Glutamine Abstracts

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Roth E Spittler A Oehler R

[Glutamine: effects on the immune system, protein balance and intestinal functions (see comments)]

Glutamin: Wirkungen auf das Immunsystem, auf Eiweisshaushalt und Darmfunktionen.

In: Wien Klin Wochenschr (1996) 108(21):669-76

Glutamine is the most abundant free amino acid of the human body. In catabolic stress situations such as after operations, trauma and during sepsis the enhanced transport of glutamine to splanchnic organs and to blood cells results in an intracellular depletion of glutamine in skeletal muscle. Glutamine is an important metabolic substrate for cells cultivated under in vitro conditions and is a precursor for purines, pyrimidines and phospholipids. Increasing evidence suggests that glutamine is a crucial substrate for immunocompetent cells. Glutamine depletion in the cultivation medium decreases the mitogen-inducible proliferation of lymphocytes, possibly by arresting the cells in the G0-G1 phase of the cell cycle. Glutamine depletion in lymphocytes prevents the formation of signals necessary for late activation. In monocytes glutamine deprivation downregulates surface antigens responsible for antigen preservation and phagocytosis. Glutamine is a precursor for the synthesis of glutathionine and stimulates the formation of heat-shock proteins. Moreover, there are suggestions that glutamine plays a crucial role in osmotic regulation of cell volume and causes phosphorylation of proteins, both of which may stimulate intracellular protein synthesis. Experimental studies revealed that glutamine deficiency causes a necrotising enterocolitis and increases the mortality of animals subjected to bacterial stress. First clinical studies have demonstrated a decrease in the incidence of infections and a shortening of the hospital stay in patients after bone marrow transplantation by supplementation with glutamine. In critically ill patients parenteral glutamine reduced nitrogen loss and caused a reduction of the mortality rate. In surgical patients glutamine evoked an improvement of several immunological parameters. Moreover, glutamine exerted a trophic effect on the intestinal mucosa, decreased the intestinal permeability and thus may prevent the translocation of bacteria. In conclusion, glutamine is an important metabolic substrate of rapidly proliferating cells, influences the cellular hydration state and has multiple effects on the immune system, on intestinal function and on protein metabolism. In several disease states glutamine may consequently, become an indispensable nutrient, which should be provided exogenously during artificial nutrition.

Comment in: Wien Klin Wochenschr 1996 ;108(21):667-8

Institutional address: Chirurgisches Forschungslaboratorium Universitatsklinik fur Chirurgie Allgemeines Krankenhaus Wien.



Ziegler TR, Benfell K, Smith RJ, Young LS, Brown E, Ferrari-Baliviera E, Lowe DK, Wilmore DW

Safety and metabolic effects of L-glutamine administration in humans.

In: JPEN J Parenter Enteral Nutr (1990 Jul-Aug Jul-Aug) 14(4 Suppl):137S-146S

A series of dose-response studies was conducted to evaluate the clinical safety, pharmacokinetics, and metabolic effects of L- glutamine administered to humans. Initial studies in normal individuals evaluated the short-term response to oral loads of glutamine at doses of 0, 0.1, and 0.3 g/kg. A dose-related increase in blood glutamine occurred after oral loading and elevation of amino acids known to be end products of glutamine metabolism occurred (including alanine, citrulline, and arginine). No evidence of clinical toxicity or generation of toxic metabolites (ammonia and glutamate) was observed. Glutamine was infused intravenously in normal subjects over 4 hr at doses of 0.0125 and 0.025 g/kg/hr. In addition, glutamine was evaluated as a component of parenteral nutrition solutions (0.285 and 0.570 g/kg/day) administered for 5 days to normal subjects. Intravenous administration of glutamine was well tolerated without untoward clinical or biochemical effects. Subsequent studies in patients receiving glutamine-enriched parenteral nutrition for several weeks confirmed the clinical safety of this approach in a catabolic patient population. In addition, nitrogen retention appeared to be enhanced when glutamine was administered at a dose of 0.570 g/kg/day in a balanced nutritional solution providing adequate calories (145% of basal) and protein (1.5 g/kg/day). Nitrogen balance in patients receiving lower doses of glutamine (0.285 g/kg/day) was similar to that in patients receiving standard formulations. Further controlled clinical trials of the metabolic efficacy, tolerance, and dose response of glutamine in other patient groups are necessary to determine the appropriate use of glutamine enrichment of nutrient solutions.

Institutional address: Department of Surgery Brigham and Women’s Hospital Boston Massachusetts.



Gismondo MR, Drago L, Fassina MC, Vaghi I, Abbiati R, Grossi E

Immunostimulating effect of oral glutamine.

