THERAPEUTIC APPROACHES OF L - GLUTAMINE

 THERAPEUTIC APPROACHES OF L - GLUTAMINE
L-glutamine is the most widespread amino acid in the bloodstream, accounting for 30-35% of the amino acid nitrogen in the plasma. Glutamine contains two ammonia groups, glutamate and another derived from free ammonia from the bloodstream, acting as a nitrogen reservoir and thus protecting the body from high levels of ammonia. Thus, glutamine can act as a buffer, accepting the excess ammonia and releasing it when there is a need for the formation of other amino acids, aminosugars, nucleotides and urea. This makes glutamine the main carrier for nitrogen transport between tissues.
Due to the body's ability to synthesize this amino acid, and because of the amount of glutamine in the body compared to other amino acids, it was considered that glutamine was not a necessary ingredient in the diet. Therefore, glutamine is considered a non-essential amino acid, as human cells can easily synthesize it with the enzyme glutamine synthetase which is at high levels of concentration in skeletal muscle, liver, brain and stomach tissue. It is consumed in the diet around five to ten grams a day of glutamine, and under normal circumstances dietary intake and synthesis is sufficient.

There are situations where a tissue has a greater need for glutamine and glutamine is transferred between the organs as required. However, under certain pathological conditions the body tissues need more glutamine than the total amount provided by the diet and the de novo synthesis. For example, during catabolic stress intracellular glutamine levels may drop more than 50% and plasma concentration by 30%.

Skeletal muscle contains the largest intracellular glutamine concentration, up to 60% of the body, and is considered to be the main glutamine storage and the primary exporter of glutamine to other tissues. During periods of metabolic stress, glutamine from the circulation is transferred to the tissue in need. The intracellular skeletal concentration of glutamine in the muscle is affected by various attacks, including injury, sepsis, prolonged stress, starvation and glucocorticoid use. The lungs are the next largest glutamine producer.

Glutamine can be converted to other amino acids, glucose in the liver and contributes to nucleotide, aminosugar and protein biosynthesis. Glutamine is one of the three amino acids involved in glutathione synthesis, an important intracellular antioxidant and hepatic detoxifying agent.

Wound healing and immune cells
Fibroblasts, lymphocytes and macrophages use glutamine as a metabolic fuel and nucleotide synthesis that regulates cell proliferation. Glutamine reduction may slow the growth of fibroblasts, while adequate glutamine can stimulate growth and cell proliferation in vitro. Glutamine dependence on fibroblasts makes glutamine a vital nutrient for therapeutic response to injuries. As shown in in vitro lymphocyte studies, these cells show no glutamate synthesis activity and are dependent on the preformed glutamine. Lymphocytes respond to glutamine supplementation by proliferation and production of more lymphocyte-derived cytokines in vitro.

Plasma glutamine levels were found to be decreased in endurance athletes who overtrain. This is due to the frequent training and high intensity so that the muscles do not fully recover between the workouts. These athletes tend to have a higher incidence of infectious diseases and allergies, swollen lymph nodes and have slower wounds healing. They also have reduced immunological performance compared to athletes who do not overtrain.

It is suggested that decreased plasma levels of glutamine are due to loss of glutamine stored in skeletal muscles during exercise, which are not likely to be re-formed before the next workout. This can lead to long-term reduced availability of glutamine for immune cells and fibroblasts. Low intensity exercise does not appear to be associated with a reduction in skeletal muscle glutamine or a harmful effect on the immune system.

The percentage of athletes who did not show infection in one week after strenuous exercise was significantly higher (81%) in the group receiving supplemental glutamine compared to the placebo group (49%).

Gastrointestinal system
The gastrointestinal tract is the greatest user of glutamine in the body, with the small intestine accounting for the highest intake of glutamine, absorbing glutamine from the lumen of the gut and from the bloodstream. Small intestinal epithelial cells use glutamine as their main metabolic fuel. Glutamine is converted in the enterocyte mitochondria to glutamate, then alpha ketoglutarate, utilized in tricarboxylic acid (Krebs) to produce ATP. Enterocytes depend on the preformed glutamine form as they have little glutamine synthetase activity.

