Glutathione dysregulation and the etiology and progression of human diseases

Abstract

Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and as a result, disturbances in GSH homeostasis are implicated in the etiology and/or progression of a number of human diseases, including cancer, diseases of aging, cystic fibrosis, and cardiovascular, inflammatory, immune, metabolic, and neurodegenerative diseases. Owing to the pleiotropic effects of GSH on cell functions, it has been quite difficult to define the role of GSH in the onset and/or the expression of human diseases, although significant progress is being made. GSH levels, turnover rates, and/or oxidation state can be compromised by inherited or acquired defects in the enzymes, transporters, signaling molecules, or transcription factors that are involved in its homeostasis, or from exposure to reactive chemicals or metabolic intermediates. GSH deficiency or a decrease in the GSH/glutathione disulfide ratio manifests itself largely through an increased susceptibility to oxidative stress, and the resulting damage is thought to be involved in diseases, such as cancer, Parkinson's disease, and Alzheimer's disease. In addition, imbalances in GSH levels affect immune system function, and are thought to play a role in the aging process. Just as low intracellular GSH levels decrease cellular antioxidant capacity, elevated GSH levels generally increase antioxidant capacity and resistance to oxidative stress, and this is observed in many cancer cells. The higher GSH levels in some tumor cells are also typically associated with higher levels of GSH-related enzymes and transporters. Although neither the mechanism nor the implications of these changes are well defined, the high GSH content makes cancer cells chemoresistant, which is a major factor that limits drug treatment. The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases.

Modulation of multiple pathways involved in the maintenance of neuronal function during aging by fisetin

“…A fairly large number of studies have shown age-dependent decreases in total GSH and/or reduced GSH levels in the brain (for reviews see [3,25,53]). In addition, age-dependent increases in glutathione disulfide (GSSG), the oxidized form of GSH have been observed in both mouse [72] and rat [67] brains.…”

c-Jun activation is required for 4-hydroxytamoxifen-induced cell death in breast cancer cells

“…These observations together with this study lead to the hypothesis that the functional output of c-Fos induction by OHT may depend on whether or not there is a concomitant c-Jun activation by JNK signaling. As antioxidant pathways are often enhanced in cancer cells (Friesen et al, 2004;Young et al, 2004;Recktenwald et al, 2008;Ballatori et al, 2009), the resistance of certain cancer cells to tamoxifen may depend on their ability to prevent ROS accumulation and in turn JNKspecific activation of c-Jun. In line with this hypothesis we found that OHT induced ROS accumulation in SkBr3 cells but not in LNCaP cells (Figure 8).…”

Antioxidant enzymes responses of polychaete Perinereis aibuhitensis following chronic exposure to 17β-estradiol

“…Low intracellular GSH levels would decrease the cellular antioxidant capacity. Several reports have suggested that a decrease in GSH levels is also associated with immune system dysfunction and inflammation in humans (Ballatori et al 2009;Ghezzi 2011). In the present study, the depletion of GSH and the elevation of GSSG could result in damage to the immune system, which would decrease the resistance to disease.…”