In: Dig Dis Sci (1998 Aug) 43(8):1752-4

Glutamine represents the principal metabolic substrate for all rapidly proliferating cells. Since part of the glutamine efficacy could be related to immunoregulating properties, we assessed the effects of orally administered glutamine on serum interleukin-2 (IL- 2) levels and intestinal T-cell populations in 48 athymic (nude) mice. Twenty-four mice received a standard diet enriched by glutamine (added to drinking water at a 4% concentration), while the other 24 served as the control group and received the same diet without glutamine. In glutamine-fed animals, we observed a marked increase in IL-2 concentrations after 10 days of treatment in comparison with control group and a modest but significant increase in intestinal T- cell counts. These results suggest that oral glutamine is able to exert local and systemic immunostimulating activity that could be of relevance in the prevention of gut integrity and immune defense loss associated, for example, with trauma, surgery, and starvation.

Institutional address: Clinical Microbiology Lab L. Sacco Teaching Hospital University of Milan Italy.



Welbourne TC

Increased plasma bicarbonate and growth hormone after an oral glutamine load.

In: Am J Clin Nutr (1995 May) 61(5):1058-61

An oral glutamine load was administered to nine healthy subjects to determine the effect on plasma glutamine, bicarbonate, and circulating growth hormone concentrations. Two grams glutamine were dissolved in a cola drink and ingested over a 20-min period 45 min after a light breakfast. Forearm venous blood samples were obtained at zero time and at 30-min intervals for 90 min and compared with time controls obtained 1 wk earlier. Eight of nine subjects responded to the oral glutamine load with an increase in plasma glutamine at 30 and 60 min before returning to the control value at 90 min. Ninety minutes after the glutamine administration load both plasma bicarbonate concentration and circulating plasma growth hormone concentration were elevated. These findings demonstrate that a surprisingly small oral glutamine load is capable of elevating alkaline reserves as well as plasma growth hormone.

Institutional address: Department of Physiology Louisiana State University College of Medicine Shreveport 71130 USA.



Welbourne T, Claville W, Langford M

An oral glutamine load enhances renal acid secretion and function.

In: Am J Clin Nutr (1998 Apr) 67(4):660-3

In a recent study, a small oral glutamine load acutely elevated plasma bicarbonate concentrations in healthy adults (Am J Nutr 1995;61:1058-61). The present study was designed to elucidate the renal mechanism underlying the base-generating response to L- glutamine. Accordingly, vehicle (489 mL diet soda) or vehicle plus 2 g L-glutamine (28 mg/kg body wt) was ingested and the gain in extracellular fluid volume bicarbonate was compared with renal acid elimination as either ammonium excretion or tubular acid secretion (titratable acid plus bicarbonate reabsorption). Vehicle alone, which contained 27 mmol acid, did not increase extracellular fluid volume bicarbonate over the 90-min period. In contrast, L-glutamine increased plasma bicarbonate concentration (from 25.4+/-2 to 27.9+/-1 mmol/L, P < 0.05) and extracellular fluid volume bicarbonate by an estimated 39+/-10 mmol. When added to that required to neutralize the ingested acid, the combined total for new bicarbonate generated gave an estimated 66+/-10 mmol. Surprisingly, ammonium excretion accounted for < 2% of this newly generated bicarbonate. However, acid secreted and excreted as net acid (5.2+/-4.0 mmol/90 min) as well as that coupled to enhanced bicarbonate reabsorption (76+/-20 mmol/90 min) readily accounted for the estimated base gain (81+/-24 compared with 66+/-10 mmol/90 min). Concomitant with enhanced renal acid secretion, the oral glutamine load elicited an increase in glomerular filtration rate. These results rule out a role for L-glutamine as a direct precursor of bicarbonate and instead point to an indirect role in accelerating acid secretion, apparently coupled to increased glomerular filtration rate.

Institutional address: Department of Physiology Louisiana State University Medical Center Shreveport 71130 USA.



Cao Y, Feng Z, Hoos A, Klimberg VS

Glutamine enhances gut glutathione production.

In: JPEN J Parenter Enteral Nutr (1998 Jul-Aug Jul-Aug) 22(4):224-7

BACKGROUND: The gastrointestinal tract is recognized as having important metabolic functions. This study examined gut glutathione (GSH) extraction and the effect of supplemental oral glutamine (GLN) on gut GSH fractional release. METHODS: Healthy female Fisher-344 rats weighing approximately 150 to 200 g were pair-fed chow and supplemented by gavage with 1 g/kg/d GLN or an isonitrogenous amount of Freamine (McGaw, St. Louis, MO). Rats were sacrificed at 6 weeks. Arterial and portal blood was assayed for GLN and GSH content. The gut GLN and GSH extractions were calculated. RESULTS: The gut GLN fractional uptake was increased by approximately 50%, and there was a near threefold increase in gut GSH fractional release in the GLN- supplemented group. CONCLUSIONS: The discovery of gut’s role as a major producer of GSH may give insight into why feeding via the gut rather than by the venous route is so important. Supplemental oral GLN further enhances GLN extraction as well as GSH fractional release in the gut.

