USE OF THE STABLE PEPTIDE, GAMMA-L-GLUTAMYL-L-TYROSINE, AS AN INTRAVENOUS SOURCE OF TYROSINE IN MICE

The relative insolubility of tyrosine (Tyr) at neutral pH limits amounts of this amino acid in solutions used for total parenteral nutrition (TPN). We have tested the potential of the natural peptide, γ-l-glutamyl-l-tyrosine (Glu(Tyr)), to release Tyr in vivo by making 20-μL injections, containing 2.9 μmol Glu(Tyr) (approximately 80 μmol/kg body weight), into the external jugular veins of mice. Mean concentrations of Glu(Tyr) in plasma were 138.5 and 11.4 μmol/L after 10 and 60 minutes, respectively; plasma Tyr was significantly elevated at 10 minutes, but returned to control levels at 60 minutes. When 5.8 μmol of Glu(Tyr) was injected, levels of Glu(Tyr) and of Tyr were significantly higher at both 10 and 60 minutes than when 2.9 μmol of peptide was injected. Animals showed no evidence of toxicity. Two percent or less of the peptide could be detected in the urine, even in mice injected with 5.8 μmol Glu(Tyr). Pretreatment of mice with acivicin, a potent inhibitor of γ-glutamyl transpeptidase (GGTase), prevented the increase in plasma Tyr seen after injection of 2.9 μmol Glu(Tyr) and led to higher levels of Glu(Tyr) in the plasma both at 10 and at 60 minutes than seen in mice given the same amount of Glu(Tyr) but no acivicin. The presence of the inhibitor also led to loss of as much as 48% of the administered peptide in the urine in 60 minutes. These data suggest that GGTase catalyzes hydrolysis of intravenous (IV) Glu(Tyr) to release Tyr in vivo. Glu(Tyr) in the blood is not partitioned into red blood cells; it remains in the plasma, available to GGTase, which functions at the external surface of cells. We suggest that this stable, soluble peptide may be useful in TPN as a means of normalizing the phenylalanine (Phe) to Tyr ratio in plasma and of providing sufficient Tyr to support optimal growth and development in low-birth-weight infants. © 1991.