Glutamine is the most abundant amino acid in the body; it is synthesized in most body tissues and absorbed from food sources. It is the major fuel source of enterocytes and is therefore essential for the maintenance of intestinal mucosal integrity and function (1). Glutamine also maintains immune function by serving as the principle metabolic fuel for lymphocytes and macrophages. It acts as a precursor for protein synthesis and, with cysteine and glycine, is involved in glutathione (GSH) synthesis. Intravenous glutamine preserves liver and intestinal glutathione stores in animal models of oxidant damage. Glutamine is also involved in nitrogen exchange, as it neutralizes and eliminates excess ammonia formed during protein catabolism. As a nitrogen donor, it contributes to the synthesis of other non-essential amino acids, including the purines and pyrimidines, and is therefore essential for the proliferation of most cells (15). Glutamine plays a supportive role during biochemical stress and sepsis. Although the mechanism in treatment of cachexia is unclear, it is thought that glutamine, a modulator of protein turnover, enhances net protein synthesis (3). Clinical evidence suggests that total parenteral nutrition supplemented with glutamine improves nitrogen balance, maintains the intracellular glutamine pool, enhances protein synthesis, and prevents deterioration of gut permeability in post-surgery patients (4).
Glutamine may potentiate the tumoricidal effect of methotrexate (MTX), since polyglutamation of MTX impairs its efflux from tumor cells and may reduce its accumulation in the gut. Rats fed a glutamine-enriched diet while receiving MTX chemotherapy exhibit less enterocolitis, improved hematologic parameters, decreased sepsis, and improved survival (16). Supplemental intravenous glutamine leads to increases of GSH in the gut, but not in tumors, in a sarcoma-bearing rat model.
However, recent findings show that glutamine transporters are upregulated in tumor cells and that glutamine acts as a mitochondrial substrate and promotes protein translation. This indicates tumor cell dependence on glutamine for its growth and maintenance (17). And a recent study demonstrated that glutamine helps cancer cells survive acidic stress, rather than provide nutrition, through enzymatic deamidation (24).