Glutathione and glutathione-dependent enzymes represent a Co-ordinately regulated defence against oxidative stress

Increases in the intracellular levels of reactive oxygen species (ROS), fre quently referred to as oxidative stress, represents a potentially toxic ins ult which if not counteracted will lead to membrane dysfunction, DNA damage and inactivation of proteins. Chronic oxidative stress has numerous pathol ogical consequences including cancer, arthritis and neurodegenerative disea se. Glutathione-associated metabolism is a major mechanism for cellular pro tection against agents which generate oxidative stress. It is becoming incr easingly apparent that the glutathione tripeptide is central to a complex m ultifaceted detoxification system, where there is substantial inter-depende nce between separate component members. Glutathione participates in detoxif ication at several different levels, and may scavenge free radicals, reduce peroxides or be conjugated with electrophilic compounds. Thus, glutathione provides the cell with multiple defences not only against ROS but also aga inst their toxic products. This article discusses how glutathione biosynthe sis, glutathione peroxidases, glutathione S-transferases and glutathione S- conjugate efflux pumps function in an integrated fashion to allow cellular adaption to oxidative stress. Go-ordination of this response is achieved, a t least in part, through the antioxidant responsive element (ARE) which is found in the promoters of many of the genes that are inducible by oxidative and chemical stress. Transcriptional activation through this enhancer appe ars to be mediated by basic leucine zipper transcription factors such as Nr f and small Maf proteins. The nature of the intracellular sensor(s) for ROS and thiol-active chemicals which induce genes through the ARE is described . Gene activation through the ARE appears to account for the enhanced antio xidant and detoxification capacity of normal cells effected by many cancer chemopreventive agents. In certain instances it may also account for acquir ed resistance of tumours to cancer chemotherapeutic drugs. It is therefore clear that determining the mechanisms involved in regulation of ARE-driven gene expression has enormous medical implications.