Glutathione: Physiological and Clinical Relevance

 Glutathione (GSH), the most abundant intracellular low molecular weight thiol, has diverse physiological roles, Microtubesand altered GSH status has been implicated in a number of chronic, acute, and age-related diseases, as well as the aging process itself. Its function as an antioxidant and determinant of cellular redox potential is crucial both for protection from reactive oxygen species as well as a signaling molecule involved in cellular proliferation, cell-cycle regulation, and apoptosis. It is also an important thiol buffer, maintaining sulfhydryl groups in their reduced form, an additional mechanism for cellular signaling. By Joe Pizzorno ND and Joseph Katzinger, ND, published in J of Restorative Medicine, Vol. 1, No. 1.
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.
 The γ-glutamyl transpeptidase (GGT) enzyme, critical to the catabolism of GSH and its conjugates, appears to be an important biomarker for xenobiotic exposure, and for increased GSH demand. We review the physiological functions of glutathione, the limiting factors for its synthesis, as well as its clinical relevance, with particular emphasis on detoxification of environmental pollutants. We also review therapeutic approaches for enhancing GSH status.

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.

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