Intestinal Permeability
Most of the research on glutamine and its association with intestinal permeability has been carried out in conjunction with the use of parenteral nutrition. Glutamine has positive effects on the gastrointestinal tract due to the ability to feed the immune cells as well as the mucosal cells. Commercial parenteral formulations commonly used in injured and operated patients do not contain glutamine and this may lead to intestinal mucosal atrophy, reduced intestinal lymphoid tissue association and increased intestinal permeability. In a mice study, they have shown the difference in parenteral nutrition supplemented with glutamine and common parenteral solution. Group that received parenteral solution with glutamine had normal lymphoid tissue activity, while mice treated with parenteral glutamine-free solution experienced mucosal atrophy.

Others have observed similar effects of decreased mucosal atrophy, increased weight of the uterus and decreased intestinal permeability by using parenteral formulations with glutamine. A possible consequence of the increase in intestinal permeability is microbial translocation. Factors such as trauma, infection, starvation, chemotherapy and anxiety can lead to a disruption of normal intestinal permeability, resulting in bacteria, fungi and toxins being transported from the mucosal area into the bloodstream and reacting with the endothelial system.

The cytokines produced by this reaction stimulate the hypothalamic-pituitary-adrenal axis, resulting in the release of cortisol which increases glutaminase activity in enterocytes and increased cleavage and use of glutamine in the small intestine. Cortisol also causes increased proteolysis in other tissues and release of glutamine from skeletal muscle. This adjustment may help to treat gut tissue hyperpermeability, severe damage to the mucosa or other tissue that uses glutamine for healing or prolonged stress, but reduces the amount of glutamine in the skeletal muscle and hence deprive it of the enterocytes, which they use more glutamine stress, which is vital for them.

Another consequence of skeletal reduction of stored glutamine is the subsequent depletion of the tripeptide containing glutamine, the antioxidant glutathione, which deficiency can lead to oxidative damage to the muscle. Glutathione production takes place in the liver, although supplemental administration of glutamine has been shown to increase glutathione production in the intestine three times more.

Trauma
Increased intestinal permeability was associated with burn injuries, surgical procedures, hemorrhagic shock and other physical trauma. Injury of any tissue other than the gut leads to the removal of glutamine from the blood and tissues, resulting in less glutamine available to the intestine. Glucocorticoids released in conditions of stress, surgery, infection, trauma, burns, sepsis or other serious illness accelerate protein catabolism. As a result, these patients can quickly lose a significant amount of protein, a large amount of skeletal muscle, in an attempt to provide a sufficient amount of glutamine for tissue healing and loss of intestinal integrity. On glutamine depletion, wound healing is impaired, intestinal permeability increases and the risk of microbial displacement and septicemia is significantly increased. In a study of supplementing glutamine in abdominal surgery, a parenteral solution containing glutamine was given to patients for three days after surgery. Skeletal muscle glutamine levels were reduced to 25%, compared with 40% loss in the control group.

A recent study shows the need for glutamine in multi-trauma patients. Sixty patients with multiple wounds were given glutamine in an enteral form for at least five days after their injury. The incidence of pneumonia was 17% in the glutamine group, compared with 45% in the control group. Bacteremia occurred in 7% of the glutamine group and 42% in the control group and only one patient (3%) in the glutamine group had sepsis, compared with eight patients with septicemia in the control group (26%).

Cancer
Many clinical studies have been conducted using glutamine combined with radiation and chemotherapy, with promising results. Glutamine, in addition to being a major metabolic fuel for rapid proliferation of immune enterocytes and cells, is also the primary fuel for fast growing tumors, which have high glutaminase activity, similar to small intestinal enterocytes. Growth of the tumor can destroy muscular glutamine and glutathione, providing less fuel for enterocytes by creating a catabolic, cachectic state. It has been suggested that the tumor may become a «glutamine trap» favoring further systemic loss of glutamine. Cancer can cause a lot of loss of glutamine from skeletal muscles, reducing the amount available for normal enterocyte metabolism. Supplemental administration of glutamine may improve the loss of glutamine, intestinal and immune function, but the potential for glutamine to also lead to increased growth of some tumors has tbe considered in further studies.

Finally, the use of glutamine in chemotherapy and radiotherapy for the treatment of cancer appears to prevent intestinal and oral toxic side effects and may even lead to an increased effectiveness of certain chemotherapy drugs.

Reference:
  • Miller, A.L. (1999) Therapeutic considerations of L-glutamine: a review of the literature. altern     Med Rev., 4:239-48.
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