Glutathione is a potent antioxidant found in both animals and plants. Often known as the “master antioxidant”, the benefits of glutathione include the ability to recycle other antioxidants such as vitamins C and E, alpha lipoic acid and CoQ10. The most abundant free radical scavenger synthesized in humans, there is a wealth of evidence which demonstrates glutathione’s status to be significant in a number of acute and chronic diseases.
In this blog, we take a brief look at the biosynthesis and function of glutathione and its specific roles in a plethora of different areas of health and health conditions. We will also examine facts that influence glutathione depletion and ways to increase our levels and benefit our health.
Biosynthesis of glutathione
Glutathione is produced in the cytoplasm of all human cells but predominantly in the liver, spleen, kidney, lens and both white and red blood cells, and its synthesis is upregulated in response to oxidative stress. The liver is a major exporter of glutathione into the plasma and bile.
Glutathione is a tripeptide, composed of the amino acids L-cysteine, L-Glutamine and glycine. Its synthesis is directly connected to the methylation cycle through homocysteine and cysteine. Approximately 50% of homocysteine leaves the methylation cycle and is metabolised via the trans-sulphuration pathway to cystathionine and cysteine. Thus, glutathione synthesis is linked to adequate availability of folate and other co-factors such as vitamins B6 and B12, as well as methionine, found in virtually all protein containing foods, and S-adenosylmethionine.
Cysteine contains a sulfhydryl group or thiol group. Thiol groups are strong reducing agents – thus glutathione serves as an electron donor and in the process is converted to its oxidised form. Once oxidised, glutathione can be recycled (i.e. reduced back) by the enzyme glutathione reductase using NADPH as an electron donor.
The ratio of reduced glutathione to oxidised (i.e. ‘spent’) glutathione within cells is used as a measure of cellular oxidative stress. In healthy cells and tissue, more than 90% of the total glutathione pool is in the reduced form and less than 10% exists in the oxidised form.
In general, the mitochondrial reduced:oxidised ratio is greater than that of the cytosol, resulting in a more ‘reducing environment’ in the mitochondria (reflecting the high degree to which reactive oxygen species are produced within mitochondria). Normally, almost all glutathione in the mitochondria is reduced glutathione, but in the presence of mitochondrial dysfunction, the proportion of oxidised glutathione increases due to the increased elimination of ROS. Therefore, this ratio is an indicator of mitochondrial function.
Functions and benefits of glutathione
The enzymes glutathione peroxidase, glutaredoxin, glutathione reductase, and glutathione-S-transferase use glutathione as a substrate in many cellular reactions. It can also participate in reactions directly i.e., without enzymatic reaction.
One of the benefits of glutathione is that it can effectively scavenge free radicals both directly and through enzymatic reaction). It can also maintain exogenous antioxidants such as vitamins C and E in their reduced (i.e. active) forms. However, the efficiency of the glutathione redox system declines as we age.
For example, as a co-factor for glutathione peroxidase (a selenium-containing enzyme) it catalyses the reduction of hydrogen peroxide, and other peroxides, to their respective alcohols and water. The reduction of hydrogen peroxide results in the formation of oxidised glutathione which then needs to be recycled back to the reduced form, as described above.
Glutathione is a substrate in reactions which are catalysed by glutathione-S-transferase enzymes; a family of enzymes which catalyse the addition of glutathione to substrates to allow them to be eliminated. Conjugation using glutathione is an important Phase II detoxification pathway in the liver – glutathione is a hydrophilic (water soluble) molecule that is conjugated to various lipophilic (fat soluble) physiological metabolites (e.g., oestrogens) and xenobiotics, biotransforming them so they can be excreted in the bile and then eliminated in the stool. Similarly, glutathione can also be conjugated and exported to plasma for elimination via the urine. Thus, in these reactions glutathione is ‘lost’ from the system and not recycled. Glutathione is also capable of participating in non-enzymatic conjugation with some chemicals.
The reducing power of glutathione is also important in DNA synthesis, cell signalling and neuromodulation. Glutathione also has a role in protein synthesis, prostaglandin and leukotriene synthesis, amino acid transport and iron metabolism. Thus, every system in the body can be affected by the state of the glutathione system, especially the immune system, the nervous system, the gastrointestinal system, the lungs and the eyes.
Low glutathione is commonly observed in wasting and negative nitrogen balance, as seen in cancer, HIV/AIDS, sepsis, trauma, burns, starvation and athletic overtraining. Levels also decline with age. Glutathione depletion is linked to a number of disease states and here we look in more detail at the links between glutathione and a number of areas of health. This list is by no means exhaustive.
Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the development and progression of neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases.
Apoptosis (programmed cell death) is key to neurodegenerative disease progression, and there is evidence that mitochondrial glutathione levels may play a key role in regulating this process. The brain is particularly susceptible to oxidative stress for a number of reasons. Firstly, it uses about 20% of the body’s oxygen supply for energy production (and energy production is a significant source of reactive oxygen species (ROS); secondly, relative to other organs, the brain has lower levels of ROS scavenging enzymes and thirdly the brain is 60% fat – a high proportion of which is unsaturated fatty acids that are highly susceptible to lipid peroxidation.1
ROS-mediated damage has been cited as a probable contributing cause for many common neurodegenerative diseases, suggesting that the natural antioxidant defence mechanisms are overwhelmed in these cases. For example, oxidative stress is associated with loss of neurons; the pathological basis for Parkinson’s disease.13
Another mechanism whereby glutathione influences neurodegenerative disease is in the regulation of protein degradation pathways involved in regulation of cell survival. These pathways remove misfolded, damaged or otherwise non-functional proteins. When misfolded proteins are not adequately removed from cells, protein aggregation may occur, and these are hallmarks of some neurodegenerative diseases including Alzheimer’s (beta amyloid plaques) and Parkinson’s (alpha synuclein-containing Lewy bodies).1
Benefits of glutathione to eye health
Glutathione is found at high concentrations in the lens especially in the epithelial layer where it has many important functions including helping to maintain lens transparency by preventing the formation of high molecular weight crystalline aggregates, removal of xenobiotics and protection against oxidative damage. A study of human lenses ranging from birth to 92 years of age showed that over the years glutathione levels reduce up to 73%, and oxidised glutathione levels (i.e., ‘spent’ glutathione) increase from 2% to 18%.4
The neurodegenerative eye disease glaucoma, a leading cause of irreversible blindness worldwide is characterised by progressive damage or degeneration of the optic nerve from oxidative stress, and lower levels of glutathione have been observed in those with the condition, compared to controls.5
The eyes are under constant exposure to irradiation and therefore have an extraordinary need for antioxidant protection, with the retinal pigment epithelial being particularly susceptible to oxidative damage. Glutathione is the most prominent antioxidant in the retina and a depletion has been shown to be involved in a number of different types of retinal cell death, as well as stress-induced premature senescence; a phenomenon characterised by an irreversible cessation in the division of normal cells.2 The degeneration of retinal pigment epithelium cells causes a number of diseases related to vision loss, including age related macular degeneration.3
Benefits of glutathione to oral health
Glutathione is an important redox regulator in the saliva and its maintenance is essential for periodontal health. Periodontal disease is a chronic inflammatory condition associated with increased inflammation in response to plaque biofilm (produced by bacteria), the excessive production of ROS and decreased antioxidant activity in saliva, resulting in loss of periodontal and bone support.
Reduced glutathione plays an important role in the regulation of pro-inflammatory cytokines, and redox disturbances, as observed in patients with periodontal disease are associated with the deregulation of anti-inflammatory pathways, resulting in neutrophil hyperactivity. The lower levels of glutathione observed in periodontal disease is suggestive of its protective role for vital cells and tissue structures from host-derived free radicals.
