Glutathione and Glutathione‐S‐Transferase in Detoxification Mechanisms

Glutathione (GSH) and glutathione-S-transferases (GSTs) are two primary lines of defence against both acute and chronic toxicities of electrophiles and reactive oxygen/nitrogen species. GSH confers cellular protection by directly or enzymatically reducing free radicals and reactive species (RS), and conjugating endogenous and exogenous electrophiles. GSTs are a superfamily of Phase 2 detoxification enzymes that detoxify both RS and toxic xenobiotics, primarily by catalysing GSH-dependent conjugation and redox reactions. Both GSH content and GST enzyme activities are under tight homeostatic control. Under normal conditions, neither GST enzyme activities nor GSH levels operate at their maximum capacity. Upon exposure to mild oxidative and electrophilic stress, they are concomitantly induced to achieve efficient protection. This chapter provides an updated understanding about GSH synthesis, the utilization of GSH for detoxification against RS, drugs and toxic xenobiotics, and its recycling from glutathione disulfide (GSSG) and GSH conjugates. This chapter also reviews the united classification/nomenclature system, structure, catalytic mechanism and functions of GST enzymes. Another focus of this chapter is the well-characterized antioxidant response element (ARE)/nuclear factor-erythroid-2-related factor 2 (Nrf2)-Kelch-like ECH associating protein 1 (Keap1) signalling pathway that regulates the basal and induced expression of GST and GSH homeostasis genes in mammals. Keywords: antioxidant response element (ARE); cytoprotection; electrophiles; glutathione (GSH); GSH homeostasis; glutathione-S-transferase (GST); induction; oxidative stress; nuclear factor-erythroid-2-related factor 2 (Nrf2); reaction