Regulatory responses to an orald-glutamate load: formation ofd-pyrrolidone carboxylic acid in humans

Abstract

Previously published studies have shown d-glutamate to be the most potent natural inhibitor of glutathione synthesis known, yet how d-glutamate is handled in humans is unknown. Therefore, we administered an oral d-glutamate load to four healthy volunteers and monitored the plasma d-glutamate concentration and excretion over a 3-h postload period. Compared with time controls, 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 time course to a level 10-fold higher than the d-glutamate plasma concentration. Excretion of d-glutamate progressively increased despite a constant filtered d-glutamate load rising from only 5 to 95% of the filtered amount. Excretion ofd-pyrrolidone carboxylic acid increased with the rise in filtered load without significant reabsorption. The amount ofd-pyrrolidone carboxylic acid excreted over the 3-h time course was 10 times the amount excreted as d-glutamate and accounted for almost 20% of the administered d-glutamate. These findings indicate that plasma d-glutamate concentration is tightly regulated through two mechanisms: 1) the transport into cells and metabolic conversion tod-pyrrolidone carboxylic acid and excretion, and 2) the enhancement of d-glutamate clearance by the kidneys.