MSG ≫ 정미료, 역할, 논란

글루탐산, 글루타민의 생리적, 의학적 기능

글루탐산 역할
- 글루탐산의 생리적, 의학적 기능
- 점막 세포의 가장 중요한 에너지원

1. Fuel
Glutamic acid takes part in more metabolic reactions than any other amino acid. It is a source of glucose which is the chief source of fuel. It maintains the normal blood glucose level and also the acidity. It serves as a source of fuel for the intestinal epithelium. Glutamine increases the body’s secretion of human growth hormone (HGH). It also plays a major role in removing excess ammonia from the bloodstream.

2. Muscle and other cell components
Glutamine is present in more than three-fifths of the human muscle tissue. It synthesizes both DNA and RNA and is essential for the synthesis of all proteins. By stimulating the release of the anabolic hormone HGH, it plays an indirect role in building the skeletal muscle. Glutamine also protects the integrity of the gastrointestinal tract when ulcers, chemotherapy agents or non-steroidal anti-inflammatory drugs are present.

3. Immune function
Glutamine is very essential for proper immune function. It is required for the proliferation of lymphocytes and cytokines. It increases the efficiency of macrophages, large immune cells which engulf and degrade foreign substances ranging from microbes to inorganic molecules. In many situations in which the immune function is compromised, for example, severe burns, sepsis or when athletes overexert themselves, glutamine depletion is at least partly responsible for the immune suppression. The administration of glutamine to patients receiving bone marrow transplants results in a lower incidence of post-operative infections and a shorter stay in the hospital.

4. Neurotransmitter
It is an important excitatory neurotransmitter. It helps in the transportation of potassium across the blood–brain barrier. It also shows promise in the future treatment of neurological conditions, ulcers, hypoglycemic coma, muscular dystrophy, epilepsy, Parkinson’s and mental retardation.



ABSTRACT
Glutamine is one of the most abundant amino acids and participates in a variety of physiological functions, namely – as a major fuel source for enterocytes, as a substrate for neoglucogenesis in kidney, lymphocytes, and monocytes, a nutrient/substrate in muscle protein metabolism in response to infection, inflammation, and muscle trauma. Studies evaluating the role of glutamine have confirmed it’s participation in maintaining mucosal integrity of the gastrointestinal tract following it’s administration in patients with major bowel surgery. The role of glutamine as a protective agent in hepatobiliary dysfunction and as a supplement in total parenteral nutrition is well established, particularly, in patients under intensive care.
L-Glutamic acid (L-GA) physiologically exists as glutamate. Glutamate along with glutamine plays a major role in amino acid metabolism and thus in maintaining nitrogen balance in the body. Glutamate is a well-established excitatory neurotransmitter in the central nervous system. There has been convincing evidence on protective activity of L-GA and α-ketoglutarate in vincristine-induced neurotoxicity.
Based on the above information, a large number of studies have been carried out. The findings of recent clinical studies are presented below. Looking at the wide profile of activity, it has been proposed that though L-GA and glutamine were once considered nonessential for health, may now be considered as – ‘conditionally essential’ amino acids. While complete therapeutic role is yet to be elucidated, it may be anticipated that L-GA and glutamine may prove to be exciting molecules of interest to clinicians. The future research may therefore be directed at confirming the above activities and at investigating their role in other clinical conditions.

Glutamine
Glutamine is strongly concentrated in skeletal muscle making up to 60% of free amino acid pool in skeletal muscle.
- Acts as a nitrogen donor for synthesis for purines and pyrimidines
- Or undergoes deamidation in kidney to produce GA and ammonia. This reaction plays a central role in maintaining acid–base balance in the body and in controlling urinary pH.

