Understanding glutathione: are supplements the answer?

Glutathione, one of the most important peptides in the body, is responsible for numerous physiological effects; it is known as the body’s most powerful antioxidant, as well as having a role in detoxification and even gene expression. Read more to find out if supplements are the answer to increase glutathione levels inside your cells.

A bit about glutathione

Glutathione is the body’s master intracellular antioxidant. It directly protects our cell’s mitochondria, our energy producing organelles, from damage and dysfunction that have been linked with many chronic diseases.

Beyond just improving our resilience to stressors, glutathione is also directly utilized in phase I and II detoxification and is involved in modulating many cellular functions relating to proliferation, programmed cell death, immune function and redox signalling, which upregulates protective and repair enzymes (1).

What is Glutathione and how is it made?

Glutathione is composed of the 3 amino acids, cysteine, glycine and glutamate, making it a tripeptide. All mammalian tissues have glutathione, though the highest amount is in the liver. 98% of the glutathione in our body is in the reduced form, GSH, while the remainder is in its oxidized form, GSSG (2).

Glutathione is formed within the cell via the bonding of cysteine, glycine and glutamate. Cysteine is often described as the rate-limiting amino acid involved in glutathione production while glutamate cysteine ligase (GCL) is the rate-limiting enzyme. First, glutamate and cysteine bond via GCL, forming γ-glutamylcysteine, which is then bound to glycine via GSH synthetase, forming glutathione. 

Hepatocytes, liver cells, are responsible for manufacturing much of the glutathione, secreting it into both blood plasma and bile.

Can it be broken down?

GSH can be broken down to GSSG outside the cell.  After being metabolised, glutathione is broken down into its constituent amino acids which are taken up by cells to be recycled into glutathione again using NADPH (2).

How is it used?

1. Antioxidant function: Glutathione, being the body’s master antioxidant, can reduce oxidative stress and prevent damage to both the cell and mitochondria directly. Too much oxidative stress can deplete GSH, reducing the ability of a cell to protect and repair itself, thus making it imperative to restore glutathione levels after prolonged stress, physical, mental or chemical (2).
2. Cell growth and death: The levels of glutathione present in a cell signal whether it should proliferate or undergo apoptosis, programmed cell death. Higher levels lead to proliferation while lower levels lead to apoptosis, causing death of old, damaged cells to make space for new cells. When glutathione levels fall extremely low, cells don’t undergo normal apoptosis and instead become necrotic, resulting in an increased inflammatory response within the body (2).
3. Detoxification: As was mentioned above, glutathione is needed for both phase I and II detoxification, causing transformation, binding (or conjugation) and elimination of endogenous and exogenous toxins (1).  Diminished glutathione leads to poor detoxification and an accumulation of these waste products, just one cause of ill health.

Glutathione Supplementation

Oral – food sources and non-liposomal glutathione

Glutathione can be found both supplementally and in whole foods such as liver, avocado, asparagus and more. Unfortunately, consuming glutathione-rich foods and standard, non-liposomal, glutathione supplements don’t appear to increase the body’s levels of glutathione. Upon ingestion, the glutathione is hydrolyzed by liver and intestinal cells, breaking glutathione down into its constituents. In fact, a study found that oral glutathione use didn’t change any markers of oxidative stress or GSH status (3).

Liposomal – Oral and IV

More recently, there has a been a surge in the popularity of liposomal products.

A liposome is an artificial vesicle consisting of one or more external phospholipid layers with an aqueous core.  Water-soluble compounds, such as glutathione, are encapsulated in the aqueous core, while fat-soluble compounds would be incorporated into the phospholipid layer. Packaging up compounds in a liposome increases its bioavailability (1). 

Liposomes can be administered orally or intravenously.  Unlike standard oral glutathione, administration of liposomal glutathione orally and intravenously has been shown to increase the body’s levels of GSH and lower markers of oxidation (1). 

Intravenous injection of liposomal GSH showed it to be more liver-protective than non-liposomal injected GSH.  Intravenous administration delivers directly into the bloodstream or in tissue specific areas, such as the trachea, depending on the desired effect and pathology present (1).

However, much of the glutathione from intravenous use is degraded after a short time.  In fact, only 1-2% of the original dose remains after 24 hours. This is in stark contrast to oral supplementation of liposomal glutathione, which had 18% and 10% remaining after 24 and 48 hours respectively (1). 

Intravenous glutathione has a number of issues with administration. It is vastly more expensive than oral liposomal, due to the need for a trained practitioner and equipment to administer the glutathione. For those with vein issues, such as excessive scarring, it is not always feasible, and it may not be practical for those who aren’t mobile enough to visit a facility.

