutarate uptake by the liver, but considerably increased net hepatic oxoglutarate uptake, indicating a decreased release of unlabeled oxoglutarate from the liver. Stepwise stimulation of hepatic glutamine synthesis led to a gradual decrease of 14CO2 production and radiolabel was recovered increasingly as [14C]glutamine in the effluent. At high rates of glutamine formation (i.e. about 0.6 mumol.g-1.min-1), about 60% of the [1-14C]oxoglutarate taken up by the liver was recovered in the effluent as [14C]glutamine. 14CO2 and [14C]glutamine production from added [1-14C]oxoglutarate were dependent on the rate of hepatic glutamine synthesis but not on the direction of perfusion. Extrapolation of 14C incorporation into glutamine to maximal rates of hepatic glutamine synthesis yielded an about 100% utilization of the [14C]oxoglutarate taken up by the liver for glutamine synthesis. This was again true for both the antegrade and the retrograde perfusion directions. On the other hand, addition of ammonia did not affect 14CO2 production from labeled oxoglutarate, when glutamine synthetase was inhibited by methionine sulfoximine. 4. The data suggest that vascular oxoglutarate is almost exclusively taken up by the small perivenous hepatocyte population containing glutamine synthetase, i.e. a cell population comprising only 6-7% of all hepatocytes. Thus, the findings demonstrate the existence of a, to date, uniquely zonally distributed oxoglutarate transport system which is probably Na+-dependent in the plasma membrane.(ABSTRACT TRUNCATED AT 400 WORDS)

Ammonia↗
PubMed1996

Responses of glutamine transport in cultured rat skeletal muscle to osmotically induced changes in cell volume.

1. In order to investigate the relationship between cellular hydration state and the rate of glutamine transport, tracer glutamine uptake into primary rat myotubes was studied at external osmolalities of 170, 320 or 430 mosmol kg-1. 2. Incubation of myotubes with glutamine (2 mM; 30 min) at 320 mosmol kg-1 increased cell volume and glutamine transport (by 35 and 36%, respectively); insulin (66 nM; 30 min) also increased cell volume and glutamine transport (by 22 and 40%, respectively) and the effects of insulin and glutamine combined were additive. The increase in glutamine uptake following glutamine pre-incubation represented an increase in Vmax of Na(+)-dependent glutamine transport. 3. There was an inverse relationship between myotube glutamine transport and external osmolality after 30 min exposure. 4. During hyposmotic (170 mosmol kg-1) exposure there were large, rapid increases of cell volume and glutamine transport; the latter increased transiently (during the cell swelling phase) by a maximum of approximately 80% at 2 min, (due to an increased Vmax for Na(+)-dependent glutamine transport) then decayed to a new elevated steady state after 30 min exposure. 5. During hyperosmotic (430 mosmol kg-1) exposure there were rapid decreases in glutamine transport and myotube cell volume (both by approximately 30%) to values which were maintained for at least 15 min. 6. The volume-sensitive glutamine transport process features characteristics of the insulin-sensitive system Nm transporter. 7. Modulation of Na(+)-dependent glutamine transport by insulin and cell volume changes may contribute towards regulation of muscle metabolism.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2001

Whole body and skeletal muscle glutamine metabolism in healthy subjects.

We measured glutamine kinetics using L-[5-15N]glutamine and L-[ring-2H5]phenylalanine infusions in healthy subjects in the postabsorptive state and during ingestion of an amino acid mixture that included glutamine, alone or with additional glucose. Ingestion of the amino acid mixture increased arterial glutamine concentrations by approximately 20% (not by 30%; P < 0.05), irrespective of the presence or absence of glucose. Muscle free glutamine concentrations remained unchanged during ingestion of amino acids alone but decreased from 21.0 +/- 1.0 to 16.4 +/- 1.6 mmol/l (P < 0.05) during simultaneous ingestion of glucose due to a decrease in intramuscular release from protein breakdown and glutamine synthesis (0.82 +/- 0.10 vs. 0.59 +/- 0.06 micromol x 100 ml leg(-1) x min(-1); P < 0.05). In both protocols, muscle glutamine inward and outward transport and muscle glutamine utilization for protein synthesis increased during amino acid ingestion; leg glutamine net balance remained unchanged. In summary, ingestion of an amino acid mixture that includes glutamine increases glutamine availability and uptake by skeletal muscle in healthy subjects without causing an increase in the intramuscular free glutamine pool. Simultaneous ingestion of glucose diminishes the intramuscular glutamine concentration despite increased glutamine availability in the blood due to decreased glutamine production.