Physiology, pharmacology, and therapeutic role of LGA and glutamine

Central nervous system

Glutamate is well established as the principal and classical excitatory neurotransmitter in the central nervous system (CNS). Multiple subtypes of glutamate receptors have been characterized pharmacologically. They are proposed to be both ligand gated and metabotropic receptors. Precise number of subunits and topography of each subunit are not yet established.[10]
Glutamate through AMPA and kainate receptors mediate fast excitatory synaptic transmission in the CNS and through NMDA receptors, it mediates slow excitatory response, which plays a role in long-term adaptive and pathological changes in the brain involving synaptic plasticity.[13]
Elevated levels of extracellular glutamate can induce seizures and excitotoxic neuronal cell death. In glioma and other brain tumors, excessive glutamate release from tumor cells may be responsible for tumor associated necrosis and also possibly to seizures caused due to peritumoral and tumoral brain tissue.[14]
A putative abnormality of glutamate metabolism is thought to be implicated in the pathogenesis of amyotropic lateral sclerosis. It is suggested that accumulation of toxic levels of glutamate, an excitatory neurotransmitter in the synapses may cause neuronal death through calcium-dependent pathways in this condition. However, no benefit has been shown with glutamate antagonists, dextromethorphan, and lamotrigine.
Several clinical trials with riluzole, which modulates glutamate transmission, have interestingly shown striking improvement in survival among these patients.[15] Imbalance of glutamatergic excitatory control of motor neurons is reported to be responsible for neuronal damage in motor neuron disease; hence antiglutamate agents such as riluzole and gabapentin have been proposed to have protective effects against this neurodegeneration.[16] Involvement of multiple neurotransmitter systems is also postulated in relation to Alzheimer’s disease, which includes glutamate along with acetylcholine. It is also known that dopamine (DA) interacts with other key systems such as glutamate in Parkinson’s disease. This explains the rationale for pallidotomy diminishing the net excitatory input of glutamate on to the dwindling DA neurons and may require further studies.[17]
Furthermore, Glutamate is accepted as a precursor for the inhibitory neurotransmitter gamma aminobutyric acid (GABA). Differential expression of two genes from hippocampal granule cells, encoding different molecular forms of GA decarboxylase (GAD), GAD65 and GAD67 after kainic acidinduced seizures in rat, has been demonstrated. Such progressive and sustained enhancement of expression of both GAD65 and GAD67 messenger mRNA is suggested to augment GABAergic neurotransmission supporting self-protective, anticonvulsive mechanisms in limbic epilepsy.[18]

Metabolism
Ammonia metabolism and nitrogen balance Both glutamate and glutamine play an important role in ammonia metabolism. They play a vital role in the disposal of ammonia and thus regulate nitrogen balance in the body. Glutamate plays a central role in transamination reaction in which amino acids funnel their amino group to α-ketoglutarate resulting in glutamate formation. Glutamate, therefore, acts as an acceptor of amino group from other amino acids and further undergoes either oxidative deamination in liver or is used as an amino group donor in synthesis of nonessential amino acids. Glutamine provides a nontoxic storage and transport form of ammonia. The formation of glutamine occurs primarily in the muscle and liver. At all times, there is net output of glutamine from muscle representing the disposal of amino groups from branched chain amino acids. Glutamine formation is a major mechanism for the removal of ammonia in the brain.[7]
Studies have shown that the glutamine supplementation improves nitrogen balance in patients who underwent major surgery or bone marrow transplant.[19],[20] Also a reduced incidence of infection and length of hospital stay have been demonstrated. Further, the lower levels of glutamine in skeletal muscle injuries have been said to indicate its role in the synthesis of muscle protein.

Protein metabolism
Glutamine plays an important role in protein regeneration, repair, and growth. It is identified as a precursor for purine/pyrimidine and a substrate for gluconeogenesis in kidney, lymphocytes, and monocytes. The lower levels of glutamine in skeletal muscle injuries have been said to indicate its role in synthesis of muscle protein. This has been the basis for supplementation of stable derivatives of glutamine in total
parenteral nutrition (TPN) for patients with injury or infection. Improvement has been attributed to its ability to alter negative nitrogen balance, hepatic protein synthesis, and to reduce protein degradation in addition to a protective role against total peripheral nitrogen-related hepatic dysfunction.[2]
Glutamate and glutamine transporters in skeletal muscle and heart appear to play a role in the control of the steadystate concentration of amino acids in the intracellular space probably through osmotic signaling mechanisms to regulate whole body protein metabolism.[21]
The possible role of glutamic acid decarboxylase antibodies (GADA) in type-I diabetes has been suggested in relation to female gender, older age, and the HLA-DR3/DQB*02 haplotype.
This conclusion is based on the strong humoral immune response to GAD, which reflects on propensity to general autoimmunity in this condition, rather than excessive beta cell destruction.[22]

