How to Increase Cellular Glutathione Levels

Learn about the only theoretical and clinically proven way to increase cellular glutathione levels.

Glutathione – what is it?

  • The antioxidant glutathione is used by all aerobic living organisms from bacteria to humans and is often referred to as the “master antioxidant”.
  • We do not need to include glutathione in our diet as it is produced by every cell in our body
  • Glutathione has many vital physiological roles including neutralizing the free radicals generated by our cells’ mitochondria during respiration.

Glutathione depletion and ill health

  • Most chronic disorders have been shown to be related to lowered cellular levels of glutathione in the affected tissue.
  • Insufficient glutathione leads to oxidative stress which results in progressive damage to cellular components, including nucleic acids, lipids and proteins.
  • As this oxidative damage accumulates, the cells and the associated tissue begin to lose physiological function, which manifests as symptoms and loss of health.

Glutathione supplement

  • If you search on the internet you will find numerous sites recommending particular supplements and foods to increase your glutathione levels. Supplements include glutathione itself, liposomal glutathione, NAC, and Ribocene.  Recommended foods include spinach, avocados and asparagus. 
  • You can try these options but none of them will elevate your glutathione above homeostasis and as a consequence they are unlikely to offer any (glutathione related) improvements to your health.
  • The only supplement that has been clinically proven to increase glutathione above homeostasis is its immediate precursor Glyteine (gamma glutamylcysteine)

Glutathione supplement benefits

  • In general, glutathione supplements do not offer any clinically proven benefits. To understand why not, we need to look at how glutathione is made in each of our cells. 
  • Glutathione is a relatively simply compound. It is composed of three amino acids (the building blocks of proteins).  Our cells use two enzymes (biological catalysts) to make their own supply of glutathione. The first enzyme joins glutamate and cysteine to produce gamma glutamylcysteine and the second adds a glycine to produce glutathione. 
  • Glutamate and glycine can be readily synthesised by cells.
  • Cysteine must be sourced from the diet either as cysteine or converted from the other sulphur containing amino acid methionine. As such, cysteine is considered to be rate limiting amino acid for glutathione synthesis.  It should be noted that Western diets have all the cysteine (e.g. it is commonly added to bread) we need to meet our glutathione making needs.

Glutathione homeostasis

  • Glutathione homeostasis within your cells is controlled by a feedback inhibition mechanism. When glutathione gets to the homeostatic set point (which varies between cell types) it interacts with the first glutathione synthesis enzyme, glutamate cysteine ligase (GCL), to slow down its activity and limit the production of gamma glutamylcysteine (GGC).
  • When glutathione begins to become depleted due to increased demand, for example during exercise, the interaction between glutathione and GCL weakens and the GCL activity increases to produce more GGC for the second enzyme, glutathione synthase (GS), to convert to glutathione.
  • The GS activity always exceeds that of GCL, which means the GGC level inside cells is always negligible relative to glutathione.
  • So, it does not matter how much glycine, glutamate, or cysteine is lying about in a cell, they are not going to be used for glutathione synthesis if the cell is already at its homeostatic set point.
  • It should be noted here, that as glutathione is used to neutralise free radicals, it itself becomes oxidised. The oxidised glutathione is then recycled back to the reduced form by the NADPH requiring enzyme glutathione reductase.

The cause of chronic glutathione depletion

  • The reason why glutathione is perpetually depleted in many chronic disorders is often related to a disruption of glutathione homeostasis.
  • What this essentially means is that the interaction between glutathione and the GCL enzyme becomes dysfunctional to the extent that the GCL activity is turned off at glutathione concentrations that are insufficient to protect the cell against oxidative stress.
  • In effect, this means the GCL enzyme is starving the cells of the GGC required to maintain a healthy level of glutathione.
  • Numerous studies have investigated the role of GCL dysfunction in the plethora of medical conditions associated with glutathione depletion.
  • These detrimental changes in GCL activity regulation may be due genetic, developmental, environmental and age-related causes.

NAC and acetaminophen overdose

  • Some benefit from NAC has been shown in conditions that involve acute glutathione depletion due to exposure to toxins.
  • Indeed, NAC is the standard treatment for acetaminophen overdose and has saved many lives since it first came into medical use in 1968.
  • Excessive consumption of acetaminophen can rapidly deplete glutathione in the liver.
  • In response, the liver attempts to make more glutathione, but it exhausts its supply of cysteine with glutathione levels continuing to decline to such an extent that the resulting extreme oxidative stress leads to cell apoptosis, tissue necrosis, complete liver failure and often death if a liver transplant does not become available.
  • The timely administration of NAC addresses the liver’s demand for cysteine to restore glutathione levels to homeostasis and consequently deal with the detoxification of the acetaminophen overdose.

Benefits of glutathione supplements or more accurately the failure of NAC and glutathione supplements

On the other hand, glutathione and NAC have repeatedly failed in clinical trials to demonstrate any tangible benefit in treating chronic glutathione depletion associated disorders.  The reason why this is the case can be explained by biochemistry and physics.



Glutathione biochemistry and why glutathione and NAC supplements do not work

  • Though glutathione does have some protective functions outside the cell in the various bodily fluids, the majority of its activity is required inside the cell.
  • This is reflected by the fact that cells contain a thousand-fold higher concentration of glutathione than extracellular fluids (e.g. plasma). So, if you take a glutathione supplement it will not be able to passively enter (via osmosis) the cells where it is often needed due to an unfavourable concentration gradient.
  • Most cell types do not have an energy dependent (ATP) active transport system for taking up glutathione against this concentration gradient.
  • What most cell types do have is an outer membrane bound enzyme, gamma glutamyltransferase (aka gamma glutamyltranspeptidase, GGT). Physicians will be quite familiar with this enzyme, as it is one that is often measured in pathology assays to confirm healthy liver function.  High serum GGT levels are indicative of liver cell damage which could be due to hepatic infection or chronic alcohol abuse.
  • This GGT enzyme effectively hydrolyses extracellular glutathione to its component amino acids, which can then enter the cell. Once inside the cell, these amino acids can then serve as substrates for the resynthesis of glutathione.  This does not mean, however, that this increased supply of glutathione building blocks will enable the cell to increase its glutathione content above any dysfunctional homeostasis.

How to increase glutathione levels in the body

  • Most physicians are well aware of the role of glutathione depletion and its associated oxidative stress in the chronic conditions suffered by many of their patients.
  • Before GGC (Glyteine) was made available to the market in the Continual G brand of supplements they had few options (and none of them efficacious) for increasing cellular glutathione.
  • All they could recommend is glutathione or NAC. But what can these really do?  The glutathione will be broken down by the GGT enzyme to the component amino acids, which can enter the cell, but they will feed into the faulty GCL enzyme and do nothing to elevate the glutathione to more healthy levels. 
  • Similarly, the NAC will enter the cell, be deacetylated, and provide cysteine to the faulty GCL enzyme, again providing no benefit in increasing glutathione to more healthy levels. This is how you can explain all the failures in clinical trials for glutathione, NAC and other similar cysteine prodrugs.

Glutathione benefits

  • Glyteine (GGC) is the one and only compound that can theoretically passively enter cells due to the absence of a concentration gradient, bypass any dysfunctional GCL activity and increase glutathione levels above homeostasis.
  • This theoretical bioavailability has been confirmed in clinical studies. For more information visit continualg.com.

Image Credit : verywellhealth.com



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