Studies on the Regulation of Glutathione Level in Rat Liver

1) On starving rats for one or two days their liver glutathione content decreased to between two-thirds and half the normal level. On feeding these animals, it rapidly returned to normal, followed by a gradual increase of glucose-6-phosphate dehydrogenase EC 1.1.1.49 (G6PD). Maintenance of the liver glutathione level in rats depended upon their food intake. 2) Actinomycin D inhibited the induction of G6PD but did not affect the increase in glutathione concentration. Cycloheximide also failed to inhibit the recovery of the glutathione level. Thus, the rapid increase in the hepatic glutathione level on feeding starved animals did not require de novo formation of glutathione-synthesizing enzymes. 3) The activities of enzymes involved in glutathione synthesis (γ-glutamylcysteine synthetase EC 6.3.2.2+glutathione synthetase EC 6.3.2.3) in the liver were similar in starved rats and rats which had been refed. 4) The hepatic concentrations of cysteine and glutamate were reduced in starved animals and increased rapidly on feeding these animals. This may cause increased glutathione synthesis, and can account quantitatively for the rapid rise of the hepatic glutathione content on refeeding. However, the concentration of adenine nucleotides was not favorable for glutathione synthesis in the early stage of refeeding: relatively higher concentrations of ADP and AMP were present, which could inhibit one or both the reactions leading to glutathione synthesis. 5) Glutathione degradation activity in the liver was lower in refed animals than in fasted ones. The turnover of hepatic glutathione was much faster in fasted rats than in refed ones. The degradation rate of glutathione appears to be involved in regulating the hepatic glutathione level.