TRANSPORT OF GAMMA-GLUTAMYL-TRANSFERASE AMINO-ACIDS - ROLE OF GLUTATHIONE AND GAMMA-GLUTAMYL-TRANSFERASE TRANSPEPTIDASE

This work relates to the hypothesis that one of the mechanisms that mediates amino acid translocation across cell membranes involves the action of membrane-bound γ-glutamyl transpeptidase on intracellular glutathione and extracellular amino acids to form γ-glutamyl amino acids. According to this idea, the latter are translocated into the cell where the γ-glutamyl moiety is removed to yield free amino acids. Previous studies in this laboratory showed that intracellular glutathione is translocated out of many cells. We have now directly examined the transport of γ-glutamyl amino acids into tissues in the mouse by use of the model substrate L-γ-glutamyl-L-[14C]methionine sulfone. Of 11 tissues examined, only the kidney showed strong and preferential uptake of the substrate. A subtantial amount of the administered L-γ-glutamyl-L-[14C]methionine sulfone was found intact in the kidney; the total uptake of this compound was greater (by about 2-fold) than that of free L-methionine sulfone. Studies with a number of other γ-glutamyl amino acids and γ-glutamyl compounds indicate that the kidney has a relatively specific transport system for γ-glutamyl amino acids. Small but significant amounts of γ-glutamylmethionine sulfone were found in the liver and pancreas, suggesting that other tissues may also have this system. Transport of γ-glutamylmethionine sulfone into the kidney was inhibited by inhibitors of glutathione synthesis and of γ-glutamyl transpeptidase. The results suggest that both the transpeptidase and glutathione may be involved in transport of γ-glutamyl amino acids.