How is glutathione synthesized?
Glutathione is the body’s most powerful antioxidant, even if it’s not the best known; it neutralises toxic free radicals from foreign substances that enter the body, reducing the oxidative stress that causes cell damage. And it also supports key metabolic functions: maintaining energy production by mitochondria; detoxification by the liver; and partnering enzymes and vitamins in daily cellular processes. The problem comes when we need so much glutathione, to combat the effects of poor diet, high toxin levels and stress, that it becomes depleted and can’t protect us. This is compounded by the lack of a good warning system and a natural decline of glutathione levels with age (1).
The good news is that almost all our cells can make glutathione and do so naturally. The biggest reservoir is in the liver, where many of our toxins are removed, but there are also stores in the kidneys and our red blood cells. It’s manufactured from three amino acids (the building blocks for protein) in a two-step energy-consuming reaction. Driven by enzymes in both stages, cysteine first binds to glutamate, then glycine is added to complete this tripeptide.
Glutathione has two forms:
- GSH is the reduced form of glutathione, the most effective antioxidant. The sulphur group supplied by cysteine is key to its action (2)
- GSSG, the oxidised form, is a dimer of two GSH molecules linked via their sulphur groups.
The rate limiting factor in glutathione manufacture is usually the amount of cysteine present (3) – later we’ll explain how you can boost your levels.
How do antioxidants like glutathione work?
Oxidative stress occurs when there is a harmful imbalance between the production and subsequent removal of toxic free radicals. Usually in the form of reactive oxygen species (ROS), these cause damage by reacting with the components in our cells including DNA and our cell communication systems (4). Glutathione helps to regulate oxidative stress by donating a spare electron (the smallest particle that makes up an atom) to the ROS and also binding to it. This conjugation means it can’t cause any further damage (5). To be useful again, the glutathione now needs to be recycled back into its reduced form, which it can do by itself. Other antioxidants like vitamin C, vitamin E, alpha-lipoic acid and co-enzyme Q10 can’t recycle themselves, so glutathione takes their excess ROS, effectively recycling them ready for further antioxidation (3). Without sufficient glutathione, free radicals will continue to cause cell damage. Oxidative stress can also suppress apoptosis (normal, controlled cell death) (3) potentially leading to cancerous cell proliferation.
Keeping our energy cells going strong
One of glutathione’s key roles is to protect mitochondria, the essential energy powerhouses for our cells. The levels of glutathione inside mitochondria are generally low as they strive to remove free radicals. Mitochondria can’t make glutathione and need to import it from the cells in which they sit; this transfer across the mitochondrial membrane consumes a lot of energy (ATP) - which would be better used to keep our cells functioning effectively - as well as producing even more free radicals. So, it’s important that glutathione and other antioxidants are available to keep oxidative stress down and avoid over-challenging our mitochondria.
A primary detoxifying agent
The liver, our primary detoxification organ, is a major producer of glutathione, both to export around the body and to use in its phase I and II detoxification processes. Many of our toxins and waste products like pesticides, heavy metals (e.g. mercury and lead), and industrial chemicals, are fat-soluble rather than water-soluble so they can’t be excreted easily. In phase I these toxins are rendered less harmful; glutathione plays an important antioxidant role in removing the free radicals released thereby reducing the risk of liver damage (5). In phase II, the fat-soluble toxins become water-soluble, enabling excretion in urine or bile. Glutathione is depleted in supplying the P450 GSH transferase enzymes used in this conversion and must subsequently be replenished to avoid oxidative stress and undesirable liver cell death (5).
The rate of glutathione synthesis is also influenced by the methylation cycle. This ultimately controls the transfer of sulphur to cysteine and affects the generation of GSH, the reduced, antioxidant form of glutathione (6).
How are we depleting our glutathione?
Many lifestyle factors create high demand for glutathione, usually to remove the resulting free radicals. These include:
- a western diet high in fat, sugars, grains and processed foods (7,8)
- stress release of adrenaline and cortisol
- poor sleep
- smoking – cigarette smoke contains huge amounts of ROS, loss of vitamin C
- oxidative medications including chemotherapy (9)
- chronic exposure to alcohol
- environmental toxins in pesticides, industrial waste and exhaust fumes
- intense physical exercise creating free radicals through high energy burn.
Making lifestyle changes could generate sufficient glutathione to protect our cells.
What happens to health when glutathione is low?
