Effects of inhibition and modulation of gamma-glutamyltransferase on glutamine and glutamate metabolism in control and acidotic rat proximal tubules.

The possible role of gamma-glutamyltransferase (gamma-GT) in renal ammonia production from glutamine remains controversial, prompting the current investigation. In rat proximal tubules, compounds known to activate the enzyme including the endogenously produced organic anion, hippurate, induced a significant increase in glutamine-ammoniagenesis both in nonacidosis and chronic metabolic acidosis although in absolute terms the increase was not more marked under the latter conditions. AT-125, which irreversibly inactivates gamma-GT, but not phosphate-dependent glutaminase, reduced the production of ammonia from glutamine in both acid-base states. In absolute terms, again, this reduction was similar under both acid-base conditions, implying an unimportant role for gamma-GT in vitro in the augmentation in renal ammoniagenesis induced by chronic metabolic acidosis. Maleate-stimulated glutamine-ammoniagenesis recently attributed to its intramitochondrial inhibitory effect in the dog is substantially due to the activation of gamma-GT in rat proximal tubules.