Regulatory responses to an oral D-glutamate load: formation of D-pyrrolidone carboxylic acid in humans

Previously published studies have shown D-glutamate to be the most potent n atural inhibitor of glutathione synthesis known, yet how D-glutamate is han dled in humans is unknown. Therefore, we administered an oral D-glutamate l oad to four healthy volunteers and monitored the plasma D-glutamate concent ration and excretion over a 3-h postload period. Compared with time control s, the plasma D-glutamate concentration increased 10-fold in the 1st h and then reached a plateau over the remaining time course. In contrast, plasma D-pyrrolidone carboxylic acid increased progressively throughout the 3-h ti me course to a level 10-fold higher than the D-glutamate plasma concentrati on. Excretion of D-glutamate progressively increased despite a constant fil tered D-glutamate load rising from only 5 to 95% of the filtered amount. Ex cretion of D-pyrrolidone carboxylic acid increased with the rise in filtere d load without significant reabsorption. The amount of D-pyrrolidone carbox ylic acid excreted over the 3-h time course was 10 times the amount excrete d as D-glutamate and accounted for almost 20% of the administered D-glutama te. These findings indicate that plasma D-glutamate concentration is tightl y regulated through two mechanisms: 1) the transport into cells and metabol ic conversion to D-pyrrolidone carboxylic acid and excretion, and 2) the en hancement of D-glutamate clearance by the kidneys.