The oxidation–reduction (redox) state of the pool of cellular thiols plays a central role in antioxidant defence and in the regulation of a large number of signal transduction pathways and metabolic functions [1]. The tripeptide glutathione (GSH), i.e. L–glutamyl-L-cysteinyl-glycine (MW 307), represents the major low-molecular-mass thiol compound participating in cellular redox reactions and thio-ether formation. Under oxidative stress, GSH is oxidized to glutathione disulphide (GSSG) and further to other products such as sulphonates. Glutathione-cysteinyl disulphides can also be formed on proteins and such bound glutathione makes up a considerable amount of the cellular glutathione pool.
In January 2004, nearly 60 000 entries could be found under the term ‘glutathione’ in the Medline database, reflecting the importance of this biomolecule. Current knowledge concerning the regulation of mammalian glutathione synthesis is given in Griffith [2]. Briefly, GSH is synthesized from L-glutamate, L-cysteine and glycine in two consecutive steps, catalyzed, respectively, by -glutamyl-cysteine synthase and glutathione synthase. The redox reactions are catalyzed by GSH peroxidases (GSH-Px) and GSSG reductases (GSSG-Rd), whereas a major class of enzymes involved in thioether formation is given by the glutathione transferases (GST). Interestingly, GSH-Px activity has been extended to new functions, such as, for instance, peroxynitrite reduction, protection against apoptosis and sperm maturation, and at present glutathione is considered as the most important antioxidant in vivo [reviewed in 3].
Besides its antioxidant activity, glutathione has many physiological functions including detoxification of xenobiotics, modulation of redox-regulated signal transduction, storage and transport of cysteine, regulation of cell proliferation, synthesis of deoxyribonucleotide, regulation of immune response, and regulation of leukotriene and prostaglandin metabolism. GSH is able to increase the activation of cytotoxic T cells in vivo. The normal functioning of T lymphocytes is dependent upon cellular supplies of cysteine. The cells acquire the amino acid largely by uptake of GSH by macrophages and lymphocytes. Impaired immune responses are associated with a reduction in the glutathione concentration of immune tissue [4].