Endogenous Metabolite; mGluR

除了充当细胞氧化的碳源之外，L-谷氨酰胺肽还是蛋白质、氨基酸、嘌呤肽、串联肽和核苷酸合成的重要前体。 0.7 mM 的 L-谷氨酰胺和 20 μM 的 L-谷氨酸是人体最丰富的氨基酸细胞外形式 [1]。用10 mM L-谷氨酰胺处理BRIN-BD11细胞培养24小时后，与1相比，148个基因的基因表达量增加了1.8倍以上，而18个基因的基因表达量下降了1.8倍以上。毫米。其中许多基因包括涉及信号唤醒、细胞凋亡、基因调控基因和岛死亡反应的基因。 L-谷氨酰胺更多地激活 Ca2+ 调节的磷酸酶钙调神经磷酸酶和胰蛋白酶 Pdx1 [2]。

L-谷氨酰胺（Gln）是标准遗传密码编码的20种氨基酸之一。它的侧链是酰胺；它是通过用胺官能团取代谷氨酸的侧链羟基而形成的。谷氨酰胺存在于蛋白质含量高的食物中，如鱼类、红肉、豆类和乳制品。谷氨酰胺是一种补充剂，用于举重、健美、耐力和其他运动，也用于肌肉痉挛或疼痛的患者，尤其是老年人。谷氨酰胺在任何一组人的饮食中的主要用途是补充身体在锻炼或日常活动中使用的氨基酸储备。迄今为止，对谷氨酰胺过量消费问题的研究已被证明是不确定的。然而，正常补充谷氨酰胺是健康的，主要是因为谷氨酰胺应该在长时间的运动（例如，需要使用氨基酸的运动或锻炼）后补充，并补充氨基酸储备；这是建议禁食期间或患有身体创伤、免疫缺陷或癌症的人服用谷氨酰胺的主要原因。有大量证据表明富含谷氨酰胺的饮食与肠道影响有关；有助于维持肠道屏障功能、肠道细胞增殖和分化，并总体上降低败血症发病率和肠易激综合征症状。这种清洁特性的原因被认为源于谷氨酰胺的肠道提取率高于其他氨基酸的提取率，因此被认为是试图缓解与胃肠道有关的疾病时最可行的选择。这些条件是在比较富含谷氨酰胺和不富含谷氨酰胺的饮食的肠道内血浆浓度后发现的。然而，尽管谷氨酰胺被认为具有清洁特性和效果，但由于各种食物中谷氨酰胺的浓度不同，谷氨酰胺在多大程度上具有临床益处尚不清楚。还已知谷氨酰胺在减少术后愈合时间方面具有多种作用。通过向患者提供含有大量谷氨酰胺的胃肠外营养方案，减少了腹部手术后的医院等待时间。临床试验表明，与饮食方案中不含谷氨酰胺的患者相比，服用含谷氨酰胺补充方案的患者改善了氮平衡，从多形核中性粒细胞产生半胱氨酰白三烯，并改善了淋巴细胞恢复和肠道通透性（术后患者）；所有这些都没有任何副作用。它是由谷氨酸和氨合成的。它是体内氮的主要载体，也是许多细胞的重要能量来源。

我们使用克隆的BRIN-BD11β细胞研究了长期暴露（24小时）于氨基酸l-谷氨酰胺对基因和蛋白质表达的影响。使用寡核苷酸微阵列分析进行BRIN-BD11细胞的表达谱分析。与1mM相比，用10mM l-谷氨酰胺培养24小时导致基因表达的显著变化，148个基因上调超过1.8倍，18个基因下调超过1.8倍。包括许多参与细胞信号传导、代谢、基因调节和胰岛素分泌反应的基因。随后的功能实验证实，l-谷氨酰胺增加了Ca（2+）调节的磷酸酶钙调磷酸酶和转录因子Pdx1的活性。此外，我们证明了β细胞衍生的l-谷氨酸以高速释放到细胞外介质中。由于钙调神经磷酸酶是谷氨酸N-甲基-d-天冬氨酸（NMDA）受体活性的调节因子，我们研究了NMDA对营养诱导的胰岛素分泌的作用，并证明了其抑制了胰岛素释放。这些观察结果表明，l-谷氨酰胺在调节β细胞基因表达、信号传导和分泌功能方面具有重要的长期作用[1]。

