S. Kim et al., SUPPRESSION OF RENAL GAMMA-GLUTAMYLCYSTEINE SYNTHETASE EXPRESSION IN DIETARY COPPER DEFICIENCY, Biochimica et biophysica acta. Molecular cell research, 1313(2), 1996, pp. 89-94
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.