Information on amino acids
The importance of amino acids in gynecology
Prof. Dr. Markus Metka / Wien
Univ. Prof. DDr. Johannes Huber / Wien
Peripheral neuropathias and intestinal problems are the most frequent complaints which can take place during chemotherapy. Numerous scientific works show that these problems can be alleviated or eliminated by the way of simple amino acids replacement. First of all, glutamine which should not be confused with glutamate, has a protective effect on enterocytes, therefore Katarina Kun has entitled her review of corresponding clinical data "glutamine as a necessary element in oncology". The attention to the importance of this amino acid was turned, when resuscitators have informed that their patients had extremely negative prognosis after admission at glutamine insufficiency, this observation was confirmed by prospective studies. Selective surgical measures or urgent as a result of accidents lower the glutamine level which results in longer period of hospitalization and negatively affects recovery process. It confirms a place of glutamine synthesis, which is an essential amino acid. It is first of all muscles, besides lungs and brain which synthetize endogenous glutamine provided that the muscle is not damaged or atrophied that often takes place at age-related sarcopenia. Therefore the ageing processes, conversion of myoblasts and adiposity have direct effect on the glutamine level. Glutamine forms a large share of the group of free proteinogenic amino acids that stresses the physical need of an organism in it. After release from a muscle and after oral administration glutamine is quickly absorbed by enterocytes, part of it is absorbed by mononuclear cells located behind the intestinal epithelium, therefore this amino acid also modulates an immune system, its small part goes to liver where it stabilizes blood glucose level because it can be transformed to glucose. The protective effect of glutamine on intestines that, first of all, is important for the patients under chemotherapy, is based, on the one hand, on preparation of amino groups, as a main task of glutamine, and on direct introduction to the citrate cycle where it participates in adenosinetriphosphoric acid synthesis. As a result enterocytes receive enough energy to initiate regenerative mechanisms necessary after chemotherapy. Numerous laboratory researches, animal experiments and clinical tests have confirmed practical prospect for oncologic gynecology and in the places where leaky gut syndrome create some problems. Moreover glutamine is an initial substance for glutathione, one of the most effective compounds for protection of cells which is not synthetized in a cancer cell in connection with acidic medium therefore the desirable apoptosis of cancer cell is not slowed down. Besides, glutamine stimulates mononuclear immune cells by various ways and, thus, raises organism immunity. It is also confirmed by the results of numerous researches which show that after simultaneous administration of glutamine the tumor growth is not accelerated, but slowed down. In this case the antidiabetogenic effect of glutamine is of special importance. On the one hand, it promotes glucogenesis and, thus, balances the glucose level, on the other hand, it is an important energy source for mitochondria, comparable to glycolysis, however, without any need for glucose. With the help of alpha-ketoglutaric acid this amino acid will be transformed directly to adenosinetriphosphoric acid by analogy with fat acids which by means of a carnitine go to mitochondria. As a result of both ways the cell needs less glucose, therefore insulinic growth factors decrease without decrease in the complex properties of mitochondria. Glycine, the smallest amino acid, has synergetic effect on glutamine. Glycine is most of all an "internal salt" or bipolar ion which synthesis is attributable to transfer of a proton of acidic carboxy-group to single pair electrons of nitrogen atom of basic amino group. As a result it, mainly, joins polypeptides in spatially narrowed positions (secondary protein structure).
In an especially large amount it is in collagen, the most frequent protein of animal organisms. There it makes almost third part of all amino acids since in connection with its small size he helps to transform collagen into its triple helical structure. Therefore glycine is important for integrity of collagen and muscular tissue.
As well as glutamine, it protects liver against hepatotoxic consequences of chemotherapy, and acts as neuromediator similar to gamma aminobutyric acid.
Glycine receptors of central nervous system are loaded and activated by progesterone type neurosteroids, which place special emphasis on connection of this amino acid with sexual steroids. Spermatozoa are also rich in glycine receptors which are agonized by female sexual steroids, - the fact requiring biological interpretation and once again showing that gynecology is bound to amino acids more closely, than had been suspected for a long period of time.
Clinical use of glutamine supplementation
Department of Anesthesia and Intensive Care Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, 14186 Stockholm, Sweden. email@example.com
Endogenous production of glutamine may become insufficient during critical illness. The shortage of glutamine is reflected as a decrease in plasma concentration, which is a prognostic factor for poor outcome in sepsis. Because glutamine is a precursor for nucleotide synthesis, rapidly dividing cells are most likely to suffer from a shortage. Therefore, exogenous glutamine supplementation is necessary. In particular, when i.v. nutrition is given, extra glutamine supplementation becomes critical, because most present formulations for i.v. use do not contain any glutamine for technical reasons. The major part of endogenously produced glutamine comes from skeletal muscle. For patients staying a long time in the intensive care unit (ICU), the muscle mass decreases rapidly, which leaves a tissue of diminishing size to maintain the export of glutamine. The metabolic and nutritional adaptation in long-staying ICU patients is poorly studied and is one of the fields that needs more scientific evidence for clinical recommendations. To date, there is evidence to support the clinical use of glutamine supplementation in critically ill patients, in hematology patients, and in oncology patients. Strong evidence is presently available for i.v. glutamine supplementation to critically ill patients on parenteral nutrition. This must be regarded as the standard of care. For patients on enteral nutrition, more evidence is needed. To guide administration of glutamine, there are good arguments to use measurement of plasma glutamine concentration for guidance. This will give an indication for treatment as well as proper dosing. Most patients will have a normalized plasma glutamine concentration by adding 20-25 g/24 h. Furthermore, there are no reported adverse or negative effects attributable to glutamine supplementation.
Glutamine: A novel approach to chemotherapy-induced toxicity.
Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
Treatment of cancer is associated with short- and long-term side-effects. Cancer produces a state of glutamine deficiency, which is further aggravated by toxic effects of chemotherapeutic agents leading to increased tolerance of tumor to chemotherapy as well as reduced tolerance of normal tissues to the side-effects of chemotherapy. This article reviews the possible role of glutamine supplementation in reducing the serious adverse events in patients treated with anticancer drugs. The literature related to the possible role of glutamine in humans with cancer and the supportive evidence from animal studies was reviewed. Searches were made and the literature was retrieved using PUBMED, MEDLINE, COCHRANE LIBRARY, CENAHL and EMBASE, with a greater emphasis on the recent advances and clinical trials. Glutamine supplementation was found to protect against radiation-induced mucositis, anthracycline-induced cardiotoxicity and paclitaxel-related myalgias/arthralgias. Glutamine may prevent neurotoxicity of paclitaxel, cisplatin, oxaplatin bortezomib and lenolidamide, and is beneficial in the reduction of the dose-limiting gastrointestinal toxic effects of irinotecan and 5-FU-induced mucositis and stomatitis. Dietary glutamine reduces the severity of the immunosuppressive effect induced by methotrexate and improves the immune status of rats recovering from chemotherapy. In patients with acute myeloid leukemia requiring parenteral nutrition, glycyl-glutamine supplementation could hasten neutrophil recovery after intensive myelosuppressive chemotherapy. Current data supports the usefulness of glutamine supplementation in reducing complications of chemotherapy; however, paucity of clinical trials weakens the clear interpretation of these findings.
Glutamine: effects on the immune system, protein balance and intestinal functions.
[Article in German]
Roth E, Spittler A, Oehler R.
Chirurgisches Forschungslaboratorium, Universitätsklinik für Chirurgie, Allgemeines Krankenhaus, Wien.
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.
Glutamine as indispensable nutrient in oncology: experimental and clinical evidence.
Department of Nutrition and Food Sciences, IEL-Nutrition Physiology, University of Bonn, Endenicher Allee 11-13, 53115, Bonn, Germany.
In hypermetabolic situations, glutamine is intensively used by rapidly dividing cells such as enterocytes, lymphocytes, and fibroblasts as nitrogen source and/or alternative energy fuel. It is hypothesized that in cancer patients the increased glutamine demands of the host increase the capacity of endogenous production resulting in a strong glutamine deprivation with detrimental effects on organ functions. In long-term periods of cancer cachexia, an adequate nutrition support including glutamine can essentially contribute to cover glutamine needs and, thus, to spare energy reserves of the host and to retard severe complications such as multi-organ failure. Due to the early in vitro knowledge that cancer cells preferably consume glutamine, oncologists often refuse to supply glutamine to the tumor-bearing host to avoid any potential risk. An objective evaluation whether supplemental glutamine supports tumor growth in vivo is, however, still lacking.
AIM OF THE STUDY:
The present review evaluates in vivo experimental and clinical data with respect to potential effects of glutamine administration in tumor-bearing hosts and draws conclusions for the use of glutamine supplements in clinical oncology.
Experimental and clinical intervention studies were identified in a systematic review of MEDLINE Database (last entry: June 2008) using key search terms and review articles. These studies were supplemented with reports identified through manual searches and other studies previously known by the authors.
Numerous experimental studies (rat/mouse model) show that oral/enteral or intravenous glutamine supports metabolism of the tumor-bearing host and can ameliorate gastrointestinal toxicity of therapeutical measures. Within the last two decades, 36 (24 oral/enteral, 12 parenteral) clinical studies evaluating the tolerance, safety and effects of glutamine in various patient groups have been published. In the great majority of these clinical studies, glutamine supplementation in cancer patients improves host metabolism and clinical situation without increasing tumor growth. Potential mechanisms of glutamine effects include maintenance of mucosal integrity, improved immune competence, inhibition of cell proliferation, increased apoptosis rate, increased synthesis of glutathione, induction of heat shock protein synthesis, and increased synthesis of glucagons-like peptides.
In various clinical situations, appropriate exogenous glutamine supply is safe and can beneficially contribute to diminish risks of high-dose chemotherapy and radiation. In addition, there is some evidence that adequate glutamine availability can beneficially affect outcome, especially in patients undergoing bone marrow transplantation.
Nonnutritive effects of glutamine.
Surgical Research Laboratories, Medical University of Vienna, A-1090 Vienna, Austria. firstname.lastname@example.org
Glutamine is the most abundant free amino acid of the human body. Besides its role as a constituent of proteins and its importance in amino acid transamination, glutamine has regulatory capacity in immune and cell modulation. Glutamine deprivation reduces proliferation of lymphocytes, influences expression of surface activation markers on lymphocytes and monocytes, affects the production of cytokines, and stimulates apoptosis. Moreover, glutamine administration seems to have a positive effect on glucose metabolism in the state of insulin resistance. Glutamine influences a variety of different molecular pathways. Glutamine stimulates the formation of heat shock protein 70 in monocytes by enhancing the stability of mRNA, influences the redox potential of the cell by enhancing the formation of glutathione, induces cellular anabolic effects by increasing the cell volume, activates mitogen-activated protein kinases, and interacts with particular aminoacyl-transfer RNA synthetases in specific glutamine-sensing metabolism. Glutamine is applied under clinical conditions as an oral, parenteral, or enteral supplement either as the single amino acid or in the form of glutamine-containing dipeptides for preventing mucositis/stomatitis and for preventing glutamine-deficiency in critically ill patients. Because of the high turnover rate of glutamine, even high amounts of glutamine up to a daily administration of 30 g can be given without any important side effects.