Adult↗
PubMed1986

Renal regulation of interorgan glutamine flow in metabolic acidosis.

The regulation of interorgan glutamine flow was studied in control and chronically metabolically acidotic rats. Net glutamine extraction or production across the kidneys, gut, liver, and hindquarters was determined in fasted anesthetized animals from organ blood flows and the arteriovenous glutamine concentration difference. In control animals glutamine flows from the hindquarters to the splanchnic bed. In chronic acidosis glutamine production by the hindquarters rose threefold and was redirected to the kidneys; splanchnic bed glutamine uptake was eliminated. Associated with this was a 39% fall and a 62% rise in arterial glutamine and ammonia concentrations, respectively. Removing the kidneys from the circulation returned arterial glutamine and ammonia concentrations to control nonacidotic levels within 30 min. Net glutamine production by the hindquarters decreased, whereas splanchnic bed glutamine extraction increased. Hindquarter glutamine production appears to be modulated by renal venous ammonia; splanchnic bed glutamine extraction is load dependent, reflecting the influence of renal glutamine consumption on the steady-state arterial levels. Thus the removal of the kidneys returns interorgan glutamine flow to that observed in nonacidotic animals consistent with a major role of the kidneys in regulating glutamine flow and nitrogen metabolism in chronic metabolic acidosis.

Acidosis↗
PubMedDate not supplied

Glutamine nutrition and requirements.

Glutamine is the most abundant free amino acid in plasma and tissue pools and an important intermediate in a number of metabolic pathways. Glutamine levels decline markedly in the course of many different catabolic disease states and it has recently been suggested that glutamine may be a conditionally essential dietary nutrient rather than a nonessential amino acid. Changes in tissue glutamine concentrations have been shown to correlate with net protein turnover, and there is evidence that glutamine may both stimulate protein synthesis and inhibit protein degradation. In experimental animals, we have shown that the fall in glutamine concentrations in plasma and tissue pools that occurs in the postoperative state can be prevented or reversed by providing large quantities of exogenous glutamine. In gastrointestinal tissues, the provision of glutamine-free total parenteral nutrition solutions is associated with atrophy of mucosal cells and pancreatic exocrine cells. Glutamine-supplemented parenteral formulas result in diminished atrophy of intestinal mucosal and pancreatic exocrine cells; both intravenous and enteral glutamine promote gastrointestinal tissue regeneration following toxic injury. In animals undergoing partial small intestine resection, glutamine feeding leads to increased adaptive hyperplasia in remaining intestinal segments and results in earlier postoperative weight gain. All of these trophic, anabolic effects of glutamine require the administration of quantities that exceed the glutamine content of normal dietary protein. These findings in experimental animals support the hypothesis that glutamine is a conditionally essential nutrient and suggest a potentially important role for glutamine-supplemented nutrition in catabolic disease states.

Animals↗
PubMed1999

Nutrient uptake by viscera drained by the portal vein in neonatal calves during intravenous infusion of glutamine.