Absorption, Distribution and Excretion
Absorption is efficient and occurs by an active transport mechanism. Tmax is 30 minutes after a single dose. Absorption kinetics following multiple doses has not yet been determined.
Primarily eliminated by metabolism. While L-glutamine is filtered though the glomerulus, nearly all is reabsorbed by renal tubules.
Volume of distribution is 200 mL/kg after intravenous bolus dose.
After an intravenous bolus dose in three subjects, the volume of distribution was estimated to be approximately 200 mL/kg.
Following single dose oral administration of glutamine at 0.1 g/kg to six subjects, mean peak blood glutamine concentration was 1028uM (or 150 mcg/mL) occurring approximately 30 minutes after administration. The pharmacokinetics following multiple oral doses have not been adequately characterized.
Metabolism is the major route of elimination for glutamine. Although glutamine is eliminated by glomerular filtration, it is almost completely reabsorbed by the renal tubules.

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Metabolism / Metabolites
Exogenous L-glutamine likely follows the same metabolic pathways as endogenous L-glutamine which is involved in the formation of glutamate, proteins, nucleotides, and amino acid sugars.
Glutamine plays an important role in nitrogen homeostasis and intestinal substrate supply. It has been suggested that glutamine is a precursor for arginine through an intestinal-renal pathway involving inter-organ transport of citrulline. The importance of intestinal glutamine metabolism for endogenous arginine synthesis in humans, however, has remained unaddressed. The aim of this study was to investigate the intestinal conversion of glutamine to citrulline and the effect of the liver on splanchnic citrulline metabolism in humans. Eight patients undergoing upper gastrointestinal surgery received a primed continuous intravenous infusion of [2-(15)N]glutamine and [ureido-(13)C-(2)H(2)]citrulline. Arterial, portal venous and hepatic venous blood were sampled and portal and hepatic blood flows were measured. Organ specific amino acid uptake (disposal), production and net balance, as well as whole body rates of plasma appearance were calculated according to established methods. The intestines consumed glutamine at a rate that was dependent on glutamine supply. Approximately 13% of glutamine taken up by the intestines was converted to citrulline. Quantitatively glutamine was the only important precursor for intestinal citrulline release. Both glutamine and citrulline were consumed and produced by the liver, but net hepatic flux of both amino acids was not significantly different from zero. Plasma glutamine was the precursor of 80% of plasma citrulline and plasma citrulline in turn was the precursor of 10% of plasma arginine. In conclusion, glutamine is an important precursor for the synthesis of arginine after intestinal conversion to citrulline in humans.
Endogenous glutamine participates in various metabolic activities, including the formation of glutamate, and synthesis of proteins, nucleotides, and amino sugars. Exogenous glutamine is anticipated to undergo similar metabolism.
Enterocytes, Hepatic

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Biological Half-Life
The half life of elimination is 1 h.
After an IV bolus dose in three subjects, the terminal half-life of glutamine was approximately 1 hour.

Toxicity Summary
Supplemental L-glutamine's possible immunomodulatory role may be accounted for in a number of ways. L-glutamine appears to play a major role in protecting the integrity of the gastrointestinal tract and, in particular, the large intestine. During catabolic states, the integrity of the intestinal mucosa may be compromised with consequent increased intestinal permeability and translocation of Gram-negative bacteria from the large intestine into the body. The demand for L-glutamine by the intestine, as well as by cells such as lymphocytes, appears to be much greater than that supplied by skeletal muscle, the major storage tissue for L-glutamine. L-glutamine is the preferred respiratory fuel for enterocytes, colonocytes and lymphocytes. Therefore, supplying supplemental L-glutamine under these conditions may do a number of things. For one, it may reverse the catabolic state by sparing skeletal muscle L-glutamine. It also may inhibit translocation of Gram-negative bacteria from the large intestine. L-glutamine helps maintain secretory IgA, which functions primarily by preventing the attachment of bacteria to mucosal cells. L-glutamine appears to be required to support the proliferation of mitogen-stimulated lymphocytes, as well as the production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma). It is also required for the maintenance of lymphokine-activated killer cells (LAK). L-glutamine can enhance phagocytosis by neutrophils and monocytes. It can lead to an increased synthesis of glutathione in the intestine, which may also play a role in maintaining the integrity of the intestinal mucosa by ameliorating oxidative stress. The exact mechanism of the possible immunomodulatory action of supplemental L-glutamine, however, remains unclear. It is conceivable that the major effect of L-glutamine occurs at the level of the intestine. Perhaps enteral L-glutamine acts directly on intestine-associated lymphoid tissue and stimulates overall immune function by that mechanism, without passing beyond the splanchnic bed.