Institutional address: University of Arkansas for Medical Sciences Department of Surgery Little Rock 72205



Inoue Y, Espat NJ, Frohnapple DJ, Epstein H, Copeland EM, Souba WW

Effect of total parenteral nutrition on amino acid and glucose transport by the human small intestine.

In: Ann Surg (1993 Jun Jun) 217(6):604-12; discussion 612-4

OBJECTIVE: The effect of total parenteral nutrition (TPN) on small intestinal amino acid transport activity was studied in humans. SUMMARY BACKGROUND DATA: Studies in humans receiving TPN indicate that a decrease in the activities of the dissacharidase enzymes occurs, but morphologic changes are minimal with only a slight decrease in villous height. METHODS: Surgical patients were randomized to receive TPN (n = 6) or a regular oral diet (controls, n = 7) for 1 week before abdominal surgery. Ileum (5 controls, 5 TPN) or jejunum (2 controls, 1 TPN) were obtained intraoperatively and brush-border membrane vesicles (BBMV) were prepared by magnesium aggregation/differential centrifugation. Transport of L-MeAlB (a selective system A substrate), L-glutamine, L-alanine, L-arginine, L- leucine, and D-glucose was assayed by a rapid mixing/filtration technique in the presence and absence of sodium. RESULTS: Vesicles demonstrated approximately 18-fold enrichments of enzyme markers, classic overshoots, transport into an osmotically active space, and similar 1-hour equilibrium values. TPN resulted in a 26-44% decrease in the carrier-mediated transport velocity of all substrates except glutamine across ileal BBMVs. In the one patient receiving TPN from whom jejunum was obtained, there was also a generalized decrease in nutrient transport, although glutamine was least affected. Kinetic studies of the system A transporter demonstrated that the decrease in uptake was secondary to a reduction in carrier Vmax, consistent with a decrease in the number of functional carriers in the brush-border membrane. CONCLUSIONS: TPN results in a decrease in brush-border amino acid and glucose transport activity. The observation that glutamine transport is not downregulated by 1 week of bowel rest may further emphasize the important metabolic role that glutamine plays as a gut fuel and in the body’s response to catabolic stresses.

Institutional address: Department of Surgery University of Florida College of Medicine Gainesville.



Niihara Y, Zerez CR, Akiyama DS, Tanaka KR

Oral L-glutamine therapy for sickle cell anemia: I. Subjective clinical improvement and favorable change in red cell NAD redox potential.

In: Am J Hematol (1998 Jun Jun) 58(2):117-21

Previously, we demonstrated that there is an increased utilization of glutamine by intact sickle red blood cells (RBC) in conjunction with nicotinamide adenine dinucleotide (NAD) metabolism in vitro. In this report, we describe the in vivo effect of L-glutamine supplementation on total NAD, nicotinamide adenine dinucleotide reduced (NADH), and NAD redox potential of sickle RBC. Seven adult sickle cell anemia patients participated in this study. The exclusion criteria were pregnancy, previous or current use of hydroxyurea, and transfusion within 3 months of initiation of the study. After proper consent, L- glutamine was started at a dose of 30 g/day administered orally. Fasting blood samples were drawn at baseline and after 4 weeks of therapy by routine phlebotomy for evaluation of RBC total NAD and NADH levels. We found significant changes in both the NADH level and NAD redox potential (ratio of NADH to NAD+ + NADH). NAD redox potential increased from 47.2 +/- 3.7% to 62.1 +/- 11.8% (P < 0.01). The NADH level increased from 47.5 +/- 6.3 to 72.1 +/- 15.1 nmol/ml RBC (P < 0.01). The total NAD level demonstrated an upward trend (from 101.2 +/- 16 to 116.4 +/- 14.7 nmol/ml RBC) but this was not statistically significant. Our data show that oral L-glutamine can significantly increase the NAD redox potential and NADH level in sickle RBC. These changes may decrease oxidative susceptibility of sickle RBC and result in clinical benefit.

Institutional address: Department of Medicine Harbor-UCLA Medical Center UCLA School of Medicine Torrance California USA.



Brown MG, Campbell GR, Rowlands BJ

Glutamine-enhanced enteral diet improves nitrogen balance without increasing portal ammonia.