OBJECTIVE: To quantify glutamine use by viscera drained by the portal vein in neonatal calves and to determine whether uptake could be stimulated by long-term IV infusion or long-term use of oral supplements. ANIMALS: 4 healthy neonatal calves. PROCEDURE: A femoral artery, jugular vein, and the portal vein were surgically cannulated in each calf. Blood flow in the portal vein was measured, using an ultrasonic transit-time flow probe. Calves were given an IV infusion of glutamine on days 6, 8, and 10 after surgery. Before the first infusion, calves were fed a diet of milk only. The diet was supplemented with glutamine for the second and third infusions. Glutamine was administered via the jugular vein during a 5-hour period. Venous and arterial blood samples were collected every hour for 5 hours. RESULTS: During glutamine infusion, uptake of glutamine by viscera drained by the portal vein increased in association with increased production of ammonia. Glutamine supplementation of the diet did not alter glutamine uptake. Glutamine infusion did not increase viscera uptake of indispensable amino acids. Long-term use of glutamine supplements or infusion of glutamine for periods of more than 1 hour increased glutamine uptake by viscera. Arterial leucine concentration and uptake of leucine by the viscera decreased during glutamine infusion, indicating that leucine became the limiting factor. CONCLUSION: Glutamine administration (supplements or infusions) to calves may require that a mixture of amino acids be provided to improve effectiveness. CLINICAL RELEVANCE: Glutamine may be beneficial in treatments designed to promote intestinal healing in diarrheic calves.

Absorption↗
PubMed1985

Regulation of glutamine synthetase, aspartokinase, and total protein turnover in Klebsiella aerogenes.

When suspensions of Klebsiella aerogenes are incubated in a nitrogen-free medium there is a gradual decrease in the levels of acid-precipitable protein and of aspartokinase III (lysine-sensitive) and aspartokinase I (threonine-sensitive) activities. In contrast, the level of glutamine synthetase increases slightly and then remains constant. Under these conditions, the glutamine synthetase and other proteins continue to be synthesized as judged by the incorporation of [14C]leucine into the acid-precipitable protein fraction and into protein precipitated by anti-glutamine synthetase antibodies, by the fact that growth-inhibiting concentrations of chloramphenicol also inhibit the incorporation of [14C]leucine into protein and into protein precipitated by anti-glutamine synthetase antibody, and by the fact that chloramphenicol leads to acceleration in the loss of aspartokinases I and III and promotes a net decrease in the level of glutamine synthetase and its cross-reactive protein. The loss of aspartokinases I and III in cell suspensions is stimulated by glucose and is inhibited by 2,4-dinitrophenol. Glucose also stimulates the loss of aspartokinases and glutamine synthetase in the presence of chloramphenicol. Cell-free extracts of K. aerogenes catalyze rapid inactivation of endogenous glutamine synthetase as well as exogenously added pure glutamine synthetase. This loss of glutamine synthetase is not associated with a loss of protein that cross-reacts with anti-glutamine synthetase antibodies. The inactivation of glutamine synthetase in extracts is not due to adenylylation. It is partially prevented by sulfhydryl reagents, Mn2+, antimycin A, 2,4-dinitrophenol, EDTA, anaerobiosis and by dialysis. Following 18 h dialysis, the capacity of extracts to catalyze inactivation of glutamine synthetase is lost but can be restored by the addition of Fe2+ (or Ni2+) together with ATP (or other nucleoside di- and triphosphates. After 40-60 h dialysis Fe3+ together with NADH (but not ATP) are required for glutamine synthetase inactivation. The results suggest that accelerated protein degradation in cells exposed to nitrogen-limited conditions reflects the differential destruction of some proteins, including aspartokinases I and III, in order to sustain the biosynthesis of others such as glutamine synthetase. The loss of glutamine synthetase activity in cell-free extracts is likely mediated in part by mixed-function oxidation systems and could represent a 'marking' step in protein turnover.

Adenosine Triphosphate↗
PubMed2000

Glutamine.