Nebulized/atomized glutathione

Nebulizing or atomizing glutathione involves inhaling it through the nose and/or mouth via the appropriate equipment. Inhaling glutathione localises the effects to the upper airway and lungs, without having a significant effect on blood levels. The primary reason for its effect in these diseases is the localised antioxidant effect.  It is also postulated that improved immune defences and better oxygenation may cause part of the benefits.  More data is needed to pin down the exact mechanism of action though.

Glutathione present in the lungs and airways is thought to be the first line of defense against oxidative stress. Nebulizing glutathione has shown potential in treating chronic otitis media with effusion, cystic fibrosis, idiopathic pulmonary fibrosis, HIV, chronic rhinitis and emphysema (4).

This method is usually not available without a medical prescription, thus representing a barrier to use.

How else can we increase glutathione?

Maintaining adequate cysteine levels inside the cell, alongside glutamate and glycine, are crucial to producing this antioxidant. There are 3 main ways we maintain cysteine levels: dietary intake, protein breakdown, and from methionine via the liver’s transsulfuration pathway. 

But there is a challenge: cysteine is only stable inside our cells. When outside the cell, cysteine it is oxidized to cystine, 2 cysteine molecules bonded together via a disulphide bond.  However, upon entering cells, cystine is metabolised and reduced to 2 cysteine molecules and used to produce glutathione (2).

N-Acetyl Cysteine

N-acetylcysteine (NAC) is a commonly used antioxidant supplement with some mixed reviews on its ability to increase glutathione levels. NAC is similar to the amino acid cysteine. Due to the acetyl group bound to the cysteine molecule, NAC, is less susceptible to oxidation outside the cell (5, 6).

Just supplementing with NAC can only increase glutathione levels up to a point.  When there are adequate levels of cysteine present, extra supplementation does not appear to increase glutathione levels, it is still necessary to maintain adequate levels of glutamate and glycine to produce glutathione (5,6 ).

NAC is not without its side effects though such as inflamed mouth and lips, coughing up blood and becoming clammy (6).

Non-denatured, native whey

Non-denatured, native whey, is one such solution that may promote the production of glutathione naturally. Amongst the plethora of nutrients in whey, are the 3 amino acids necessary for glutathione production in a bioavailable form, with high levels of cystine. As was mentioned earlier, cystine is the oxidized form of cysteine and is stable extracellularly.  

The presence of glutamate and glycine alongside the cystine overcomes the issues of NAC mentioned above. Not just any whey will do though, consuming non-denatured, native whey has been shown to increase tissue glutathione levels more than standard denatured whey, due to the much higher concentration of unprocessed amino acids (7).

Conclusion

Summing up, glutathione is a crucial peptide involved in many important cellular functions.  Low levels have the potential to increase the prevalence of disease and chronic illness via the inability to adequately detoxify or protect the cells and mitochondria from oxidation. Some even suggest that glutathione levels can be used as a proxy for aging, the lower they are the older our biological age. 

In terms of the supplemental route, it appears that oral liposomal glutathione presents the most widely accessible and affordable form of glutathione, but long-term supplementation may present some unwanted side effects and it is not clear whether it is safe in pregnancy, breastfeeding and during any other adjuvant treatments. Non-liposomal glutathione doesn’t appear to have much efficacy, nebulized can only be accessed via a medical prescription and is isolated to the lungs and intravenous has its own set of potential deterrents.

Beyond supplementing with glutathione directly, ingesting bioavailable forms of cysteine (or cystine), glutamate and glycine enable your body to make its own glutathione. It is usually much more convenient and affordable to make your own glutathione from the foods you ingest, with non-denatured whey protein being one such option, having large, bioavailable amounts of these amino acids.

References

1. Suntres, Z.E., 2011. Liposomal antioxidants for protection against oxidant-induced damage. Journal of toxicology, 2011.
2. Lu, S.C., 2013. Glutathione synthesis. Biochimica et Biophysica Acta (BBA)-General Subjects, 1830(5), pp.3143-3153.
3. Allen, J. and Bradley, R.D., 2011. Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. The Journal of Alternative and Complementary Medicine, 17(9), pp.827-833.
4. Prousky, J., 2008. The treatment of pulmonary diseases and respiratory-related conditions with inhaled (nebulized or aerosolized) glutathione. Evidence-Based Complementary and Alternative Medicine, 5(1), pp.27-35.
5. Atkuri, K.R., Mantovani, J.J., Herzenberg, L.A. and Herzenberg, L.A., 2007. N-Acetylcysteine—a safe antidote for cysteine/glutathione deficiency. Current opinion in pharmacology, 7(4), pp.355-359.
6. Bauchart-Thevret, C., Stoll, B. and Burrin, D.G., 2009. Intestinal metabolism of sulfur amino acids. Nutrition research reviews, 22(2), pp.175-187.
7. Bounous, G. and Gold, P., 1991. The biological activity of undenatured dietary whey proteins: role of glutathione. Clin Invest Med, 14(4), pp.296-309.