In: Br J Surg (1991 Nov) 78(11):1305-6

Following surgical stress the jejunum actively metabolizes endogenous glutamine, a non-essential amino acid, to produce alanine and ammonia, which augments substrate flow to the liver at a time when oral intake of nutrients is decreased. Oral glutamine supplementation theoretically may modify the response to injury. This study was designed to demonstrate the role of the jejunum in postinjury glutamine metabolism and to evaluate the influence of enteral glutamine supplements on nitrogen and ammonia metabolism after laparotomy and bowel resection in dogs. Oral glutamine in the presence of an intact small bowel significantly improved nitrogen balance (461 mg kg body-weight-1 day-1) compared with a control diet (-370 mg kg-1 day-1) (P less than 0.05, analysis of variance). Removal of the proximal small bowel prevented this beneficial effect of glutamine (-507 mg kg-1 day-1). Glutamine-supplemented and control diets were associated with similar portal ammonia concentrations throughout the study.

Institutional address: Department of Surgery Queen’s University Belfast UK.



Martinez J

[The intestines, their role in the critical patient and the concept of bacterial translocation]

El intestino; su papel en el paciente critico y el concepto de translocacion bacteriana.

In: Rev Med Chil (1993 Jul) 121(7):800-10

The gut is a central organ during critical illnesses that occur as a result of injuries or postoperative infections. After the successful treatment of shock, pulmonary and renal failure, a prolonged septic state emerges, frequently without apparent origin. An immunological host defense failure, associated with the intensive care support that fails to provide the essential amino acid glutamine to the gut, promotes a iatrogenic host invasion by microorganism or soilage by their toxins. This process is called “Bacterial Translocation”. The increased permeability of the intestine, coupled with changes in intestinal flora, allows the bowel to serve as a reservoir of pathogens that can enter the portal and systemic circulations and fuel the ongoing septic process. Activating the hepatic reticuloendothelial system, bacterial translocation initiates the Multiple Organ Failure Syndrome. We discuss new therapeutic approaches derived from the aforementioned concepts.

Institutional address: Servicio de Urgencia Facultad de Medicina Pontificia Universidad Catolica Santiago de Chile.



Fink MP

Gastrointestinal mucosal injury in experimental models of shock, trauma, and sepsis.

In: Crit Care Med (1991 May) 19(5):627-41

BACKGROUND AND METHODS: The mucosa of the GI tract serves as an important barrier limiting the systemic absorption of luminal microbes and microbial products. Two methods commonly used to assess the integrity of the GI mucosal barrier are assessment of the extent of microbial translocation and measurement of mucosal permeability to hydrophilic probes. RESULTS: Studies using these methods have provided convincing evidence that the barrier function of the intestinal mucosa is deranged in numerous animal models of shock, trauma, and sepsis. CONCLUSIONS: Although the mechanisms underlying mucosal injury under these circumstances remain incompletely understood, current evidence suggests that mucosal damage in shock, trauma, and sepsis is likely due to various combinations of intracellular hypoxia due to ischemia, tissue injury caused by reactive oxygen metabolites, the deleterious effects of various lipid mediators (e.g., platelet-activating factor) and/or cytokines (e.g., tumor necrosis factor), and deficient utilization or supply of key nutritional substrates (e.g., glutamine).

Institutional address: Department of Surgery University of Massachusetts Medical Center Worcester 01605.




Intestinal epithelial barrier dysfunction in Crohn’s disease.

In: Proc Soc Exp Biol Med (1997 Apr) 214(4):318-27

Despite extensive research, the etiology of Crohn’s disease remains unknown. Accumulating evidence suggests the possibility that a primary defect of intestinal barrier function may be present in Crohn’s disease. In this review, the possible role of intestinal barrier defect in Crohn’s disease is discussed. It has been recognized for some time that Crohn’s patients have a defective intestinal epithelial barrier function manifested by an increase in intestinal permeability. Recent studies indicate that a subgroup of healthy first-degree relatives of Crohn’s patients (a population at high risk for developing Crohn’s disease) also have increased intestinal permeability. Additionally, this subgroup of patients have evidence of increased exposure to foreign antigens, suggesting a possible link between increase in intestinal permeability and increase in antigenic penetration. Furthermore, exacerbation of Crohn’s disease is produced by agents that disrupt intestinal epithelial barrier function, while remission of active disease is induced by decreasing intestinal antigenic load. A “leaky gut” hypothesis is advanced which proposes that a preexisting disorder of intestinal permeability is responsible for the intestinal inflammation of Crohn’s disease.

Institutional address: Department of Medicine DVA Medical Center Long Beach California 90822 USA.



