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 .
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) 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 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  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) .
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].
- 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.