Renal clearance of glutathione measured in rats pretreated with inhibitors of glutathione metabolism.

Renal clearance measurements were performed in rats pretreated with various inhibitors of glutathione metabolism. Approximately 97% of the renal gamma-glutamyltranspeptidase was inactivated by infusion of AT-125. Within 4.5 h arterial plasma concentration and urinary excretion of glutathione increased from 4 microM and 1.2 nmol/h to 27 microM and 3,900 nmol/h, respectively. The ratio of excreted to filtered glutathione increased from less than 0.01 to 1. When renal glutathione was decreased to 35% of normal by pretreating rats with D,L-buthionine-S,R-sulfoximine, the subsequent inactivation of the transpeptidase caused only a two-fold increase in arterial plasma glutathione, and urinary excretion increased to only 70% of the filtered load. The filtered load of glutathione was reduced by intravenous infusion of purified gamma-glutamyltranspeptidase. At 1 to 3 h after infusion, arterial glutathione decreased to 0.3 microM. Under these conditions, the amount of glutathione excreted by an AT-125-treated rat was 40-fold greater than the filtered load. When similar experiments were carried out in rats that were pretreated with D,L-buthionine-S,R-sulfoximine and AT-125, urinary excretion of glutathione was decreased 10-fold, but it still exceeded the amount filtered. These results firmly establish that apical secretion contributes to the glutathione catabolized in the tubular lumen.