Elsevier

Biochemical Pharmacology

Volume 64, Issues 5–6, September 2002, Pages 1027-1035
Biochemical Pharmacology

Glutathione catabolism as a signaling mechanism

https://doi.org/10.1016/S0006-2952(02)01173-5Get rights and content

Abstract

Glutathione (GSH) is the main intracellular thiol antioxidant, and as such participates in a number of cellular antitoxic and defensive functions. Nevertheless, non-antioxidant functions of GSH have also been decribed, e.g. in modulation of cell proliferation and immune response. Recent studies from our and other laboratories have provided evidence for a third functional aspect of GSH, i.e. the prooxidant roles played by molecular species originating during its catabolism by the membrane ectoenzyme γ-glutamyl transpeptidase (GGT). The reduction of metal ions effected by GSH catabolites is capable to induce redox cycling processes leading to the production of reactive oxygen species (superoxide, hydrogen peroxide), as well as of other free radicals. Through the action of these reactive compounds, GSH catabolism can ultimately lead to oxidative modifications on a variety of molecular targets, involving oxidation and/or S-thiolation of protein thiol groups in the first place. Modulating effects of this kind have been observed on several important, redox-sensitive components of the signal transduction chains, such as cell surface receptors, protein phosphatase activities and transcription factors. Against this background, the prooxidant reactions induced by GSH catabolism appear to represent a novel, as yet unrecognized mechanism for modulation of cellular signal transduction.

Section snippets

GSH, GGT and iron reduction

γ-Glutamyl transpeptidase (E.C. 2.3.2.2) is normally found in serum, and is expressed by a wide range of normal cell types [1], [2] as well as in a number of neoplastic cell lines [3] and human spontaneous tumors (reviewed in [4]). GGT catalyzes the first step in the degradation of extracellular GSH, i.e. the hydrolysis of the γ-glutamyl bond between glutamate and cysteine [5]. In so doing GGT releases cysteinyl-glycine, which is subsequently cleaved to cysteine and glycine by plasma membrane

GSH/GGT-dependent prooxidants and the redox status of protein thiols

By cleaving the γ-glutamyl bond in GSH, GGT provides the first step in catabolism of extracellular GSH. With the contribution of membrane dipeptidase activities, precursor aminoacids glycine and cysteine are then released, which can cross the plasma membrane and are re-utilized for intracellular GSH synthesis [14]. Since it has been documented that a continuous efflux of GSH occurs from a number of cell types through specific out-transporters [15], it is conceivable that a major function of GGT

Effects on the cellular proliferation/apoptosis balance

It is widely recognized that prooxidants can play a modulatory role on the transduction of proliferative/apoptotic signals, due to their ability to interact with redox-sensitive regions of growth factor receptors, protein kinases and transcription factors [24], [25], [26]. A first indication that prooxidant reactions originating from GSH catabolism could play a role in these processes came from studies with human A2780 ovarian cancer cells, showing that exogenous GSH exerts an antiproliferative

Molecular targets in the signal transduction chains

The described effects on the proliferative/apoptotic balance of cells imply the interaction of GSH/GGT-mediated prooxidants with critical targets in the intracellular signal transduction cascade, of which PARP is a first example. Among several redox-sensitive targets, the transcription factor NF-κB is perhaps the best known and studied [29]. Studies were thus aimed to verify the likely involvement of NF-κB in redox changes consequent to GSH catabolism. Using murine V79-GGT cells, highly

Concluding remarks

The experimental evidence obtained in our and other laboratories allows to describe a novel aspect of glutathione metabolism, i.e. the redox changes consequent to its cleavage by GGT. With the mediation of iron—and conceivably of other transition metals as well—GSH catabolism leads to the generation of ROS and thiyl radicals, whose prooxidant action is detectable on protein thiol groups in the first place (Fig. 5, Fig. 6). Such processes appear to involve a variety of cellular targets,

Acknowledgements

The authors are indebted to the Associazione Italiana Ricerca sul Cancro (AIRC, Milan, Italy) for its generous financial support to the research presented in this report.

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