Excretion of cysteine and gamma-glutamylcysteine moieties in human and experimental animal gamma-glutamyl transpeptidase deficiency.

Abstract

Animals [rats and mice] treated with potent .gamma.-glutamyl transpeptidase inhibitors and a patient with severe .gamma.-glutamyl transpeptidase deficiency excrete much larger than normal amounts of glutathione, .gamma.-glutamylcysteine and cysteine in their urine; these compounds were found in disulfide forms. The metabolic function of .gamma.-glutamyl transpeptidase is associated with the metabolism or transport (or both) of cysteine, .gamma.-glutamylcysteine and glutathione, and that .gamma.-glutamylcysteine is a physiological substrate of the enzyme. The occurrence of .gamma.-glutamylcysteine in urine and other considerations suggest that this dipeptide is formed as an extracellular metabolite of glutathione in addition to its recognized role as an intracellular precursor of glutathione. The dipeptide may be formed by a pathway involving transpeptidation or by cleavage of the Cys-Gly bond of glutathione. The mixed disulfide between glutathione and .gamma.-glutamylcysteine is a good substrate of glutathione reductase.