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
- 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.
- Meister, A. and M.E. Anderson, Glutathione. Annu Rev Biochem, 1983. 52: p. 711-60.
- 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.
- 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.
- Wu, G., et al., Glutathione metabolism and its implications for health. Journal of Nutrition, 2004. 134(3): p. 489-92.
- Stark, A.A., et al., The role of gamma-glutamyl transpeptidase in the biosynthesis of glutathione. Biofactors, 2003. 17(1-4): p. 139-49.
- 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.
- 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.
- Quintana-Cabrera, R., et al., γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor. Nat Commun, 2012. 3: p. 718.
- Nakamura, Y.K., M.A. Dubick, and S.T. Omaye, γ-Glutamylcysteine inhibits oxidative stress in human endothelial cells. Life Sciences, 2011(0).
- 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.
- 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.
- 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.
- 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.
- Yang, Y., et al., γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level. Redox Biology, 2019. 20: p. 157-166.
thanks for this blog. Glutathione has helped me tremendously with eliminating mold toxicity. However, I am not finding the same results, now that I have long Covid. Have you gotten any feedback from anyone with a Long Covid on the effectiveness or ineffectiveness of Gamma-Glutamylcysteine in raising the body’s own glutathione levels. My specific goal, is to eliminate the spike proteins that result from both the vaccine and a bout of Long Covid, Which I have had for the past 6 1/2 months. I am finding that normal affective supplements are no match for spike proteins and I want them out of my body, yesterday!
Hi Cynthia
Sorry to hear of your troubles with long covid. We wrote a blog on this subject a little while ago at https://www.glutathionereporter.com/glutathione-and-long-covid-or-chronic-fatigue-syndrome/
It seems there are a lot of similarities between long covid and chronic fatigue syndrome and both are associated with a condition called oxidative stress. The body’s main defence against oxidative stress is antioxidants and glutathione being the master antioxidant it’s critical that it’s maintained at an optimum concentration. Gamma-Glutamylcysteine is the only known way to supplement cellular glutathione effectively; however, at this stage, we have not seen Gamma-Glutamylcysteine being tested for in any clinical trials on these specific conditions as yet.
You say it is not possible without gamma glutamyl cysteine to increase cellular Glutathion, however did you ever think about IV with S-Acetyl-Glutathion? This is very promising in Europe and seems to be increasing cellular Glutathion very efficiently.
Also what about taking Lipoic Acid or other Antioxidants like Vitamin C that relieves the Gluthation system?
Dear Pascalda
Regarding S-acetylglutathione (SAG) we have several comments. Firstly, unlike gamma-glutamylcysteine, SAG is not a naturally occurring compound it is a synthetic chemical. Secondly, we were able to find one human clinical trial published on the use of SAG in comparison to treatment with normal glutathione. Both were delivered orally, and the results of the trial showed no significant difference between SAG and normal glutathione. Neither of these treatments showed any significant increases in plasma or erythrocyte glutathione over 24 hours.
Regarding the use of intravenous (IV) SAG, if you have knowledge of a published clinical trial confirming that it is effective in increasing cellular glutathione, we would be grateful if you could send a link to the article. However, we would hardly think that IV treatment is a convenient, risk-free, or cost-effective way of increasing cellular glutathione. Even if it was effective in transiently increasing cellular glutathione considering that glutathione is a rapid turnover biochemical you would require a daily IV infusion to maintain any significant increase in cellular glutathione over time.
Regarding Lipoic acid and Vitamin C, they both may have a sparing effect on glutathione. However, neither address the fundamental problem which is a deficiency or damage in the first enzyme that produces gamma-glutamylcysteine which is the root cause of low cellular glutathione.
Hi There
Can you recommend any supplements, affordable to most people, that can effectively increase Glutathione inside the cells?
I’ve looked over your articles that NAC and GSH supplements dont help. The only products i’ve found that use Gamma-Glutamylcysteine to help, are USD 130 / month, and just not affordable for the masses.
thank U
Hi Peter,
Unfortunately, the only compound which can increase cellular glutathione is Gamma Glutamyl Cysteine as it is the immediate precursor to glutathione. https://www.glutathionereporter.com/raising-cellular-glutathione-levels-with-gamma-glutamylcysteine/ Therefore we cannot recommend any other compound or supplement as they simply cannot work.