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 an d synthesis, respectively, which leads to a 50-80% increase in plasma GSH. Moreover, the kidneys of CuD rats remove 40% more GSH from the bl ood than copper adequate (CuA) rats. These findings have led us to pro pose that the increase in hepatic synthesis of GSH in CuD rats is acco mpanied by a comparable increase in the hepatic expression of gamma-gl utamylcysteine synthetase (gamma-GCS), the rate limiting enzyme of glu tathione biosynthesis, and that the enhanced uptake of GSH by the kidn ey 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 mu g Cu/g) or CuA (5.8 mu g/g) diet for 70 days; and in exp eriment 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 i n hepatic GSH concentration, but hepatic gamma-GCS activity and mRNA a bundance were unchanged. In contrast, renal GSH concentration was unaf fected by the CuD diet. However, renal gamma-GCS activity was reduced 40% and this was paralleled by a 50% decrease in gamma-GCS mRNA. Moreo ver, the decrease in renal gamma-GCS mRNA was caused by a reduction in renal gamma-GCS gene transcription. The results of these studies indi cate that the increase in renal uptake of GSH resulting from a dietary Cu deficiency is associated with a compensatory decrease in gamma-GCS expression.