Home Glutathione Facts Gamma-Glutamylcysteine increases cellular glutathione

Gamma-Glutamylcysteine increases cellular glutathione

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Gamma-glutamylcysteine, (GGC) is a naturally occurring dipeptide found in all mammalian life and is a key intermediate in the gamma (γ) -glutamyl cycle first described by Meister in the 1970s [1, 2]. It is the most immediate precursor to the essential antioxidant glutathione (GSH) [3].

Supplementation with glutathione (GSH) is incapable of increasing cellular glutathione (GSH) since the glutathione (GSH) concentration found in the extracellular environment is much lower than that found intracellularly by about a thousand-fold. This large difference means that there is an insurmountable concentration gradient that prohibits extracellular glutathione entering cells and it is only inside the cell where glutathione performs its essential functions.

Gamma-Glutamylcysteine (GGC) is not subject to such a concentration gradient as it occurs in human plasma in the range of 1 – 5 µM [2, 3] and intracellularly at 5 – 10 µM [4]. The intracellular concentration of gamma-glutamylcysteine (GGC) is generally low allowing it (GGC) to diffuse into the cell. Once inside the cell it (GGC) rapidly bonds to glycine to form glutathione (GSH). This second and final reaction step in glutathione (GSH) biosynthesis is catalyzed by the activity of the ATP dependent glutathione synthase (GS) enzyme. Although currently unproven, gamma-glutamylcysteine (GGC) may be the pathway intermediate of glutathione transportation in multicellular organisms [5, 6].

A human clinical study in healthy, non-fasting adults demonstrated that orally administered gamma-glutamylcysteine (GGC) can significantly increase lymphocyte glutathione (GSH) levels indicating systemic bioavailability, validating the therapeutic potential of gamma-glutamylcysteine (GGC) [7]. Gamma-glutamylcysteine (GGC) is also capable of being a powerful antioxidant in its own right as well [8-10].

Since the production of cellular gamma-glutamylcysteine (GGC) in humans slows down with age, as well as during the progression of many chronic diseases, it has been postulated that supplementation with gamma-glutamylcysteine (GGC) could offer health benefits. Other benefits of gamma-glutamylcysteine (GGC) supplementation may extend to situations where glutathione (GSH) has been acutely lowered below optimum such as following strenuous exercise, and during trauma or episodes of poisoning.

Several review articles have been published regarding the therapeutic potential of gamma-glutamylcysteine (GGC) to replenish glutathione (GSH) in age related [11] and chronic disease states such as Alzheimer’s disease [12].

As gamma-glutamylcysteine (GGC) has become commercially available several researchers have reported invitro, animal and human studies investigating a potential therapeutic role for gamma-glutamylcysteine (GGC) in both the reduction of oxidant stress-induced damage in tissues including the brain [13, 14] and as a treatment for sepsis [15].

References

  1. Orlowski, M. and A. Meister, The gamma-glutamyl cycle: a possible transport system for amino acids. Proc Natl Acad Sci U S A, 1970. 67(3): p. 1248-55.
  2. Meister, A. and M.E. Anderson, Glutathione. Annu Rev Biochem, 1983. 52: p. 711-60.
  3. Anderson, M.E. and A. Meister, Transport and direct utilization of gamma-glutamylcyst(e)ine for glutathione synthesis. Proceedings of the National Academy of Sciences of the United States of America., 1983. 80(3): p. 707-11.
  4. Mårtensson, J., Method for determination of free and total glutathione and γ-glutamylcysteine concentrations in human leukocytes and plasma. Journal of Chromatography B: Biomedical Sciences and Applications, 1987. 420(0): p. 152-157.
  5. Wu, G., et al., Glutathione metabolism and its implications for health. Journal of Nutrition, 2004. 134(3): p. 489-92.
  6. Stark, A.A., et al., The role of gamma-glutamyl transpeptidase in the biosynthesis of glutathione. Biofactors, 2003. 17(1-4): p. 139-49.
  7. Zarka, M.H. and W.J. Bridge, Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study. Redox Biology, 2017. 11: p. 631-636.
  8. Quintana-Cabrera, R. and J.P. Bolanos, Glutathione and gamma-glutamylcysteine in the antioxidant and survival functions of mitochondria. Biochemical Society Transactions, 2013. 41: p. 106-110.
  9. Quintana-Cabrera, R., et al., γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor. Nat Commun, 2012. 3: p. 718.
  10. Nakamura, Y.K., M.A. Dubick, and S.T. Omaye, γ-Glutamylcysteine inhibits oxidative stress in human endothelial cells. Life Sciences, 2011(0).
  11. Ferguson, G. and W. Bridge, Glutamate cysteine ligase and the age-related decline in cellular glutathione: The therapeutic potential of γ-glutamylcysteine. Archives of Biochemistry and Biophysics, 2016. 593: p. 12-23.
  12. Cao, P., et al., Therapeutic approaches to modulating glutathione levels as a pharmacological strategy in Alzheimer’s disease. Curr Alzheimer Res, 2015. 12(4): p. 298-313.
  13. Le, T.M., et al., gamma-Glutamylcysteine ameliorates oxidative injury in neurons and astrocytes in vitro and increases brain glutathione in vivo. Neurotoxicology, 2011. 32(5): p. 518-25.
  14. Braidy, N., et al., -glutamylcysteine (GGC)-mediated upregulation of glutathione levels can ameliorate toxicity of natural beta-amyloid oligomers in primary adult human neurons, in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 2013, Elsevier. p. P854.
  15. Yang, Y., et al., γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level. Redox Biology, 2019. 20: p. 157-166.

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