Certain bacteria species e.g. Fusobacterium spp. and others, as well as cigarette smoking and smokeless tobacco are capable of degrading glutathione to form toxic hydrogen sulphide within the periodontal cells.6,7 Conversely, nonsurgical periodontal therapy such as scaling and root planing have demonstrated an increase in glutathione levels, suggestive of an improved antioxidant status and reduction in oxidative stress, perhaps partly due to a reduction in the proteolytic activity of bacteria and reductions in inflammation. Studies have demonstrated that these improvements are seen up to 3 months post therapy, but for longer term benefits individuals should supplement with micronutrients for elevating their glutathione levels.8
Benefits of glutathione to fertility
Oxidative stress has a well-established role in the pathogenesis of infertility in both male and females, where free radicals such as ROS can influence oocytes, spermatozoa and embryos and their environments. For example, in male infertility, the membranes and cytoplasm of sperm cells contain large amounts of fatty acids and are therefore very vulnerable to ROS, causing a decrease in sperm motility, viability and the ability to fertilise oocytes. Glutathione peroxidases are one of the antioxidant defense systems for sperm cells, where they participate in the protection of the maturing spermatozoa in the epididymis and is found in high concentrations in the testes.9 Glutathione is also present in the female reproductive tract and it has been suggested that sperm cells might use this fluid as a source of glutathione to protect against oxidative stress – especially when we consider that sperm cells have a very small cytoplasm which is the primary storehouse for defensive enzymes. The ability of sperm cells to utilize exogenous glutathione gives them a survival advantage.10
Likewise, in females, excess ROS can directly cause damage to the oocytes and is implicated in a number of conditions linked to fertility such as polycystic ovarian syndrome and endometriosis. ROS affect a variety of physiological functions of the ovary, including oocyte maturation, ovulation and luteal maintenance in pregnancy.11
Glutathione shields eggs from oxidative damage during folliculogenesis, and as such, egg quality is dependent upon it. Research also suggests that oocytes with higher levels of intracellular glutathione produce healthier and stronger embryos. In their younger reproductive years, women’s ovaries have exhibited higher intracellular glutathione levels, and deficiency has been linked to premature ovarian ageing. As an antiaging antioxidant, it may positively affect egg health, which is one of the cells most affected by the ageing process.12
Glutathione and immunity
The antioxidant property of reduced GSH can prevent immune cell damage caused by ROS and a number of studies have evidenced supplementing with glutathione providing support against a number of different infections:
Tuberculosis (TB) – glutathione supplementation reduces the viability of mycobacterium tuberculosis (M. Tb. – the causative agent of TB) and enhances a Th-1 cytokine response, allowing for the encapsulation of M. tb. within granulomas where they are starved of oxygen and fail to replicate. Liposomal glutathione supplementation increased glutathione levels in the lungs, and a consequent increase in the levels of immune-supportive cytokines and decreased oxidative stress. Natural killer (NK) cells have an important role against M. tb infection, and their activity can become critically impaired in patients with low levels of GSH.15
COVID-19 – morbidity and mortality of COVID-19 are due in large part to severe cytokine storm brought on by dysregulated inflammatory immune response and a glutathione deficiency has been associated with more severe clinical manifestations of coronavirus.18 It has been proposed that the administration of liposomal glutathione may be a potential therapeutic option in certain high risk COVID-19 patients.16
It has been shown that influenza viruses induce oxidative stress mediated by an excess of ROS and a decrease of reduced glutathione, and that such conditions favour viral replication, with glutathione depletion pivotal for the folding and maturation of the viral glycoprotein – and therefore viral replication. Viruses also possess a variety of adaptive mechanisms to deplete glutathione levels in host cells.16
One study looked at the administration of oral liposomal glutathione in healthy subjects and found that it effectively increased body stores of glutathione and had a positive effect on several parameters including decreases in markers of oxidative stress and enhancement in immune functions, including lymphocyte proliferation and natural killer cell activity. Indeed, lymphocyte proliferation was enhanced up to 60% within one week and Natural Killer cell cytotoxicity was increased up to 400% as early as week 2.14
Low levels of glutathione can occur by a number of different factors, including an increased need for glutathione as a result of a higher level of oxidative stress. This may be as a result of alcohol consumption, as glutathione is used in the metabolism of alcohol, exposure to toxins and an increase in inflammation from factors such as poor diet, lack of sleep, smoking and poor gut health.20
Impaired protein digestion may also be a limiting factor in ensuring healthy glutathione levels. A reduction in hydrochloric acid and/or digestive enzyme insufficiency, common in the ageing population could contribute to low levels. As the precursors and foundation of glutathione are amino acids, even a modestly reduced protein intake could detrimentally influence the amino acid pool from which to draw to synthesise glutathione.21