Reproduction and growth
Glutamine and glutamate are shown to play an important role in fetal and placental metabolism.[23] Since milk contains good amount of glutamate in free form, it is proposed to be important in postnatal development.[2] Further, supplementation of glutamine is suggested to offer significant benefits in low birth weight infants including critically ill patients especially in terms of decreased nosocomial infections.[23]
Glutathione, a free-radical scavenger synthesized from glutamate in erythrocytes, hepatic tissue, and intestinal mucosa, is found to be depleted in children with low birth weight and kwashiorkor. Therefore, supplementing glutathione and other amino acids have been proposed to be useful in maintaining the integrity of immune system and normal health.[2]

Gastrointestinal secretions
Glutamine is claimed to participate in the maintenance of gut barrier function modulated through the synthesis of nucleotides, glucosamine, and mucus glycoprotein. The GIT is the principal organ of glutamine utilization with 12–13% of circulating glutamine and 50–60% of enterally supplied glutamine. Glutamine is considered to act as a major fuel and primary source of energy for enterocytes and to enhance mucosal immunologic function. Its presence is shown to stimulate blood flow to the gut, maintain mucosal integrity, prevent villous atrophy, bacterial translocation, and subsequent pro-inflammatory responses. Gut, the main organ for nitrogen processing in the body has been demonstrated to contribute significantly to the supply of glutamine to peripheral tissues.
Impaired gut function is said to be associated with significant fall in glutamine levels, resulting in impaired ability to incorporate amino acids into protein. Clinical trials have shown that glutamine enriched solutions improve nitrogen balance and gut morphology.[2],[19],[23]
There is reported evidence on the reduction in intestinal mucosal permeability and atrophic changes following administration of TPN containing glutamine dipeptide.[24] Glutamine deficiency is shown to be associated with mucosal atrophy and loss of function. In surgical stress, glutamine uptake by the GIT is known to increase.[2]

Immunity
In addition to the role of glutamine in immune function in the gut, it is reported to act as a source of nutrition for cells of immune system released from muscles, adipose tissue and other sources. It is said to help in maintenance of general immunocompetence by supporting synthesis of cellular proteins of the immune system and hepatic acute phase protein response. In sepsis, glutamine uptake, and utilization are known to fall with increase in bacterial translocation.[2]
L-Glutamine as precursor of GABA has been stated to have antistress activity and to improve cell-mediated immunity in several studies through nucleogenesis of rapidly proliferating cells.[25] It is claimed that such activity may be useful in the treatment of HIV.

Respiration
In an animal study, it was demonstrated that GA supplementation reduced and brought heart to body weight ratio to normal which was raised in hypoxia and also GA-treated animals showed higher resistance to fall in rectal temperature than control animals when they were subjected to cold stress.
These findings suggest that glutamate in optimal doses may enhance tolerance to hypoxia and cold.[26]

Anticancer activity
The prevalence of cancer-related fatigue in the absence of antineoplastic therapy is said to be 40–75% and is reported to be due to circulating cytokines such as cathepsin-D and Tumor necrosis factor (TNF) (also called asthenins) are proposed to be responsible for metabolic process underlying muscle mass breakdown observed in cancer patients. It is suggested that nitric oxide could reduce the levels of cathepsin by modulating its synthesis and therefore may benefit cancer patients with fatigue. A double blind placebo-controlled cross over study with oral administration of arginine-glutamate 6 g/day for 6 weeks was reported to increase the endogenous production of NO in patients with endothelial dysfunction. However, the relation between the asthenins and improvement in fatigue is said to require further studies.[27]
In 2000, Oldham et al. have shown superior anticancer activity of paclitaxel an anticancer agent when combined with L-GA in human breast cancer. It’s anticancer effect has been attributed to it’s ability to produce favorable pharmacokinetic profile and distribution of paclitaxel. The L-GA conjugated with paclitaxel is known to form a new anticancer called poly (LGA)-paclitaxel (PG-TXL) with superior antitumor activity, favorable pharmacokinetic properties and/or mechanism of action different from that of Paclitaxel alone. It is suggested that superior activity of PG-TXL may be due to continuous release of paclitaxel.[28]
In a double blind placebo-controlled study, administration of GA prevented the vincristine-induced neurotoxicity, a wellknown principal limiting side effect.[29] The loss of tendo-Achilles reflex as an objective parameter of vincristine-induced neurotoxicity was reported to be significantly higher in placebo group as compared to GA group. Intra-thecal administration of vincristine produced ascending paralysis and death, which was prevented by i.v. GA. Inhibition of disruption of microtubular structures by GA have been proposed to play a role.