Glutathione depletion, and the concomitant oxidative stress, have been linked to ageing and many chronic or degenerative diseases (3,7). Levels of glutathione are highest in young healthy people and have been shown to reduce sequentially with age, chronic and acute disease (1); conversely oxidative damage increases with age (10) and disease, as expected (1).
Diseases and conditions associated with GSH depletion are:(3).
- neuro degenerative - Alzheimer’s and Parkinson’s disease
- respiratory/lung - COPD and asthma
- immune system - HIV, autoimmunity
- cardiovascular - hypertension, heart attack
- cancer, cystic fibrosis and liver diseases
- age-related - cataracts, glaucoma, hearing loss.
How can I increase my glutathione levels?
Exercise increases the number of muscle mitochondria and levels of glutathione (11). A combination of aerobic exercise and circuit weight training is most effective. Even meditation can help (3).
From a dietary point of view, foods rich in either glutathione itself, its building blocks, or anything used in its manufacture, will help. However, cooking destroys almost 100% of glutathione so those that can be eaten raw are best – asparagus, avocado and spinach are good examples. Optimal glutathione manufacture requires sulphur (good sources are broccoli, cauliflower, cabbage, garlic and onions), vitamins C and D, and the minerals zinc and selenium. Oral glutathione supplements are less useful as much is broken down in the gut.
Cysteine is the critical precursor for glutathione production so ensuring a good supply in our cells is a priority. The most effective way to supply cysteine is in its dimer form, cystine, which remains intact during digestion (12). Of all the supplements available, undenatured whey provides the highest concentration of intact native proteins including cysteine (as cystine), methionine to help provide sulphur, and lactoferrin, another antioxidant (3,9). In scientific studies, a whey-rich diet resulted in liver and heart glutathione being significantly higher compared to a casein-rich or normal diet, along with increased longevity (13). Clinical trials in cancer, HIV, hepatitis B, and heart disease have also shown benefits in using whey (3,9).
- Nuttall, S., Martin, U., Sinclair, A., Kendall, M. (1998). Glutathione: in sickness and in health. Lancet, 351(9103), p. 645-646.
- Forman, H., Zhang, H., Rinna, A. (2009). Glutathione: overview of its protective roles, measurement, and biosynthesis. Molecular aspects of medicine, 30(1-2), p. 1-12.
- Pizzorno, J. (2014). Glutathione! Integrative medicine, 13(1), p. 8-12.
- https://www.foundationalmedicinereview.com/blog/a-closer-look-at-the-benefits-of-glutathione-supplementation/ accessed May 15th 2019.
- Kidd, P. (1997) Glutathione: Systemic Protectant Against Oxidative and Free Radical Damage Dedicated to the memory of Professor Daniel Mazia, my PhD mentor and a pioneer in cell biology. Alternative Medicine Review x, 2.
- Van Konynenburg, R (2016): Theory of Glutathione Depletion and Methylation Blockade in Chronic Fatigue Syndrome [online] accessed May 15th 2019
- Wu, G., Fang, Y., Yang, S., Lupton, J., Turner, N. (2004). Glutathione Metabolism and Its Implications for Health. The Journal of Nutrition, 134(3), p. 489-492.
- https://articles.mercola.com/vitamins-supplements/glutathione.aspx accessed May 15th 2019.
- Marshall, K. (2004). Therapeutic applications of whey protein. Alternative Medicine Review, 9(2), p. 136-157.
- Erden-Inal, M., Sunal, E., Kanbak, G. (2002). Age-related changes in the glutathione redox system. Cell Biochemistry and Function, 20(1), p. 61-66.
- Elokda, A., Nielsen, D. (2007). Effects of exercise training on the glutathione antioxidant system. Eur J Cardiovasc Prev Rehabil, 14(5), p.630-637.
- Winter, A., Ross, E., Daliparthi, V., Sumner, W., Kirchhof, D., Manning, E., Wilkins, H., Linseman, D. (2017). A Cystine-Rich Whey Supplement (Immunocal®) Provides Neuroprotection from Diverse Oxidative Stress-Inducing Agents In Vitro by Preserving Cellular Glutathione. Oxidative medicine and cellular longevity, 2017, Article ID 3103272.
- Bounous, G., Gervais, F., Amer, V., Batist, G., Gold, P. (1989). The Influence of Dietary Whey Protein on Tissue Glutathione and the Diseases of Ageing. Clinical and Investigative Medicine, 12(6), p. 343-349.