Suppression of renal gamma-glutamylcysteine synthetase expression in dietary copper deficiency.

A dietary deficiency of copper (CuD) is associated with a 50-70% and a 2-fold increase in hepatic reduced glutathione (GSH) concentration and synthesis, respectively, which leads to a 50-80% increase in plasma GSH. Moreover, the kidneys of CuD rats remove 40% more GSH from the blood than copper adequate (CuA) rats. These findings have led us to propose that the increase in hepatic synthesis of GSH in CuD rats is accompanied by a comparable increase in the hepatic expression of gamma-glutamylcysteine synthetase (gamma-GCS), the rate limiting enzyme of glutathione biosynthesis, and that the enhanced uptake of GSH by the kidney would lead to a compensatory decrease in renal gamma-GCS expression. In experiment I, male weanling rats (3-4 weeks) were ad libitum fed a CuD (0.5 microgram Cu/g) or CuA (5.8 micrograms/g) diet for 70 days; and in experiment II, male weanling rats were pair-meal fed the CuD or CuA diet for 35 days. In both studies, CuD diet caused a significant increase in hepatic GSH concentration, but hepatic gamma-GCS activity and mRNA abundance were unchanged. In contrast, renal GSH concentration was unaffected by the CuD diet. However, renal gamma-GCS activity was reduced 40% and this was paralleled by a 50% decrease in gamma-GCS mRNA. Moreover, the decrease in renal gamma-GCS mRNA was caused by a reduction in renal gamma-GCS gene transcription. The results of these studies indicate that the increase in renal uptake of GSH resulting from a dietary Cu deficiency is associated with a compensatory decrease in gamma-GCS expression.