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Hepatotoxicity
In clinical trials of L-glutamine in patients with sickle cell disease, serum aminotransferase elevations were not mentioned, and there were no reports of clinically apparent liver injury. Patients with sickle cell disease frequently have jaundice, largely due to chronic hemolysis which raises serum indirect bilirubin levels. They also can have fluctuating liver test abnormalities due to complications of sickle cell disease, such as gall stone disease (from chronic hemolysis), viral hepatitis and iron overload (from blood transfusions), congestive liver disease (due to pulmonary hypertension), and veno-occlusive crises involving the liver which can be associated with serum aminotransferase elevations and hepatic dysfunction. In preregistration trials of L-glutamine, hepatic events were not reported and serious adverse events were no more common with the active drug than with placebo. L-glutamine is a normal constituent of virtually all tissues and is unlikely to have intrinsic toxicity, even in high doses.
Glutamine supplementation has a potential of worsening hepatic encephalopathy in patients with advanced cirrhosis. Glutamine is metabolized to glutamate and ammonia which can overwhelm the hepatic elimination of ammonia in patients with severe liver dysfunction. Ingestion of 10 to 20 grams of glutamine has been shown to cause elevations of serum ammonia levels and to worsen psychometric measures of hepatic encephalopathy in patients with decompensated cirrhosis. Plasma ammonia levels do not increase with glutamine supplementation in patients with normal hepatic function, and its effects in patients with cirrhosis is not due to hepatic injury. Nevertheless, use of L-glutamine should be avoided in patients with sickle cell disease and advanced cirrhosis.
Likelihood score: E (unlikely cause of acute liver injury with jaundice).

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Interactions
Radiotherapy is often used to treat prostate tumors, but the normal bladder is usually adversely affected. Using an animal model of pelvic radiation, /the authors/ investigated whether glutamine nutritional supplementation can prevent radiation-induced damage to the bladder, especially in its more superficial layers. Male rats aged 3-4 months were divided into groups of 8 animals each: controls, which consisted intact animals; radiated-only rats, which were sacrificed 7 (R7) or 15 (R15) days after a radiation session (10Gy aimed at the pelvico-abdominal region); and radiated rats receiving l-glutamine supplementation (0.65g/kg body weight/day), which were sacrificed 7 (RG7) or 15 (RG15) days after the radiation session. Cells and blood vessels in the vesical lamina propria, as well as the urothelium, were then measured using histological methods. The effects of radiation were evaluated by comparing controls vs. either R7 or R15, while a protective effect of glutamine was assessed by comparing R7 vs. RG7 and R15 vs. RG15. The results showed that, in R7, epithelial thickness, epithelial cell density, and cell density in the lamina propria were not significantly affected. However, density of blood vessels in R7 was reduced by 48% (p<0.05) and this alteration was mostly prevented by glutamine (p<0.02). In R15, density of blood vessels in the lamina propria was not significantly modified. However, epithelial thickness was reduced by 25% (p<0.05) in R15, and this effect was prevented by glutamine (p<0.01). In R15, epithelial cell density was increased by 35% (p<0.02), but glutamine did not protect against this radiation-induced increase. Cell density in the lamina propria was likewise unaffected in R15. Density of mast cells in the lamina propria was markedly reduced in R7 and R15. The density was still reduced in RG7, but a higher density in RG15 suggested a glutamine-mediated recovery. Alpha-actin positive cells in the lamina propria formed a suburothelial layer and were identified as myofibroblasts. Thickness of this layer was increased in R7, but was similar to controls in RG7, while changes in R15 and RG15 were less evident. In conclusion, pelvic radiation leads to significant acute and post-acute alterations in the composition and structural features of the vesical lamina propria and epithelium. Most of these changes, however, can be prevented by glutamine nutritional supplementation. These results emphasize, therefore, the potential use of this aminoacid as a radioprotective drug.
Glutamine is a neutral amino acid that is used by rapidly dividing cells such as erythrocytes, lymphocytes, and fibroblasts. It is also the substrate of glutathione synthesis. In normal metabolic rates, glutamine is an amino acid synthesized endogenously, but in high metabolic conditions such as cancer, it must be taken exogenously. Animal studies strongly demonstrate that glutamine protects both the upper and lower gastrointestinal tract mucosa from the effects of chemotherapy, radiotherapy, or other causes of injury. In this study, ... the protective effect of glutamine on radiation-induced diarrhea /was investigated/.The patients were divided into glutamine-treated and placebo groups. In the glutamine-treated group, 15 g of oral glutamine was administered three times daily. The patients were evaluated for diarrhea grade according to the National Cancer Institute Common Toxicity Criteria version 3.0, need for loperamide use, need for supportive parenteral therapy, and treatment breaks due to diarrhea. There was no difference in overall diarrhea incidence when the two groups were compared. When diarrhea grade was evaluated, none of the patients in the glutamine-treated group had grade 3-4 diarrhea, but in the placebo group, grade 3-4 diarrhea was seen in 69% of the patients. In the placebo-treated group, patients requiring loperamide and parenteral supportive therapy were 39 and 92 %, respectively. There was no treatment break in glutamine-treated patients. Glutamine may have protective effect on radiation-induced severe diarrhea.

