Selective colocalization of lipid peroxidation and protein thiol loss in chemically induced hepatic preneoplastic lesions: the role of γ-glutamyltranspeptidase activity

Abstract

A number of studies indicate that cell proliferation can be modulated by changes in the redox balance of (soluble and protein) cellular thiols. Free radical processes, including lipid peroxidation (LPO), can affect such a balance, and a role for LPO in multistage carcinogenesis has been envisaged. The present study was aimed to assess the relationships between the protein thiol redox status and the LPO process in chemically induced preneoplastic tissue. The Solt-Farber's initiation-promotion model of chemical carcinogenesis in the rat liver was used. In fresh cryostat sections, preneoplastic lesions were identified by the reexpression of gamma-glutamyltranspeptidase (GGT) activity. In serial sections, different classes of protein thiols were stained; in additional sections, LPO was elicited by various prooxidant mixtures and determined thereafter by the hydroxynaphthoic hydrazide-Fast Blue B procedure. The incubation of sections in the presence of chelated iron plus substrates for GGT activity leads to the development of LPO in selected section areas closely corresponding to GGT-positive lesions, indicating the ability of GGT activity to initiate LPO. Protein-reactive thiols, as well as total protein sulfur, were decreased by 20-25% in cells belonging to GGT-positive preneoplastic nodules, suggesting the occurrence of oxidative conditions in vivo. The incubation of additional adjacent sections with the prooxidant mixture H2O2 plus iron(II), in order to induce the complete oxidation of lipid present in the section, showed a decreased basal concentration of oxidizable lipid substrate in GGT-rich areas. The decreased levels of both protein thiols and lipid-oxidizable substrate in GGT-positive nodules suggest that the observed GGT-dependent pathway of LPO initiation can be chronically operative in vivo during early stages of chemical carcinogenesis, in cells expressing GGT as part of their transformed phenotype.

Hepatoprotective Effect of Andrographolide Against Hexachlorocyclohexane-Induced Oxidative Injury

“…34 Earlier work in immunohistochemical and enzyme histochemical studies on γ-GTP in rat liver has been used during 3-me-DAB hepatocarcinogenesis. 35 Pompella et al 36 showed the decreased levels of protein thiols in GGTpositive nodules induced by chemical carcinogenesis in the rat liver. These findings correlate with the results of this study, showing elevated levels of γ-GTP in liver tumors induced by BHC.…”

γ‐Glutamyltransferase‐dependent prooxidant reactions: A factor in multiple processes

“…Subsequent studies evidenced the prooxidant action potentially played by GGT reexpressed in chemically-induced preneoplastic lesions of rat liver. When fresh cryostat sections of liver were exposed to GSH, chelated Fe(III) and glycyl-glycine, the GGT activity present in transformed cells was able to catalyze the initiation of a lipid peroxidation process, which could be revealed by means of histochemical reactions [22,23]. Experiments showed that transferrin could serve as a source of redox-active iron.…”

Hydrogen peroxide produced during γ‐glutamyl transpeptidase activity is involved in prevention of apoptosis and maintainance of proliferation in U937 cells

“…In this respect, recent studies from our laboratory and others have shown that another source of cellular basal production of oxidants is represented by g-glutamyl transpeptidase (GGT), 2 the plasma membranebound ectoactivity that, in a number of cell types, is in charge of metabolizing extracellular reduced glutathione (GSH). In fact, it has recently been documented that GGT activity can give rise to redox reactions, due to the interplay of reactive thiol metabolites of GSH (cysteinyl-glycine in the first place) with transition metal ions; these reactions were shown to induce the production of reactive oxygen species and lipid peroxidation (15)(16)(17)(18).…”