Relatively little was known about glutamine metabolism until the 1930s, when Sir Hans Krebs first demonstrated glutamine hydrolysis and biosynthesis in the kidney. Subsequent studies by Rose in 1938 demonstrated that glutamine is a nonessential (dispensable) amino acid, as it can be readily synthesized de novo in virtually all tissues in the body. Because the body has the capacity to synthesize considerable quantities of glutamine, it has been assumed that glutamine is not required in the diet. However, this amino acid becomes quite depleted during the course of a catabolic insult such as injury or infection, indicating that the ability of glutamine production to meet demands during a variety of surgical illnesses is impaired. In states of health, the assumption that glutamine is not required in the diet is probably valid, although it is difficult to test the hypothesis, as glutamine is present in virtually all dietary proteins. Most naturally occurring food proteins contain 4% to 8% of their amino acid residues as glutamine; therefore less than 10 g of dietary glutamine is likely to be consumed daily by the average person. In contrast to this usual dietary availability, studies in stressed patients indicate that considerably larger amounts of glutamine (20-40 g/day) may be necessary to maintain glutamine homeostasis. Thus from a nutritional standpoint, glutamine may be thought of as a drug as well as a nutrient. This paper reviews the physiology and biochemistry of glutamine with an emphasis on its metabolism in surgical illnesses and its role as a conditionally essential amino acid.

Critical Illness↗
PubMed1999

Effects of vascular or luminal administration and of simultaneous glucose availability on glutamine utilization by isolated rat small intestine.

This study examined whether the route of glutamine administration and the simultaneous availability of glucose affect intestinal glutamine metabolism. We measured net substrate exchange rates of glutamine and its nitrogenous products in the isolated vascularly and luminally perfused rat small intestine (a) as a function of glutamine provision from either the vascular or the luminal or simultaneously from both sides and (b) as a function of simultaneous availability of glucose from various routes. When glutamine was provided from the lumen, only 19-32% of absorbed glutamine appeared intact in the venous effluent, but the release of metabolic products was 170 +/- 5 nmol N min-1 g-1. This measure of intestinal glutamine metabolism was unchanged when glutamine was available only in the vascular perfusate (164 +/- 6 nmol N min-1 g-1). It increased, however, to 271 +/- 14 nmol N min-1 g-1 (P < 0.001) when glutamine was available simultaneously from both the luminal and the vascular perfusate. Glutamine consumption (-110 +/- 6 vs. -70 +/- 5 or -91 +/- 5 vs. -73 +/- 7 nmol min-1 g-1; P < 0.05 each) and the production of citrulline (11.4 +/- 0.7 vs. 10.0 +/- 0.8 or 9.8 +/- 0.5 vs. 7.8 +/- 0.4 nmol min-1 g-1; P < 0.05 each) or ammonia (124 +/- 7 vs. 88 +/- 4; P < 0.01 or 78 +/- 4 vs. 68 +/- 5 nmol min-1 g-1) decreased when glucose (vascular or luminal perfusate) became available in addition to glutamine. We conclude that glutamine is utilized by the small intestine very efficiently regardless of the route of administration being enteral or parenteral. The two routes can be used interchangeably to provide the intestinal mucosa with glutamine. Glucose and glutamine may partially substitute each other, most likely for the purpose as a metabolic fuel.

Ammonia↗
PubMed1991

An Na(+)-dependent and an Na(+)-independent system for glutamine transport in rat liver basolateral membrane vesicles.

In the present study the transport of glutamine across rat liver basolateral membrane was examined with special emphasis on the existence of an Na(+)-independent system and on the characteristics of the Na(+)-dependent system with respect to stoichiometry of glutamine to Na+. Well-validated and purified liver basolateral membrane vesicles were used in the study. Results of studies on the effect of incubation medium osmolarity and incubation temperature indicated that glutamine uptake by liver basolateral membrane vesicles is largely the result of transport of the substrate into the intravesicular compartment with little binding to basolateral membrane vesicles. Transport of glutamine with time was Na+ gradient dependent (out greater than in) with a distinct "overshoot" phenomenon. Replacing Na+ with an equivalent concentration of K+, NH4+, choline, or mannitol caused significant inhibition of the initial rate of glutamine transport; on the other hand, Li+ could partially substitute for Na+. The initial rate of transport of glutamine as a function of concentration (0.05-12 mmol/L) was saturable both in the presence and in the absence of an inwardly directed Na+ gradient. Apparent Km values of 2.95 and 3.35 mmol/L and Vmax values of 11,565 and 6663 pmol.mg protein-1.10s-1 were calculated in the presence and absence of a Na+ gradient, respectively. Both in the presence and absence of an Na+ gradient (out greater than in), transport of [3H]glutamine was significantly inhibited by the addition to the incubation medium of unlabeled glutamine as well as histidine, asparagine, and serine. Transport of glutamine by the Na(+)-dependent process was significantly inhibited or stimulated, respectively, by inducing a relatively positive or negative intravesicular space. On the other hand, glutamine transport by the Na(+)-independent process was not affected by changes in transmembrane electrical potential. Using the "activation method," the stoichiometry of glutamine Na+ transport was found to be 1:1. These results show that glutamine transport in rat liver basolateral membrane vesicles is carrier mediated both in the presence and absence of an Na+ gradient. Furthermore, the Na(+)-dependent process is electrogenic in nature (net positive) and cotransports one glutamine molecule with one Na+. Transport of glutamine by the Na(+)-independent system, on the other hand, is electroneutral in nature.

