Inhibition of elevated hepatic glutathione abolishes copper deficiency cholesterolemia

FASEB J. 1992 Apr;6(7):2467-71. doi: 10.1096/fasebj.6.7.1563598.


Dietary copper deficiency causes hypercholesterolemia and increased hepatic 3-hydroxy-3-methyl-glutaryl coenzyme A (MHG-CoA) reductase activity and increased hepatic glutathione (GSH) in rats. We hypothesized that inhibition of GSH production by L-buthionine sulfoximine (BSO), a specific GSH synthesis inhibitor, would abolish the cholesterolemia and increased HMG-CoA reductase activity of copper deficiency. In two experiments, two groups of 20 weanling male rats were fed diets providing 0.4 and 5.8 micrograms Cu/g, copper-deficient (Cu-D) and copper-adequate (Cu-A), respectively. At 35 days plasma cholesterol was significantly elevated by 30 to 43% in Cu-D and 10 animals in each of the Cu-D and Cu-A groups were randomly assigned to receive 10 mM BSO solution in place of drinking water and continued on the same diets for another 2 wk. At necropsy Cu-D animals had a significant 52 to 58% increase in plasma cholesterol. BSO administration abolished the cholesterolemia in Cu-D rats, but had no influence on plasma cholesterol of Cu-A rats. Hepatic GSH was increased 39 to 82% in Cu-D rats and BSO abolished this increase. BSO was without effect on cardiac hypertrophy, plasma and liver copper, and hematocrit indices of copper status. Liver microsome HMG-CoA reductase activity was significantly increased 85 to 288% in Cu-D rats and BSO administration abolished this increase in activity in Cu-D rats. The results suggest that copper deficiency cholesterolemia and elevated HMG-CoA reductase activity are a consequence of elevated hepatic GSH, and provide evidence for GSH regulation of cholesterol metabolism in intact animals.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Buthionine Sulfoximine
  • Cholesterol / metabolism
  • Copper / deficiency*
  • Glutathione / metabolism*
  • Hydroxymethylglutaryl CoA Reductases / metabolism
  • Hypercholesterolemia / drug therapy*
  • Hypercholesterolemia / etiology
  • Hypercholesterolemia / metabolism
  • Liver / enzymology
  • Liver / metabolism*
  • Male
  • Methionine Sulfoximine / analogs & derivatives*
  • Methionine Sulfoximine / therapeutic use
  • Oxidation-Reduction
  • Rats
  • Rats, Inbred Strains


  • Methionine Sulfoximine
  • Buthionine Sulfoximine
  • Copper
  • Cholesterol
  • Hydroxymethylglutaryl CoA Reductases
  • Glutathione