Expression of gamma-glutamylcysteine synthetase in the liver of copper-deficient rats.

Copper deficiency in rats increases hepatic glutathione concentration. The present study was undertaken to determine the biochemical and molecular basis for the glutathione elevation. Weanling Sprague-Dawley rats were fed a purified diet deficient in copper (0.4 micrograms/g diet) or one containing adequate copper (5.7 micrograms/g diet) for 4 weeks. Hepatic glutathione concentration, the activity of the rate-limiting enzyme in glutathione biosynthesis, gamma-glutamylcysteine synthetase (gamma-GCS) and the relative amount of mRNA for the enzyme were determined. Hepatic glutathione concentration in copper-deficient rats was significantly elevated (6.6 vs 5.6 mumol/g). The activity of hepatic gamma-GCS was 1.6 times higher in the copper-deficient than in the copper-adequate rats (58.0 vs 35.9 nmol NADH/min.mg protein). The steady-state amount of mRNA for gamma-GCS was increased 5-fold in the copper-deficient rat liver. The findings demonstrate that the elevated hepatic glutathione concentration in copper-deficient rats results from upregulation of gamma-GCS activity. This study provides further understanding of changes in hepatic glutathione metabolism induced by copper deficiency.