Stress-induced intracellular glutamine depletion. The potential use of glutamine-containing peptides in parenteral nutrition

Abstract

Of the total pool of muscle free intracellular amino acids glutamine represents about 60%. A uniform reduction of approximately 50% of the intracellular free glutamine pool is the most typical feature in various catabolic conditions. Since nutritional or therapeutical efforts to beneficially influence cellular glutamine pool failed and because free glutamine cannot be infused owing to its instability, the question arose as to whether maintenance of this pool is feasible by intravenous provision of glutamine-containing peptides. Our basic research plan attempted to combine the synthesis and characterization of, among other peptides, L-alanyl-L-glutamine (Ala-Gln) with investigations aimed at examining in vivo uptake and subsequent utilization of this solute. The synthesis of Ala-Gln was performed by applying the N-carboxy anhydride method in the aqueous phase. The purity in the final product approached 100% and the structure could be fully confirmed by field-desorption mass spectrometry and proton magnetic resonance spectrometry. The synthetic peptide Ala-Gln is highly soluble (568 g/l H2O; 20 degrees C) and stable during heat sterilization at various pH. Thus, Ala-Gln complies with each criterion to be included in future parenteral solutions. Isotope studies with Ala[U14C]Gln in experimental rat and dog strongly indicate that the peptide is easily available and the constituent amino acids are rapidly used for protein synthesis, preferentially in muscle tissue. In catabolic rats, continuous TPN without inclusion of Ala-Gln resulted in a profound decrease in tissue free glutamine levels compared with normal rats. Inclusion of Ala-Gln to TPN was followed by an increase in tissue free glutamine pool, considerably in liver and markedly in muscle. These findings indicate a preferential capacity of muscle tissue to take up Ala-Gln and suggest subsequent utilization of the liberated free glutamine in this tissue. For the first time, in vivo utilization of Ala-Gln was evaluated in healthy humans and substantiated with kinetic studies and under conditions of continuous infusion of peptide-supplemented amino acid solution. The peptide elimination t1/2 was 3.1 +/- 0.16 min and that for the liberated free amino acids glutamine and alanine 8.2 +/- 0.82 and 6.8 +/- 0.34 min, respectively. During infusion of an amino acid solution supplemented with Ala-Gln and Gly-Tyr, the increments of plasma glutamine and tyrosine were 33% +/- 2.2 and 67% +/- 5.7 over the initial values. No peptide could be detected in the urine.(ABSTRACT TRUNCATED AT 400 WORDS)