Li J Langkamp-Henken B Suzuki K Stahlgren LH

Glutamine prevents parenteral nutrition-induced increases in intestinal permeability [see comments]

In: JPEN J Parenter Enteral Nutr (1994 Jul-Aug) 18(4):303-7

In addition to its role in absorbing nutrients, the intestinal mucosa provides an important barrier against toxins and bacteria in the bowel lumen. This study evaluated changes in rat jejunal permeability and histology after total parenteral nutrition (TPN) or TPN supplemented with glutamine. Lactulose and mannitol were used to measure jejunal permeability, and fixed stained histologic specimens were used to measure mucosal dimensions. After the insertion of central venous catheters, 18 male rats were randomly divided into three groups: CHOW, saline infusion with a standard laboratory rat diet ad libitum; TPN; and GLN, 2% L-glutamine-supplemented TPN. The TPN and GLN groups received isocaloric, isovolumic, and isonitrogenous feedings. After 7 days of infusion, a laparotomy was performed, and lactulose and mannitol were instilled into the lumen of a 25-cm ligated segment of jejunum. Urine was collected for 5 hours and assayed for lactulose, mannitol, and creatinine. The jejunum was harvested, and wet weight, villus height, mucosal thickness, and villus width were measured. Intestinal permeability to lactulose and the lactulose to mannitol ratio significantly increased after TPN compared with CHOW, and these effects were prevented with the addition of glutamine to the TPN solution. Jejunal villus height and mucosal thickness significantly decreased following TPN but were not significantly different from CHOW when glutamine was added to the TPN solution. These data suggest that TPN was associated with increased jejunal permeability and that glutamine, when added to the TPN solution, prevented this effect. In addition, glutamine reduced TPN-associated atrophy of the jejunum.

Comment in: JPEN J Parenter Enteral Nutr 1994 Jul-Aug;18(4):289-90

Institutional address: Department of Surgery Saint Joseph Hospital Denver CO 80218.



Buchman AL Moukarzel AA Bhuta S Belle M Ament ME Eckhert CD Hollander D Gornbein J Kopple JD Vijayaroghavan SR

Parenteral nutrition is associated with intestinal morphologic and functional changes in humans.

In: JPEN J Parenter Enteral Nutr (1995 Nov-Dec) 19(6):453-60

BACKGROUND: Numerous animal studies have demonstrated intestinal villus atrophy occurs when luminal nutrition is withheld and total parenteral nutrition (TPN) is provided. Intestinal morphologic and functional changes have not been well studied in humans during TPN. METHODS: Eight normal volunteers were hospitalized in the Clinical Research Center for 3 weeks. The subjects received TPN as an exclusive means of nutritional support for 14 days followed by 5 days of enteral refeeding with either a standard or a glutamine and arginine-supplemented formula. Endoscopic jejunal biopsies were taken before and after TPN and after enteral refeeding. Intestinal morphology was examined by light and transmission electron microscopy. Mucosa DNA, RNA, and protein concentrations were measured. Lactose breath hydrogen and intestinal permeability testing (urinary lactulose and mannitol excretion after an oral dose) were performed before and after TPN and after enteral refeeding. RESULTS: Total mucosal thickness decreased after TPN (645 +/- 19 to 512 +/_ 19 microns, p = .003) and increased significantly towards baseline after enteral refeeding (575 +/- 19 microns, p = .04). The change was related solely to villus height; crypt depth was unaffected. Villus cell count decreased from 179 +/- 15 to 163 +/- 12 after TPN (p = .03) and increased after enteral refeeding to 176 +/- 21 (p = .06). Crypt cell count was unaffected by TPN or refeeding. A nonsignificant decrease in the mitotic index after TPN was seen. Intracellular edema developed during TPN and resolved with enteral refeeding. The urinary lactulose-mannitol ratio increased with TPN [0.06 +/- 0.03 to 0.11 +/- 0.05 after TPN and 0.14 +/_ 0.09 after short-term enteral refeeding (p = .05)], indicating increased intestinal permeability. The urinary lactulose-mannitol ratio was significantly greater after refeeding with standard formula than the free amino acid peptide formula with glutamine and arginine (0.20 +/- 0.05, vs 0.08 +/- 0.01, p = .05). No significant differences were noted in mucosal RNA, DNA, protein, DNA- protein or RNA-DNA rations or breath hydrogen after lactose ingestion after either TPN or enteral refeeding. No significant difference in plasma glutamine was found during TPN (462.7 +/ 38.7 vs 491.8 +/- 46.1 mumol/L) or after enteral refeeding (457.3 +/- 51.4 mumol/L). CONCLUSIONS: Intestinal morphologic and functional changes occur in human for whom TPN is the sole nutritional source, although the findings in humans are substantially less significant than observed in animal models. The loss of mucosal structure may be sufficient to cause increased intestinal permeability, the clinical significance of which remains to be defined. Enteral nutrition is important in restoring and probably preventing morphologic intestinal changes associated with TPN, and a peptide and free amino acid-based formula supplemented with glutamine and arginine may have some added role. Our findings also suggest sepsis is associated with gut adaptation rather than degradation.

