Glutathionists in the battlefield of gamma-glutamyl cycle.

The critical finding of our work showed that the major role of gamma-glutamyl transferase is to hydrolyze GSH and related gamma-glutamyl peptides to form free amino acids and cysteine-S-conjugates on the apical membranes of cells of various tissues and basolateral membranes of the kidney and that the resulting metabolites are transported into cells to synthesize GSH and mercapturic acids. We also showed that GSH and its S-conjugates of xenobiotics are actively secreted from cells into the circulation and/or lumenal space of the liver. The excretory transport and extracellular hydrolysis of GSH and its S-conjugates of various metabolites by gamma-glutamyl transferase and related peptidases followed by absorption of the hydrolyzed amino acids to synthesize GSH forms intra-organ and inter-organ cycles for GSH metabolism in the liver, kidney, pancreas, small intestine and other tissues that have gamma-glutamyl transferase. The series of our experiments with Helmut showed that gamma-glutamyl cycle proposed by Alton Meister does not function as the putative amino acid transporter but plays critical role in the regulation of redox metabolism of toxic free radicals and xenobiotics.