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Non-Human Toxicity Values
LD50 Mouse oral 700 mg/kg
LD50 Rat oral 7500 mg/kg

[1]. Mary Corless , et al. Glutamine Regulates Expression of Key Transcription Factor, Signal Transduction, Metabolic Gene, and Protein Expression in a Clonal Pancreatic Beta-Cell Line. J Endocrinol. 2006 Sep;190(3):719-27.
[2]. Newsholme P, et al. Glutamine and glutamate as vital metabolites. Braz J Med Biol Res. 2003 Feb;36(2):153-63. Epub 2003 Jan 29.[1].
[3]. Brosnan JT. Interorgan amino acid transport and its regulation. J Nutr. 2003 Jun;133(6 Suppl 1):2068S-2072S.
[4]. Newsholme P. Why is L-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection? J Nutr. 2001 Sep;131(9 Suppl):2515S-22S; discussion 2523S-4S.

Therapeutic Uses
EXPL THER Glutamine depletion has negative effects on the functional integrity of the gut and leads to immunosuppression. Very low birth weight (VLBW) infants are susceptible to glutamine depletion, as enteral nutrition is limited in the first weeks of life. Enteral glutamine supplementation may have a positive effect on feeding tolerance, infectious morbidity and short-term outcome. The aim of the study was to determine the effect of enteral glutamine supplementation on plasma amino acid concentrations, reflecting one aspect of safety of enteral glutamine supplementation in VLBW infants. In a double-blind placebo-controlled randomized controlled trial, VLBW infants (gestational age <32 weeks or birth weight <1500 g) received enteral glutamine supplementation (0.3 g/kg per day) or isonitrogenous placebo supplementation (alanine) between day 3 and day 30 of life. Supplementation was added to breast milk or to preterm formula. Plasma amino acid concentrations were measured at four time points: before the start of the study and at days 7, 14 and 30 of life.Baseline patient and nutritional characteristics were not different in glutamine (n = 52) and control (n = 50) groups. Plasma concentrations of most essential and non-essential amino acids increased throughout the study period. There was no effect of enteral glutamine supplementation. In particular, the increase of plasma glutamine and glutamate concentrations was not different between the treatment groups (P = 0.49 and P = 0.34 respectively, day 30).Enteral glutamine supplementation in VLBW infants does not alter plasma concentrations of glutamine, glutamate or other amino acids. Enteral supplementation in a dose of 0.3 g/kg per day seems safe in VLBW infants.
EXPL THER Critically ill patients have considerable oxidative stress. Glutamine and antioxidant supplementation may offer therapeutic benefit, although current data are conflicting.In this blinded 2-by-2 factorial trial, we randomly assigned 1223 critically ill adults in 40 intensive care units (ICUs) in Canada, the United States, and Europe who had multiorgan failure and were receiving mechanical ventilation to receive supplements of glutamine, antioxidants, both, or placebo. Supplements were started within 24 hours after admission to the ICU and were provided both intravenously and enterally. The primary outcome was 28-day mortality. Because of the interim-analysis plan, a P value of less than 0.044 at the final analysis was considered to indicate statistical significance. There was a trend toward increased mortality at 28 days among patients who received glutamine as compared with those who did not receive glutamine (32.4% vs. 27.2%; adjusted odds ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.64; P=0.05). In-hospital mortality and mortality at 6 months were significantly higher among those who received glutamine than among those who did not. Glutamine had no effect on rates of organ failure or infectious complications. Antioxidants had no effect on 28-day mortality (30.8%, vs. 28.8% with no antioxidants; adjusted odds ratio, 1.09; 95% CI, 0.86 to 1.40; P=0.48) or any other secondary end point. There were no differences among the groups with respect to serious adverse events (P=0.83). Early provision of glutamine or antioxidants did not improve clinical outcomes, and glutamine was associated with an increase in mortality among critically ill patients with multiorgan failure.
NutreStore (L-glutamine powder for oral solution) is indicated for the treatment of Short Bowel Syndrome (SBS) in patients receiving specialized nutritional support when used in conjunction with a recombinant human growth hormone that is approved for this indication. /Included in US product label/