Institutional address: Division of Gastroenterology Baylor College of Medicine Houston Texas 77030 USA.



Richards EW, Long CL, Pinkston JA, Ellis V, Mostaghimi M, Gandy RE

The role of oral glutamine supplementation in the prevention of radiation-induced enterocolitis in prostate cancer patients (Meeting abstract).

In: FASEB J (201992) 6(5):A1680

Several animal studies have demonstrated that oral glutamine supplementation protects the gastrointestinal mucosa from both radiation- and chemotherapy-induced injury. Utilizing both detailed patient (pt) accounts of the incidence and frequency of clinical symptoms associated with radiation-induced enterocolitis, combined with histological and morphometric analysis of endoscopically directed rectosigmoid biopsies, we have evaluated the prophylactic efficacy of oral glutamine supplementation in a group of 26 prostate cancer pts. Upon entry in the study, pts were randomly assigned to receive either oral glutamine or placebo (sucrose; 21 g/day divided into 7-g doses x 3 daily with meals) throughout the course of a standardized radiotherapy protocol for prostate cancer. Although av number of bowel movements per day, stool vol and stool consistency were not different between the 2 groups, pre- and 11 day postradiation (after approx 2300-cGy whole-pelvis irradiation) biopsies revealed significant improvements in histological and morphometric parameters, as assessed by light microscopy. In addition, the glutamine group appeared to require less medication (diphenoxylate) for the control of diarrhea. This observation suggests that further study of oral glutamine supplementation in such pts is warranted.

Institutional address: Dept. of Res. Baptist Medical Centers Birmingham AL



Inoue Y, Bode BP, Souba WW

Dietary regulation of the hepatic system n glutamine transporter in tumor-bearing rats.

In: Am J Surg (1995 Jan Jan) 169(1):173-8

BACKGROUND: Hepatocytes possess a novel, plasma-membrane, sodium ion (Na+)-independent, glutamine transporter (system n), which functions to transport glutamine out of the cell into the blood. In the tumor- bearing rat, the activity of system n increases but its regulation is unknown. We hypothesized that the increase in system n that occurs in rats with cancer was related to a fall in the circulating glutamine concentration. METHODS: Ten male rats underwent flank implantation with a cube of methylcholanthrene-induced fibrosarcoma cells and 10 rats underwent a sham operation. After 9 days of standard diet, all rats were randomized to receive either a glutamine-enriched oral diet or an isonitrogenous diet without supplemental glutamine, for 1 week. Tumors and livers were harvested 16 days postimplantation. Arterial blood samples were obtained from all animals. Hepatic plasma membrane vesicles were prepared and the carrier-mediated, Na(+)-independent transport of glutamine was assayed. RESULTS: When compared to nontumor-bearing animals, tumor-bearing rats that were fed a control diet exhibited hypoglutaminemia and a 2.3-fold increase in the activity of system n. Glutamine dietary supplementation produced blood glutamine levels that were similar in both tumor-bearing and nontumor-bearing rats, apparently abrogating the increase in system n activity that was observed in tumor-bearing rats that were not fed supplemental glutamine. Tumor-bearing animals receiving supplemental glutamine had a decreased number of system n carriers (Vmax) in the hepatic plasma membrane compared to that of tumor-bearing animals receiving a control diet; this apparently abrogated the glutamine efflux rate. Glutamine feeding did not alter system n activity in nontumor-bearing controls. CONCLUSIONS: In the tumor-bearing animal model, system n is modulated by the circulating glutamine concentration. This is the first study that demonstrates the ability of specialized nutrition to “downregulate” transport activity in vivo. Provision of glutamine-enriched diets to the host with cancer may maintain hepatic glutamine levels and prevent host glutamine depletion.

Institutional address: Department of Surgery University of Florida College of Medicine Gainesville.



Rouse K, Nwokedi E, Woodliff JE, Epstein J, Klimberg VS

Glutamine enhances selectivity of chemotherapy through changes in glutathione metabolism.

