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Can Glutathione supplementation increase intracellular Glutathione

By far the best, if not the only way to increase your cellular glutathione (GSH) is to take the glutathione precursor, gamma-glutamylcysteine (Glyteine). GSH is produced in two steps in every cell of your body, the first makes gamma-glutamylcysteine (a dipeptide of glutamate and cysteine) and the second adds a glycine to the gamma-glutamylcysteine to make the GSH tripeptide. During ageing and in many chronic illnesses, our cells lose their capacity to make enough gamma-glutamylcysteine, which means in turn we don’t make enough GSH to protect our cells against oxidative stress [1].  So, if you would like to boost your GSH levels in an effort to address this potential health risk then why can’t you just take a GSH supplement?

The reason is relatively straightforward and here is why

There are two very different environments in the tissues of your body. 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.  A lot of these reactions generate free radicals that can, if not controlled (neutralized), cause damage inside your body (oxidative stress). To counter this, your cellular 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 your cells and removal of waste products which in turn are processed in the liver and kidneys. The GSH concentration found in this environment (micromolar) is much lower than that found intracellularly (millimolar) by about a thousand-fold.  This large difference means that there is an insurmountable concentration gradient that prohibits extracellular glutathione entering cells.

So, when you take a GSH supplement orally or by injection, it will ‘hang around’ in the extracellular environment but will not be able to enter the cell where it is needed the most to combat any oxidative stress.

But what happens to all of that extracellular GSH I paid good money for?  Well, GSH is made up of some valuable amino acids and your cells have a system of scavenging them before they are excreted into the urine.  Most cells in your body have an enzyme (gamma-glutamyltransferase) [1] which starts the process of breaking GSH down to its constituent amino acids (protein building blocks). 

Several researchers who have confirmed this (for example [2]) came to the conclusion that “dietary GSH is not a major determinant of circulating GSH, and it is not possible to increase circulating GSH to a clinically beneficial extent by the oral administration of a single dose of 3 g of GSH”. Similarly authors [3]of the first well-controlled double-blind, randomized, placebo-controlled clinical trial of oral 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 GSH concentrations following 4 weeks of oral (2 x 500mg daily) GSH supplementation”.

Glyteine, 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 Glyteine concentration increases and therefore it can easily diffuse through the cell membrane to inside of the cell.  Once inside, it is immediately used to produce glutathione [4]. 

In summary, the problem in ageing and most chronic disease is that our cells lose the ability to make enough Glyteine to make enough glutathione. Glutathione supplements cannot enter cells but Glyteine supplements can [5, 6]

References

  1. 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.
  2. Witschi, A., et al., The systemic availability of oral glutathione. European Journal of Clinical Pharmacology, 1992. 43(6): p. 667-669.
  3. 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.
  4. Wu, G., et al., Glutathione metabolism and its implications for health. Journal of Nutrition, 2004. 134(3): p. 489-92.
  5. 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.
  6. 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.
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