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Drug Warnings
The safety and effectiveness of L-glutamine in pediatric patients have not been established.
It is not known whether L-glutamine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when L-glutamine is administered to a nursing woman.
Glutamine is metabolized to glutamate and ammonia, which may increase in patients with hepatic dysfunction. Therefore, routine monitoring of renal and hepatic function is recommended in patients receiving intravenous parenteral nutrition (IPN) and NutreStore, particularly in those with renal or hepatic impairment.
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
For more Drug Warnings (Complete) data for Glutamine (7 total), please visit the HSDB record page.

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Pharmacodynamics
Like other amino acids, glutamine is biochemically important as a constituent of proteins. Glutamine is also crucial in nitrogen metabolism. Ammonia (formed by nitrogen fixation) is assimilated into organic compounds by converting glutamic acid to glutamine. The enzyme which accomplishes this is called glutamine synthetase. Glutamine can then be used as a nitrogen donor in the biosynthesis of many compounds, including other amino acids, purines, and pyrimidines. L-glutamine improves nicotinamide adenine dinucleotide (NAD) redox potential.

C5H10N2O3

146.14

146.069

C, 41.09; H, 6.90; N, 19.17; O, 32.84

56-85-9

D-Glutamine;5959-95-5;DL-Glutamine;6899-04-3;L-Glutamine-15N;80143-57-3;L-Glutamine-13C5;184161-19-1;L-Glutamine-d5;14341-78-7;L-Glutamine-5-13C;159680-32-7;L-Glutamine-1-13C;159663-16-8;L-Glutamine-13C5,15N2;285978-14-5;L-Glutamine-15N2;204451-48-9;L-Glutamine-15N-1;59681-32-2;L-Glutamine-1,2-13C2;L-Glutamine-2-13C;180991-02-0;L-Glutamine-13C5,15N2,d5;2123439-02-9;L-Glutamine-15N2,d5

5961

White crystalline powder
Fine opaque needles from water or dilute ethanol

1.5±0.1 g/cm3

353.5±52.0 °C at 760 mmHg

185ºC

167.6±30.7 °C

0.0±1.8 mmHg at 25°C

1.564

-1.28

106.41

3

4

4

10

146

1

O([H])C([C@]([H])(C([H])([H])C([H])([H])C(N([H])[H])=O)N([H])[H])=O

ZDXPYRJPNDTMRX-VKHMYHEASA-N

InChI=1S/C5H10N2O3/c6-3(5(9)10)1-2-4(7)8/h3H,1-2,6H2,(H2,7,8)(H,9,10)/t3-/m0/s1

(2S)-2,5-diamino-5-oxopentanoic acid

Glavamin; Glumin; Glutamine; L-glutamine; glutamine; 56-85-9; Levoglutamide; L-(+)-Glutamine; Glutamic acid amide; Cebrogen; Stimulina;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~33.33 mg/mL (~228.07 mM)

配方 1 中的溶解度: 7.69 mg/mL (52.62 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。 (<60°C).

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。