Animals↗
PubMed1988

Interorgan glutamine metabolism in the tumor-bearing rat.

The effects of progressive malignant disease on gut/liver glutamine metabolism were studied in order to gain further insight into the altered glutamine metabolism that characterizes the host with cancer and to further elucidate the causes and consequences of glutamine depletion in tumor-bearing rats. Rats were inoculated on Day 0 with 2 X 10(6) viable fibrosarcoma cells and blood glutamine was measured every 6 days. On Day 24 the animals underwent laparotomy and sampling of arterial, portal venous, and hepatic venous blood. Arterial glutamine fell by more than one-third in tumor-bearing rats and the arterial-portal venous concentration difference for glutamine across the intestinal tract was diminished by 50% (P less than 0.01). Simultaneously the fractional extraction of glutamine by the gut was reduced from 21 to 15% (P less than 0.05). The liver switched from an organ of near glutamine balance in control rats to one of marked glutamine output in tumor-bearing rats (P less than 0.01). The wet weight of the small intestine was diminished by 15% in tumor-bearing rats and villous height was uniformly decreased in tumor-bearing rats with an average reduction in villous height of 26% (P less than 0.05). The causes of glutamine depletion in this tumor-bearing rat model remain unclear. The growing tumor may behave as a glutamine trap but also appears to alter glutamine metabolism in vital metabolic processing centers such as the gut and liver. Malignant cells may compete with gut mucosal cells for glutamine resulting in a diminished gut glutamine utilization and detrimental changes in mucosal architecture.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Fate of intraluminal glutamine in the perfused renal tubule.

To determine the fate of intraluminal glutamine and specifically the role of brush border gamma glutamyltransferase in its hydrolysis and reabsorption, proximal convoluted tubules of rabbits were isolated and perfused with an artificial ultrafiltrate containing 1 mM 14C-glutamine and 3H-PEG as a volume absorption marker. The tubules, average length 0.80 +/- 0.09 mm, were bathed in perfusate containing albumin, 6.5 percent but no glutamine. Aliquots of collectate and bathing media were monitored for total 14C counts while the distribution of radioactive 14C between glutamine and glutamate in the collectate was determined by separation on a Dowex X8 formate form ion-exchange column. After 3 ten minute control periods the perfusate was switched to one containing 1 mM AT-125 in addition to glutamine and after equilibration an additional 3 collections were obtained. Control period glutamine load averaged 16.1 +/- 2.4 pmole/min of which 35 percent was absorbed and 38 and 27 percent excreted as glutamine and glutamate respectively; of the absorbed glutamine 25 percent was metabolized. During AT-125 administration, glutamine delivery averaged 15.0 +/- 2.1 pmole/min of which 57 percent was absorbed; increased absorption occurred at the expence of intraluminal glutamate formation which fell to less than 10 percent. Thus luminal transport and gamma glutamyltransferase mediated hydrolysis appear to compete for available glutamine. Significantly, reducing intraluminal glutamine hydrolysis doubles the cellular metabolism of absorbed glutamine suggesting that extracellular conversion of glutamine to glutamate alters the metabolic fate of filtered glutamine.

Absorption↗