In: Ann Surg (1995 Apr Apr) 221(4):420-6

OBJECTIVE: Chemotherapy doses are limited by toxicity to normal tissues. Intravenous glutamine protects liver cells from oxidant injury by increasing intracellular glutathione (GSH) content. The authors hypothesized that supplemental oral glutamine (GLN) would increase the therapeutic index of methotrexate (MTX) by improving host tolerance through changes in glutathione metabolism. The authors examined the effects of oral glutamine on tumor and host glutathione metabolism and response to methotrexate. METHODS: Thirty-six 300-g Fischer 344 rats were implanted with fibrosarcomas. On day 21 after implantation, rats were randomized to receive isonitrogenous isocaloric diets containing 1 g/kg/day glutamine or glycine (GLY) by gavage. On day 23 after 2 days of prefeeding, rats were randomized to one of the following four groups receiving an intraperitoneal injection of methotrexate (20 mg/kg) or saline (CON): GLN+MTX, GLY+MTX, GLN-CON, or GLY-CON. On day 24, rats were killed and studied for arterial glutamine concentration, tumor volume, kidney and gut glutaminase activity, and glutathione content (tumor, gut, heart, liver, muscle, kidney, and lung). RESULTS: Provision of the glutamine- enriched diets to rats receiving MTX decreased tumor glutathione (2.38 +/- 0.17 in GLN+MTX vs. 2.92 +/- 0.20 in GLY+MTX, p < 0.05), whereas increasing or maintaining host glutathione stores (in gut, 2.60 +/- 0.28 in GLN+MTX vs. 1.93 +/- 0.18; in GLY+MTX, p < 0.05). Depressed glutathione levels in tumor cells increases susceptibility to chemotherapy. Significantly decreased glutathione content in tumor cells in the GLN+MTX group correlated with enhanced tumor volume loss (-0.8 +/- 1.0 mL in GLN+MTX vs. +9.5 +/- 2.0 mL in GLY+MTX, p < 0.05). CONCLUSION: These data suggest that oral glutamine supplementation will enhance the selectivity of antitumor drugs by protecting normal tissues from and possibly sensitizing tumor cells to chemotherapy treatment-related injury.

Institutional address: University of Arkansas for Medical Sciences Little Rock USA.



Rubio IT, Cao Y, Hutchins LF, Westbrook KC, Klimberg VS

Effect of glutamine on methotrexate efficacy and toxicity.

In: Ann Surg (1998 May May) 227(5):772-8; discussion 778-80

OBJECTIVE: To examine the effect of oral glutamine (GLN) on the efficacy and toxicity of methotrexate (MTX). SUMMARY BACKGROUND DATA: The use of high-dose chemotherapy regimens is limited by the severity of their toxicities. Oral GLN has been shown to decrease the gut toxicity seen with MTX treatment while enhancing its tumoricidal effect. METHODS AND RESULTS: Studies were done in laboratory rats and in breast cancer outpatients. Fischer 344 rats were randomized to 48 hours of prefeeding with GLN (1 g/kg/day) or an isonitrogenous amount of glycine. Rats were killed 24 hours after receiving a 20-mg/kg intraperitoneal dose of MTX. In the GLN group, there was a threefold increase in total MTX in the tumor as compared with the control group, and this increase was in both the diglutamated and pentaglutamated MTX. Inversely, there was a significant decrease in the total polyglutamated MTX in the gut in the GLN group. Given the results of this preclinical study, the authors performed a phase I trial. Nine patients diagnosed with inflammatory breast cancer received GLN (0.5 g/kg/day) during MTX neoadjuvant therapy, escalating from doses of 40 mg/m2 to 100 mg/m2 weekly for 3 weeks, followed by a doxorubicin-based regimen. No toxicity of oral GLN was detected. No patient showed any sign of chemotherapy-related toxicity. One patient had a grade I mucositis. Except for one, all patients responded to the chemotherapy regimen. Median survival was 35 months. CONCLUSIONS: These studies suggest that GLN supplementation is safe in its administration to the tumor-bearing host receiving MTX. By preferentially increasing tumor retention of MTX over that of normal host tissue, GLN may serve to increase the therapeutic window of this chemotherapeutic age.

Institutional address: Department of Surgery University of Arkansas for Medical Sciences Little Rock 72205 USA.



Anderson PM, Schroeder G, Skubitz KM

Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy.

In: Cancer (1998 Oct 1) 83(7):1433-9

BACKGROUND: Mouth sores and/or difficulty swallowing are common and painful consequences of cytotoxic chemotherapy for cancer. In previous studies oral glutamine was found to protect animals from the effects of whole abdominal radiation and methotrexate-induced enteritis. Glutamine also was found to reduce oral mucositis in a nonrandomized pilot study in humans. Therefore, the authors attempted to determine the efficacy of oral glutamine in a randomized, double blind, crossover trial in cancer patients receiving chemotherapy. METHODS: Twenty-four patients (16 children and 8 adults) received glutamine or placebo (glycine) suspension (2 g amino acid/M2/dose twice daily) to swish and swallow on days of chemotherapy administration and for at least 14 additional days. Patients completed a calendar indicating days of mouth pain associated with each chemotherapy course and the effect of mouth pain on oral intake. RESULTS: Paired data indicated significant amelioration of stomatitis associated with glutamine administration after chemotherapy. The duration of mouth pain was 4.5 days less in chemotherapy courses in which glutamine supplementation was compared with placebo (Wilcoxon’s signed rank test, P=0.0005). The severity of oral pain also was reduced significantly when glutamine was provided with chemotherapy (the amount of days mucositis restricted oral intake to soft foods [> or =Grade 2; Modified Eastern Cooperative Oncology Group grading system] was 4 days less with glutamine compared with placebo; Wilcoxon’s signed rank test, P=0.002). CONCLUSIONS: Low dose oral glutamine supplementation during and after chemotherapy significantly reduced both the duration and severity of chemotherapy-associated stomatitis. Oral glutamine appears to be a simple and useful measure to increase the comfort of many patients at high risk of developing mouth sores as a consequence of intensive cancer chemotherapy.

