Glutathione is exclusively made inside cells and is produced in two steps: The first makes gamma-glutamylcysteine (GGC) from the amino acids glutamate and cysteine, and the second adds a glycine to the gamma-glutamylcysteine (GGC) to make the GSH tripeptide. During aging and in many chronic illnesses, our cells lose the capacity to make enough gamma-glutamylcysteine (GGC), which means cells do not produce sufficient glutathione (GSH) to protect against oxidative stress [1].
Supplementation with glutathione will not increase cellular glutathione (GSH) for one simple reason. In the tissues of your body there are two very different environments. One is the fluid inside your cells (intracellular, about 70% of the total fluids) and the other is the fluid outside your cells (extracellular, about 30% of total fluids).
The intracellular environment, which is bound by your cellular membranes, is where most of the essential reactions such as protein synthesis and energy production occur. Many of these reactions generate free radicals that can, if not controlled (neutralized), cause damage inside your body (oxidative stress). To counter this, your cellular glutathione (GSH) levels must be maintained at an optimal concentration (homeostasis) and in a tightly controlled (regulated) manner.
The extracellular environment, such as the plasma of your blood, allows the transportation of nutrients to the cells and removal of waste products which in turn are processed in the liver and kidneys. The glutathione (GSH) concentration found in this environment (micromolar) is much lower than that found intracellularly (millimolar) by about a thousand-fold. This large concentration difference means that there is an insurmountable concentration gradient that prohibits extracellular glutathione (GSH) entering cells.
So, when you take a glutathione supplement orally or by injection, it will ‘hang around’ in the extracellular environment but will not be able to enter cells to combat oxidative stress.
But what happens to all of that extracellular glutathione (GSH)? Well, glutathione (GSH) is made up of some valuable amino acids and cells have a system of scavenging them before they are recycled. Most cells in the body have an outer membrane bound enzyme (gamma-glutamyltransferase)[1] which starts this process by breaking glutathione (GSH) down to its constituent amino acids (protein building blocks).
Several researchers have confirmed this thesis. For example a group of researchers[2] concluded that “dietary glutathione (GSH) is not a major determinant of circulating glutathione (GSH), and it is not possible to increase circulating glutathione (GSH) to a clinically beneficial extent by the oral administration of a single dose of 3g of glutathione (GSH)”. Similarly, authors [3] of the first double-blind, randomized, placebo-controlled clinical trial of oral glutathione (GSH) supplementation performed in healthy adult humans concluded that “despite the biochemical plausibility, optimal dose, recommended timing of administration and appropriate choice of outcome measures, no significant changes were observed in oxidative stress biomarkers or erythrocyte glutathione (GSH) concentrations following 4 weeks of oral (2 x 500mg daily) glutathione (GSH) supplementation”.
Gamma-glutamylcysteine (GGC), on the other hand, does not have this concentration gradient problem. It is found in roughly the same low concentration both intracellularly and extracellularly. Once ingested however, the extracellular gamma-glutamylcysteine (GGC) concentration increases and therefore it can easily diffuse through the cell membrane to the inside of cells. Once inside, it is immediately used to produce glutathione (GSH) [4].
In summary, the problem in aging and most chronic disease is that our cells lose the ability to make enough gamma-glutamylcysteine (GGC) which results in insufficient glutathione (GSH) production. Glutathione supplements cannot enter cells as there is an insurmountable concentration gradient across the cell membrane and, although there are well understood membrane transporters for transporting glutathione from the inside to the outside of the cell, there are no known transporters for transporting extracellular glutathione to inside the cell. However, Gamma-glutamylcysteine (GGC) does get transported into the cell [5, 6].
References
- Franco, R., et al., The central role of glutathione in the pathophysiology of human diseases. Archives Of Physiology And Biochemistry, 2007. 113(4-5): p. 234-258.
- Witschi, A., et al., The systemic availability of oral glutathione. European Journal of Clinical Pharmacology, 1992. 43(6): p. 667-669.
- Allen, J. and R.D. Bradley, Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. J Altern Complement Med, 2011. 17(9): p. 827-33.
- Wu, G., et al., Glutathione metabolism and its implications for health. Journal of Nutrition, 2004. 134(3): p. 489-92.
- 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.
- 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.
Hi there,
Great article by the way as it is often hard to find good information amongst lots of marketing speil. I have two questions that I hope you can answer:
1. There is a study on an ingredient called Setria which is a human study and the results show that taking their oral glutathione supplement increased glutathione within the cell. Here is the study https://pubmed.ncbi.nlm.nih.gov/24791752/
2. So based on what you are saying, should you just take more Glutamine or cysteine. I had read that we had plenty of Glutamine in the body so am just wondering what you suggest is best?
