Glutathione has emerged a key modulator of xenobiotic toxicity, most notably the persistent organic pollutants which are associated with many diseases of impaired metabolic activity, including diabetes, obesity, and cardiovascular disease.
There is a growing recognition of the importance of glutathione (GSH) physiology, and of the number of physiological functions involving this small but critical tripeptide. Given its potent redox capabilities, and its high intracellular concentration and widespread distribution, its role as a potent defense mechanism against oxidative and electrophilic stress is well-established.
Yet as our understanding of cellular signaling and regulatory pathways has developed, so has our insight into the involvement of GSH homeostasis in many other key processes, including the regulation of cellular proliferation and apoptosis and the post-transcriptional modification of proteins through S-glutathionylation, as well as the importance of GSH in the detoxification of hydroperoxides and diverse xenobiotic compounds. Additionally, GSH has been shown to be vital to mitochondrial function and maintenance of mtDNA, and may be relevant to DNA methylation. Given the diverse roles of GSH in cellular physiology, the clinical importance of altered glutathione homeostasis is gaining well-deserved attention. Disturbances in GSH homeostasis have been implicated in neurodegenerative disorders, liver disease, cystic fibrosis, pulmonary and cardiovascular diseases, as well as the chronic age-related diseases and the aging process itself.
Recent data also suggests it plays a role in metabolic and inflammatory diseases such as multiple sclerosis, the metabolic syndrome, and diabetes, at least in part by influencing the effect of multiple environmental toxins, an underappreciated yet surprisingly significant association. In this review, we will briefly describe glutathione physiology and the clinical implications of altered GSH homeostasis, as well as research on the use of various forms of glutathione as a therapeutic strategy. In light of the growing risk of persistent organic pollutants, particular attention will be given to their influence on chronic disease development, and how GSH may modulate this risk.