Gamma-glutamyl transpeptidase-dependent iron reduction and LDL oxidation--a potential mechanism in atherosclerosis

J Investig Med. 1999 Mar;47(3):151-60.


Background: gamma-Glutamyl transpeptidase (gamma-GT) is found in serum and in the plasma membranes of virtually all cell types. Its physiologic role is to initiate the hydrolysis of extracellular glutathione (GSH), a tripeptide in which cysteine lies between alpha-glycine and gamma-glutamate residues. Cysteine and other thiol compounds are known to promote LDL oxidation by reducing Fe(III) to redox active Fe(II); therefore, we sought to determine whether similar reactions can be sustained by GSH and influenced by gamma-GT.

Methods: Fe(III) reduction and LDL oxidation were studied by monitoring the formation bathophenanthroline-chelatable Fe(II) and the accumulation of thiobarbituric acid-reactive substances, respectively. Human atheromatous tissues were examined by histochemical techniques for the presence of oxidized LDL and their colocalization with cells expressing gamma-GT activity.

Results: A series of experiments showed that the gamma-glutamate residue of GSH affected interactions of the juxtaposed cysteine thiol with iron, precluding Fe(III) reduction and hence LDL oxidation. Both processes increased remarkably after addition of purified gamma-GT, which acts by removing the gamma-glutamate residue. GSH-dependent LDL oxidation was similarly promoted by gamma-GT associated with the plasma membrane of human monoblastoid cells, and this process required iron traces that can be found in advanced or late stage atheromas. Collectively, these findings suggested a possible role for gamma-GT in the cellular processes of LDL oxidation and atherogenesis. Histochemical analyses confirmed that this may be the case, showing that gamma-GT activity is expressed by macrophage-derived foam cells within human atheromas, and that these cells colocalize with oxidized LDL.

Conclusions: Biochemical and histochemical correlates indicate that gamma-GT can promote LDL oxidation by hydrolyzing GSH into more potent iron reductants. These findings may provide mechanistic clues to the epidemiologic evidence for a possible correlation between persistent elevation of gamma-GT and the risk of fatal reinfarction in patients with ischemic heart disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arteriosclerosis / metabolism*
  • Catalase / pharmacology
  • Chelating Agents / metabolism
  • Foam Cells / enzymology
  • Foam Cells / pathology
  • Glutathione / pharmacology
  • Humans
  • Immunoenzyme Techniques
  • Iron / chemistry
  • Iron / metabolism*
  • Lipid Peroxidation / physiology
  • Lipoproteins, LDL / chemistry
  • Lipoproteins, LDL / metabolism*
  • Male
  • Middle Aged
  • Phenanthrolines / metabolism
  • Superoxide Dismutase / metabolism
  • Thiobarbituric Acid Reactive Substances / metabolism
  • U937 Cells
  • gamma-Glutamyltransferase / metabolism*


  • Chelating Agents
  • Lipoproteins, LDL
  • Phenanthrolines
  • Thiobarbituric Acid Reactive Substances
  • bathophenanthroline disulfonic acid
  • Iron
  • Catalase
  • Superoxide Dismutase
  • gamma-Glutamyltransferase
  • Glutathione