Institutional address: Department of Pediatrics and Adolescent Medicine Mayo Clinic Rochester Minnesota 55905



MacLean DA, Graham TE, Saltin B

Stimulation of muscle ammonia production during exercise following branched-chain amino acid supplementation in humans.

In: J Physiol (Lond) (1996 Jun 15) 493 ( Pt 3):909-22

1. This study examined the effects of a large (308 mg kg-1) oral dose of branched-chain amino acids (BCAAs) on muscle amino acid and ammonia (NH3) metabolism during 90 min of dynamic knee extensor exercise (64 +/- 2% of maximum workload). 2. BCAA supplementation resulted in a 4-fold increase in the arterial BCAA level (from 373 to 1537 microM, P < 0.05) and a 1.5-fold increase in the intramuscular BCAA level (from 3.4 +/- 0.2 to 5.2 +/- 0.5 mmol (kg dry weight)-1, P < 0.05) by the onset of exercise. Over the 90 min exercise period, the exercising muscle removed a total of 7104 +/- 2572 mumol kg-1 of BCAAs. In contrast, in the control trial, there was a total release of 588 +/- 86 mumol kg-1 (P < 0.05) of BCAAs. 3. The total release of NH3 over the 90 min exercise period was 2889 +/- 317 mumol kg-1 (P < 0.05) in the control trial and 4223 +/- 552 mumol kg-1 (P < 0.05) in the BCAA trial. Similarly, the total release of alanine and glutamine was 1557 +/- 153 and 2213 +/- 270 mumol kg-1, respectively, for the control trial and 2771 +/- 178 and 3476 +/- 217 mumol kg-1, respectively, for the BCAA trial. 4. The lactate release and arterial lactate values were all consistently lower in the BCAA trial than in the control trial. The net production of lactate (intramuscular shifts + total release) was lower (P < 0.05) in the BCAA trial (49.9 +/- 11.4 mmol kg-1) than in the control trial (64.0 +/- 11.7 mmol kg- 1). 5. It is concluded that: (1) the administration of BCAAs can greatly increase their concentration in plasma and subsequently their uptake by muscle during exercise, and (2) long-term exercise following BCAA administration results in significantly greater muscle NH3, alanine and glutamine production, as well as lower lactate production, than is observed during exercise without BCAA supplementation. These data strongly suggest that BCAAs are an important source of NH3 during submaximal exercise and that their contribution to NH3, alanine and glutamine production can be significantly altered by changes in BCAA availability.

Institutional address: Copenhagen Muscle Research Center Rigshospitalet Denmark.



Galassetti P, Gibbons FK, Hamilton KS, Lacy DB, Cherrington AD, Wasserman DH

Enhanced muscle glucose uptake facilitates nitrogen efflux from exercised muscle.

In: J Appl Physiol (1998 Jun Jun) 84(6):1952-9

The hypothesis that glucose ingestion in the postexercise state enhances the synthesis of glutamine and alanine in the skeletal muscle was tested. Glucose was infused intraduodenally for 150 min (44.5 micromol . kg-1 . min-1) beginning 30 min after a 150-min period of exercise (n = 7) or an equivalent duration sedentary period (n = 10) in 18-h-fasted dogs. Prior exercise caused a twofold greater increase in limb glucose uptake during the intraduodenal glucose infusion compared with uptake in sedentary dogs. Arterial glutamine levels fell gradually with the glucose load in both groups. Net hindlimb glutamine efflux increased in response to intraduodenal glucose in exercised but not sedentary dogs (P < 0. 05-0.01). Arterial alanine levels, depleted by 50% with exercise, rose with intraduodenal glucose in exercised but not sedentary dogs (P < 0.05- 0.01). Net hindlimb alanine efflux also rose in exercised dogs in response to intraduodenal glucose (P < 0.05-0.01), whereas it was not different from baseline in sedentary controls for the first 90 min of glucose infusion. Beyond this point, it, too, rose significantly. We conclude that oral glucose may facilitate recovery of muscle from prolonged exercise by enhancing the removal of nitrogen in the form of glutamine and alanine.

Institutional address: Department of Molecular Physiology and Biophysics Vanderbilt University School of Medicine Nashville Tennessee 37232 USA.