Critical illness
Glutamine has been reported to be of value in the intensive care of critically ill patients. It is shown to improve nitrogen retention, hepatic protein synthesis and reduced protein degradation coupled with increased glutathione and hence protection of enterocytes through antioxidant action and hence is proposed to subserve as an organ-specific amino acid. It is said that enteral glutamine supplementation preoperatively for 10 days reduces infective complications and length of stay in the hospital.[2]

Coagulation
GA is present in coagulation factors like II, VII, XI, X as Vcarboxyl glutamate residues without which these factors cannot be activated. Hence GA is reported to play an important role in coagulation.[13]

Endocrine
Significant amounts of GA present in prostate gland are said to be implicated in normal function of this gland. In a study involving 45 men, who were given GA in doses of 780 mg for 2 weeks and 390 mg for the next 2.5 months in combination with equal amounts of alanine and glycine, has shown significant improvement in symptoms associated with hyperplasia of prostate. Hence GA is claimed to benefit patients with prostatic hyperplasia.[30]

Potential uses
Taking into account the biochemical, physiological, and pharmacological aspects of L-GA and glutamine, these may be proposed to be useful molecules in several clinical conditions. However, there is no known deficiency of GA and Glutamine encountered in clinical practice.

Food industry
- The MSG is used as a flavor enhancer in savories.
- Use in food is reported to be growing. The MSG is found in most soups, salad dressings, processed meats, frozen entrees, ice creams, frozen yogurt, crackers, bread, in ‘low fat’ foods to make up for flavor lost when fat is reduced or eliminated.[31]
- Maca, a dehydrated, cruciferous root vegetable containing vitamins and essential amino acids including GA, consumed as a dietary substance is said to be beneficial in women to control menopausal symptoms, in osteoporosis, in premenstrual symptoms and used
as an energy booster, by doctors in Peru and US. It is said to be beneficial in impotence, chronic fatigue syndrome in men.[38]

Gastrointestinal disorders
- In symptomatic treatment of achlorhydria or hypochlorhydria, it is used orally – 0.5–1 g with meals. The GA hydrochloride is shown to release hydrochloric acid in the stomach.
- Glutamine can be used as a mucosal protective for patients following gastrointestinal surgeries.
- For short bowel syndrome in a dose of 5–10 g dissolved in water 2–3 times a day.[2]
- Levoglutamide with alanine by parenteral route is said to maintain postoperative nitrogen balance in patients undergoing major bowel surgery.[19]

Cancer
Studies have shown that GA may be beneficial as an adjuvant to anticancer drugs.
- It may act by increasing the efficacy of anticancer drugs. In breast carcinoma paclitaxel conjugate with GA exhibited superior efficacy when compared to paclitaxel alone.[28]
- It may act by reducing certain side effects associated with cancer chemotherapy.
- Vincristine induced neurotoxicity was prevented by treatment with 500 mg GA three times a day, orally.[29]
- Studies have also shown that GA 6 g/day reduced cancer-related fatigue.

Parenteral nutrition
In many studies, glutamine has been used as a nutritional agent in parenteral therapy. Since glutamine is unstable, its stable derivatives like glutamine dipeptide or α-ketoglutarate were employed and is found to be effective in:
- maintaining cardiac function perioperatively and in promoting glucagon metabolism;[21]
- intensive care for the management of critically ill patients;
- following bone marrow transplantation;[20]
- following surgery or trauma;[9]
- in reducing portal endotoxemia and attenuate hepatobiliary complication, e.g. stone formation;[2]
- low birth weight and kwashiorkor.[2]

Neurological conditions
In muscular dystrophy, epilepsy, psychiatric disorders, mental retardation, and Parkinsonism the agents, which modulate glutamine transmission are proposed to be useful.[13]