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, gamma-L-glutamyl-L-tyrosine (Glu(Tyr], to release Tyr in vivo by making 20-microL injections, containing 2.9 mumol Glu(Tyr) (approximately 80 mumol/kg body weight), into the external jugular veins of mice. Mean concentrations of Glu(Tyr) in plasma were 138.5 and 11.4 mumol/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 mumol of Glu(Tyr) was injected, levels of Glu(Tyr) and of Tyr were significantly higher at both 10 and minutes than when 2.9 mumol 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 mumol Glu(Tyr). Pretreatment of mice with acivicin, a potent inhibitor of gamma-glutamyl transpeptidase (GGTase), prevented the increase in plasma Tyr seen after injection of 2.9 mumol 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.(ABSTRACT TRUNCATED AT 250 WORDS)