I actually have another one, sorry?
3. So what about the third amino Acid, where does this come in to it?
Hope you can help answer my questions. Thanks in advance
Dear Mr Lloyd
We are aware of the Setria study. Unfortunately, it is a technically flawed study that has obvious conflicts of interest from the authors. Its results are in contradiction to several other human studies showing that oral glutathione is ineffective (please see https://pubmed.ncbi.nlm.nih.gov/1362956/ and https://pubmed.ncbi.nlm.nih.gov/21875351/ ). No theoretical reason as to how or why oral glutathione should be transported into cells was given by the authors of the Setria study nor has any other researcher given any plausible mechanism for intact glutathione to be transported from outside a cell to inside a cell.
To your second question, no given a normal diet and functioning liver there is no need to supplement any of the three amino acids (glutamic acid, cysteine, and glycine) that go into making up glutathione. None are essential in the diet as our bodies can already make them. The major cause of low glutathione is not an undersupply of the amino acids but a lack of or a dysfunctional enzyme that produces the dipeptide called gamma-glutamylcysteine (GGC) which is the most immediate precursor to glutathione.
To your third question, GGC has been shown to have the unique ability to be orally bioavailable and be transported to inside cells where it is rapidly reacted enzymatically with the third amino acid called glycine to make the final product glutathione. So if you are looking for a way of increasing your cellular glutathione then an oral supplement containing gamma-glutamylcysteine (GGC) is the only effective way of doing that.
I have heard of a company called Life Vantage which sells a product called Protandim. They claim to be able to increase Glutathione in humans by 300%. After reading your article, I have doubts. What do you think and have you heard of this product. A lot of peer reviewed articles on it so I’m interested in your take. Thanks.
Hi Lisa
Thanks for bringing this to our attention. After reading the Wikipedia page on Protandim I cannot say that we are impressed by the offering of this multilevel marketing company. They were sent a warning letter from the FDA for making illegal advertising claims about it being able to cure various ailments, including cancer and diabetes. Although they seem to have cleaned up their act it still doesn’t change the fact that their product is an unremarkable mixture of herbal ingredients that can be purchased off the shelf separately from any supplement store for probably a 10th of the price. Just clever marketing. Also, on inspection of their peer-reviewed articles, most studies seem to be done in either cell culture or on animals. These types of studies are very easily and cheaply done however a far stretch from actual human clinical studies.
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After reading various reports , am I to understand that it is a waste of money to buy Gultathione?
Dear Gary, If your objective is to elevate the concentration of glutathione inside your cells above homeostatic levels, it would appear that it is not achievable by consuming glutathione.
Thanks for finally writing about > Glutathione Supplementation Cannot Increase Cellular Glutathione Levels | Glutathione
Reporter < Loved it!
I firmly believe that glutathione can create immune deficiency in healthy individuals.
Both me mad my sister took large amounts and end up having auto immune disease. I read many articles after that indicates how badly it can effect and imbalance the immunity.
(The immune system works best if the lymphoid cells have a delicately balanced intermediate level of glutathione. Even moderate changes in the intracellular glutathione level have profound effects on lymphocyte functions. ) it all adds up to give auto immune disease
Cannot say that we are aware of such effects of glutathione on the immune system that have been published in peer-reviewed literature. Perhaps you could share the articles that you have read that back up your belief? Glutathione certainly plays a key role in the immune system if you would like to read more about that I would direct you to our article on that and the peer-reviewed literature that it refers to:- https://www.glutathionereporter.com/glutathione-and-the-immune-system/
What about an IV glutathione push do you think that would be received better than the supplements orally I’m thinking about doing some IV and glutathione push around my neighborhood there’s a place that just opened up that gives these treatments or therapy
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Dear Ms. Clifford
We are very glad that you are getting value from our website. The contributors to this site are experts in the science of glutathione and have been engaged in this field for more than 20 years but who are also otherwise employed. They firmly believe that this remarkable molecule can address many chronic health issues for which there are few, if any, treatment options with limited benefits at best. and without any side effects. Should you or anyone you know be interested in undertaking research on the relationship between diseases and glutathione do email us and we will forward these interests to our contributors who would then respond directly to the person(s) concerned. An objective of this website is to encourage collaboration between the contributors to this website and researchers studying diseases potentially resulting from oxidative stress and who are able to obtain the resources required to undertake such research.”