Epigenetics is a rapidly growing field that studies gene expression modifications not involving changes in the DNA sequence. Histone H3, one of the basic proteins in the nucleosomes that make up chromatin, is S-glutathionylated in mammalian cells and tissues, making Gamma-L-glutamyl-L-cysteinylglycine, glutathione (GSH), a physiological antioxidant and second messenger in cells, a new post-translational modifier of the histone code that alters the structure of the nucleosome. However, the role of GSH in the epigenetic mechanisms likely goes beyond a mere structural function. Evidence supports the hypothesis that there is a link between GSH metabolism and the control of epigenetic mechanisms at different levels (i.e., substrate availability, enzymatic activity for DNA methylation, changes in the expression of microRNAs, and participation in the histone code). However, little is known about the molecular pathways by which GSH can control epigenetic events. Studying mutations in enzymes involved in GSH metabolism and the alterations of the levels of cofactors affecting epigenetic mechanisms appears challenging. However, the number of diseases induced by aberrant epigenetic regulation is growing, so elucidating the intricate network between GSH metabolism, oxidative stress and epigenetics could shed light on how their deregulation contributes to the development of neurodegeneration, cancer, metabolic pathologies and many other types of diseases.

Reactive oxygen species, formed in various biochemical reactions, are normally scavenged by antioxidants. Glutathione in its reduced form (GSH) is the most powerful intracellular antioxidant, and the ratio of reduced to oxidised glutathione (GSH:GSSG) serves as a representative marker of the antioxidative capacity of the cell. Several clinical conditions are associated with reduced GSH levels which as a consequence can result in a lowered cellular redox potential. GSH and the redox potential of the cell are components of the cell signaling system influencing the translocation of the transcription factor NF kappa B which regulates the synthesis of cytokines and adhesion molecules. Therefore, one possibility to protect cells from damage caused by reactive oxygen species is to restore the intracellular glutathione levels. Cellular GSH concentration can be influenced by exogenous administration of GSH (as intravenous infusion or as aerosol), of glutathione esters or of GSH precursors such as glutamine or cysteine (in form of N-acetyl-L-cysteine, alpha-lipoic acid). The modulation of GSH metabolism might present a useful adjuvant therapy in many pathologies such as intoxication, diabetes, uremia, sepsis, inflammatory lung processes, coronary disease, cancer and immunodeficiency states.

BACKGROUND: The pathogenesis of chronic hepatitis C virus (HCV) infection is associated with a defective host antiviral immune response and intrahepatic oxidative stress. Oxidative stress and lipid peroxidation play major roles in the fatty liver accumulation (steatosis) that leads to necro-inflammation and necrosis of hepatic cells. Previous trials suggested that antioxidative therapy may have a beneficial effect on patients with chronic HCV infection. AIMS: To determine the safety and efficacy of treatment of chronic HCV patients via a combination of antioxidants. METHODS: Fifty chronic HCV patients were treated orally on a daily basis for 20 weeks with seven antioxidative oral preparations (glycyrrhizin, schisandra, silymarin, ascorbic acid, lipoic acid, L-glutathione, and alpha-tocopherol), along with four different intravenous preparations (glycyrrhizin, ascorbic acid, L-glutathione, B-complex) twice weekly for the first 10 weeks, and followed up for an additional 20 weeks. Patients were monitored for HCV-RNA levels, liver enzymes, and liver histology. Assessment of quality of life was performed using the SF-36 questionnaire. RESULTS: In one of the tested parameters (eg, liver enzymes, HCV RNA levels, or liver biopsy score), a combination of antioxidants induced a favorable response in 48% of the patients (24). Normalization of liver enzymes occurred in 44% of patients who had elevated pretreatment ALT levels (15 of 34). ALT levels remained normal throughout follow-up period in 72.7% (8 of 11). A decrease in viral load (one log or more) was observed in 25% of the patients (12). Histologic improvement (2-point reduction in the HAI score) was noted in 36.1% of the patients. The SF-36 score improved in 26 of 45 patients throughout the course of the trial (58% of the patients). Treatment was well tolerated by all patients. No major adverse reactions were noted. CONCLUSIONS: These data suggest that multi antioxidative treatment in chronic HCV patients is well tolerated and may have a beneficial effect on necro-inflammatory variables. A combination of antiviral and antioxidative therapies may enhance the overall response rate of these patients.

BACKGROUND: The pathogenesis of chronic hepatitis C virus (HCV) infection is associated with a defective host antiviral immune response and intrahepatic oxidative stress. Oxidative stress and lipid peroxidation play major roles in the fatty liver accumulation (steatosis) that leads to necro-inflammation and necrosis of hepatic cells. Previous trials suggested that antioxidative therapy may have a beneficial effect on patients with chronic HCV infection. AIMS: To determine the safety and efficacy of treatment of chronic HCV patients via a combination of antioxidants. METHODS: Fifty chronic HCV patients were treated orally on a daily basis for 20 weeks with seven antioxidative oral preparations (glycyrrhizin, schisandra, silymarin, ascorbic acid, lipoic acid, L-glutathione, and alpha-tocopherol), along with four different intravenous preparations (glycyrrhizin, ascorbic acid, L-glutathione, B-complex) twice weekly for the first 10 weeks, and followed up for an additional 20 weeks. Patients were monitored for HCV-RNA levels, liver enzymes, and liver histology. Assessment of quality of life was performed using the SF-36 questionnaire. RESULTS: In one of the tested parameters (eg, liver enzymes, HCV RNA levels, or liver biopsy score), a combination of antioxidants induced a favorable response in 48% of the patients (24). Normalization of liver enzymes occurred in 44% of patients who had elevated pretreatment ALT levels (15 of 34). ALT levels remained normal throughout follow-up period in 72.7% (8 of 11). A decrease in viral load (one log or more) was observed in 25% of the patients (12). Histologic improvement (2-point reduction in the HAI score) was noted in 36.1% of the patients. The SF-36 score improved in 26 of 45 patients throughout the course of the trial (58% of the patients). Treatment was well tolerated by all patients. No major adverse reactions were noted. CONCLUSIONS: These data suggest that multi antioxidative treatment in chronic HCV patients is well tolerated and may have a beneficial effect on necro-inflammatory variables. A combination of antiviral and antioxidative therapies may enhance the overall response rate of these patients.