Increasing glutathione levels
Adequate protein intake is important for endogenous glutathione synthesis. In addition:
- Calcitriol, the active metabolite of vitamin D3, increases glutathione levels in the brain and appears to be a catalyst for glutathione production
- S-adenosylmethionine (SAMe), a co-substrate involved in methyl group transfer, has been shown to increase cellular glutathione content. SAM production requires adequate B vitamins – folate, B12, B6 – and zinc in particular. B6 is also a cofactor for the CBS enzyme in the trans-sulphuration pathway which converts homocysteine to cysteine21
- Supplementation with N-acetyl cysteine (NAC) – which provides the cysteine substrate has been shown to increase levels19
- The non-essential amino acid, serine may positively influence glutathione production through increased cysteine availability and a decrease of hypermethylation, as well as its metabolism into glycine, one of glutathione’s precursors.21
- Alpha-lipoic acid is a multifunctional compound in its ability to serve as a direct scavenger of free radical species and to also help in the regeneration of endogenous antioxidants such as glutathione21
- Supplementing with vitamin C has been shown to increase glutathione levels by exerting their antioxidant action first, thus sparing glutathione. Vitamin C also appears to be able to reprocess glutathione by converting it back to its reduced form17
- Several foods contain the thiol-rich compounds (glutathione, NAC and cysteine) and should be included in the diet daily. Particularly rich foods are green foods, asparagus, avocado, cucumber, green beans, and spinach and adherence to a Mediterranean style diet has been associated with higher plasma glutathione levels21,22
- Meditation has been shown to raise glutathione levels by as much as 20%20
Until recently, oral supplementation with glutathione has been difficult. Because glutathione is a tripeptide, it is broken down in the gastrointestinal tract by proteases to its constituent amino acids. In addition, if it does survive intact then there is the problem of transport across the cell membrane. Supplements therefore need to be in ‘liposomal’ form – the liposome provides protection from digestion and enables efficient transport across cell membranes.14
- Glutathione is the body’s most potent antioxidant and plays an important role in a number of different areas of health
- Glutathione synthesis is linked to the methylation cycle, which requires adequate levels of nutrients such as folate and other co-factors; vitamins B6 and B12, methionine and S-adenosylmethionine
- Conjugation using glutathione is an important Phase II detoxification pathway in the liver
- Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are implicated in the development and progression of neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases
- Glutathione is the most prominent antioxidant in the eye and a depletion has been shown to be involved in a number ocular diseases
- Glutathione deficiency can come about due to a number of different factors including poor nutrient intake and increased toxic load
- A number of different dietary and lifestyle factors can positively influence glutathione levels, and a liposomal supplement can effectively raise levels
- Aoyama K. Glutathione in the Brain. Int J Mol Sci. 2021 May 9;22(9):5010. doi: 10.3390/ijms22095010. PMID: 34065042; PMCID: PMC8125908.
- Sun Y, Zheng Y, Wang C, Liu Y. Glutathione depletion induces ferroptosis, autophagy, and premature cell senescence in retinal pigment epithelial cells. Cell Death Dis. 2018 Jul 9;9(7):753. doi: 10.1038/s41419-018-0794-4. PMID: 29988039; PMCID: PMC6037763.
- Kim J, Lee YJ, Won JY. Molecular Mechanisms of Retinal Pigment Epithelium Dysfunction in Age-Related Macular Degeneration. Int J Mol Sci. 2021 Nov 14;22(22):12298. doi: 10.3390/ijms222212298. PMID: 34830181; PMCID: PMC8624542.
- Pescosolido N, Barbato A, Giannotti R, Komaiha C, Lenarduzzi F. Age-related changes in the kinetics of human lenses: prevention of the cataract. Int J Ophthalmol. 2016 Oct 18;9(10):1506-1517. doi: 10.18240/ijo.2016.10.23. PMID: 27803872; PMCID: PMC5075670.
- Ramdas WD. The relation between dietary intake and glaucoma: a systematic review. Acta Ophthalmol. 2018;96(6):550-556. doi:10.1111/aos.13662
- Bains VK, Bains R. The antioxidant master glutathione and periodontal health. Dent Res J (Isfahan). 2015 Sep-Oct;12(5):389-405. doi: 10.4103/1735-3327.166169. PMID: 26604952; PMCID: PMC4630702.
- Koregol AC, Kalburgi NB, Pattanashetty P, Warad S, Shirigeri NS, Hunasikatti VC. Effect of smokeless tobacco use on salivary glutathione levels among chronic periodontitis patients before and after non-surgical periodontal therapy. Tob Prev Cessat. 2020 Mar 5;6:15. doi: 10.18332/tpc/115062. PMID: 32548352; PMCID: PMC7291912.
- Palwankar P, Rana M, Arora K, Deepthy C. Evaluation of non-surgical therapy on glutathione levels in chronic periodontitis. Eur J Dent. 2015 Jul-Sep;9(3):415-422. doi: 10.4103/1305-7456.163226. PMID: 26430373; PMCID: PMC4569996.
- O’Flaherty C. Orchestrating the antioxidant defenses in the epididymis. Andrology. 2019;7(5):662-668. doi:10.1111/andr.12630
- Fafula RV, Paranyak NM, Besedina AS, Vorobets DZ, Iefremova UP, Onufrovych OK, Vorobets ZD. Biological Significance of Glutathione S-Transferases in Human Sperm Cells. J Hum Reprod Sci. 2019 Jan-Mar;12(1):24-28. doi: 10.4103/jhrs.JHRS_106_18. PMID: 31007463; PMCID: PMC6472203.
