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

Background:gamma-Glutamyl transpeptidase (gamma-GT) is found in serum and i n the plasma membranes of virtually all cell types. Its physiologic role is to initiate the hydrolysis of extracellular glutathione (GSH), a tripeptid e 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(In) to redox active Fe(II); therefore, we sought to determine w hether 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 th iobarbituric acid-reactive substances, respectively. Human atheromatous tis sues 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, prec luding 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 cell s, and this process required iron traces that can be found in advanced or l ate 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 g amma-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-G T can promote LDL oxidation by hydrolyzing GSH into more potent iron reduct ants, These findings may provide mechanistic clues to the epidemiologic evi dence for a possible correlation between persistent elevation of gamma-GT a nd the risk of fatal reinfarction in patients with ischemic heart disease.