The role of glutathione in hepatic hydroperoxide metabolism.

Meister, 1979~) . In kidney and probably at other sites of high pglutamyl transpeptidase concentration, intracellular glutathione is transported to the membrane-bound enzyme; the products of enzyme action (y-glutamyl amino acids, cysteinylglycine) are taken up by the cell. Tissues such as muscle and liver, which have low activities of transpeptidase, transport glutathione to the blood plasma. Glutathione is removed from plasma by the action of transpeptidase, much of which is found in the kidney. A large fraction of the glutathione utilized by the kidney is transported out of renal cells. Studies on anephric animals indicate that about 70% of plasma glutathione is used by the kidney and the remainder by extrarenal transpeptidase (Griffith & Meister, 1 9 7 9 ~ ; Haberle et al., 1979). Hepatic-vein plasma has a much higher concentration of glutathione than arterial plasma, and renal-venous plasma has about 20% of the glutathione content of arterial plasma (Anderson et al., 1980; Haberle et al., 1979). These and other studies show that there is inter-organ transport of glutathione as well as an intra-organ cycle. Translocation of glutathione may function to provide a source of thiol to the cell membrane and its immediate environment. The interaction of glutathione with the transpeptidase thus seems to function in transport processes as well as in the recovery of the amino acid constituents of glutathione. Blocks at different steps of the y-glutamyl cycle have been found in certain patients and have also been achieved in animals by use of inhibitors. Studies on patients with glutathione synthetase deficiency led to the finding that glutathione normally feedback-inhibits pglutamylcysteine synthetase (Wellner et al., 1974; Richman & Meister, 1975; Meister, 1978). Thus, with marked glutathione deficiency, y-glutamylcysteine is overproduced and converted by y-glutamyl cyclotransferase to 5 oxoproline. The accumulation of 5-oxoproline exceeds the capacity of 5-oxoprolinase so that 5-oxoproline concentrations increase in the blood and tissues and large quantities are excreted in the urine. Inhibition in vivo of 5-oxoprolinase produced by giving a competitive inhibitor leads to 5-oxoproline accumulation. Administration of an effective inhibitor of y-glutamyl cyclotransferase decreases tissue 5-oxoproline. Studies with model substrates of cyclotransferase (Bridges et al., 1980) and transpeptidase (Griffith & Meister, 1979b) provide measures of the extent of such inhibition in vivo. Inhibition of 5-oxoprolinase in viuo by administration of 2-oxothiazolidine4-carboxylate inhibits utilization of 5-oxoproline, and leads also to an increase of liver glutathione because 2-oxothiazolidine4-carboxylate is a substrate of 5-oxoprolinase, which converts this compound to cysteine (Williamson & Meister, 1981). These findings (and studies that show that administration of L2-oxothiazolidine-4-carboxylate to mice reverses the marked decreases in hepatic glutathione and associated toxicity produced by paracetamol) indicate that this compound can serve usefully as an intracellular delivery system for cysteine.