- Lu J, Wang Z, Cao J, Chen Y, Dong Y. A novel and compact review on the role of oxidative stress in female reproduction. Reprod Biol Endocrinol. 2018 Aug 20;16(1):80. doi: 10.1186/s12958-018-0391-5. PMID: 30126412; PMCID: PMC6102891.
- Adeoye O, Olawumi J, Opeyemi A, Christiania O. Review on the role of glutathione on oxidative stress and infertility. JBRA Assist Reprod. 2018 Mar 1;22(1):61-66. doi: 10.5935/1518-0557.20180003. PMID: 29266896; PMCID: PMC5844662.
- Iskusnykh IY, Zakharova AA, Pathak D. Glutathione in Brain Disorders and Aging. Molecules. 2022 Jan 5;27(1):324. doi: 10.3390/molecules27010324. PMID: 35011559; PMCID: PMC8746815.
- Sinha R, Sinha I, Calcagnotto A, Trushin N, Haley JS, Schell TD, Richie JP Jr. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. Eur J Clin Nutr. 2018 Jan;72(1):105-111. doi: 10.1038/ejcn.2017.132. Epub 2017 Aug 30. PMID: 28853742; PMCID: PMC6389332.
- Kachour N, Beever A, Owens J, Cao R, Kolloli A, Kumar R, Sasaninia K, Vaughn C, Singh M, Truong E, Khatchadourian C, Sisliyan C, Zakery K, Khamas W, Subbian S, Venketaraman V. Liposomal Glutathione Helps to Mitigate Mycobacterium tuberculosisInfection in the Lungs. Antioxidants (Basel). 2022 Mar 30;11(4):673. doi: 10.3390/antiox11040673. PMID: 35453358; PMCID: PMC9031130.
- Guloyan V, Oganesian B, Baghdasaryan N, Yeh C, Singh M, Guilford F, Ting YS, Venketaraman V. Glutathione Supplementation as an Adjunctive Therapy in COVID-19. Antioxidants (Basel). 2020 Sep 25;9(10):914. doi: 10.3390/antiox9100914. PMID: 32992775; PMCID: PMC7601802.
- Lenton KJ, Sané AT, Therriault H, Cantin AM, Payette H, Wagner JR. Vitamin C augments lymphocyte glutathione in subjects with ascorbate deficiency. Am J Clin Nutr. 2003;77(1):189-195. doi:10.1093/ajcn/77.1.189
- Polonikov A. Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients. ACS Infect Dis. 2020;6(7):1558-1562. doi:10.1021/acsinfecdis.0c00288
- Ghezzi P, Lemley KV, Andrus JP, De Rosa SC, Holmgren A, Jones D, Jahoor F, Kopke R, Cotgreave I, Bottiglieri T, Kaplowitz N, Nakamura H, Staal F, Ela SW, Atkuri KR, Tirouvanziam R, Heydari K, Sahaf B, Zolopa A, Frye RE, Mantovani JJ, Herzenberg LA, Herzenberg LA. Cysteine/Glutathione Deficiency: A Significant and Treatable Corollary of Disease. The Therapeutic Use of N-Acetylcysteine (NAC) in Medicine. 2018 Jul 19:349–86. doi: 10.1007/978-981-10-5311-5_20. PMCID: PMC7120747.
- Pizzorno J. Glutathione! Integr Med (Encinitas). 2014 Feb;13(1):8-12. PMID: 26770075; PMCID: PMC4684116.
- Minich DM, Brown BI. A Review of Dietary (Phyto)Nutrients for Glutathione Support. Nutrients. 2019 Sep 3;11(9):2073. doi: 10.3390/nu11092073. PMID: 31484368; PMCID: PMC6770193.
- Bettermann EL, Hartman TJ, Easley KA, Ferranti EP, Jones DP, Quyyumi AA, Vaccarino V, Ziegler TR, Alvarez JA. Higher Mediterranean Diet Quality Scores and Lower Body Mass Index Are Associated with a Less-Oxidized Plasma Glutathione and Cysteine Redox Status in Adults. J Nutr. 2018 Feb 1;148(2):245-253. doi: 10.1093/jn/nxx045. PMID: 29490099; PMCID: PMC6251672.
Related reading: Can eating the rainbow support healthy cognition?
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Last updated on 2nd February 2023 by cytoffice