Mitochondria are cellular substructures that function as energy powerhouses for almost all eukaryotic cells, including those of humans [1]. The number of mitochondria in a cell can vary widely [2]. Red blood cells, for example, have none, whereas liver cells can contain up to two thousand [2]. Mitochondria are integral to our survival due to the variety of roles they play in our biochemistry, the most important of which is the production of adenosine triphosphate (ATP) by aerobic respiration [1]. This process involves oxidative phosphorylation, which utilizes oxygen to release the energy contained in the foods we eat. The energy is initially stored in ATP, which subsequently releases this energy to power the body’s metabolic reactions. During this process, ATP is broken down into adenosine diphosphate (ADP) and inorganic phosphate (P_i).

Since mitochondria are essential to our very existence, it is unsurprising that the effects of mitochondrial diseases can be severe, and sometimes lethal, spanning a wide-ranging spectrum of physiological and biochemical symptoms [1,3,4] (see Table 1 for examples). Mitochondrial diseases in humans can arise from a myriad of mutations in mitochondrial and nuclear (cellular) DNA [4]. Collectively, mitochondrial diseases are reported to affect 1 in every 5,000 adults, making them quite prevalent in comparison to other hereditary metabolic disorders [4].

Table 1. Some well-known clinically defined primary mitochondrial diseases and their respective symptoms.

Mitochondrial diseases are characterized by both a diminished capacity to produce ATP as well as an elevated production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [3]. Commonly known as free radicals, ROS and RNS are naturally produced during oxidative phosphorylation and serve an essential role as signalling molecules in the normal functioning of a cell [4]. However, a dysregulated increase in the level of these free radicals, as seen in mitochondrial diseases, can result in oxidative damage by overwhelming the cellular antioxidant defence mechanism, of which glutathione is the principal component [4]. The consequent depletion of glutathione [3] impedes the efficient quenching of free radicals, leading to redox imbalance and oxidative stress [4]. This, in turn, can compromise the structural and functional integrity of the cell’s nucleic acids, proteins and lipids [4]. As a result, the activity of the electron transport chain (ETC) is hindered, decreasing ATP production during oxidative phosphorylation [8]. Since the cellular synthesis of glutathione is ATP-dependent, decreased ETC activity also undermines glutathione synthesis, further exacerbating oxidative stress in a vicious cycle [8]. Hence, mitochondrial diseases present as a two-front attack on cellular glutathione levels; the excess free radicals deplete glutathione reserves, and the decreased ATP production slows glutathione replenishment, ultimately resulting in chronic glutathione deficiency [8].

The appreciably high incidence of mitochondrial diseases highlights a growing need to devise effective therapeutic strategies. With the current absence of technologies to rectify the actual mutations that underlie mitochondrial diseases, medical science can only address the resulting oxidative stress as a potential therapeutic option. Therefore, therapy primarily focuses on providing patients with supportive care to manage their symptoms using dietary supplements [9]. Commonly prescribed or recommended dietary supplements include coenzyme Q₁₀ and vitamin B, C, E and K [9,10]. Unfortunately, no concrete evidence of their efficacy exists to support their beneficial use in addressing the symptoms of mitochondrial diseases [9, 10].

Given the strong association between glutathione depletion and the progression of mitochondrial diseases, dietary supplements with the potential to increase intracellular glutathione reserves have been the subject of much research in recent years [11]. One of the prime candidates has been N-acetylcysteine (NAC), which is the gold standard antidote for acute acetaminophen (paracetamol) overdose. In this particular case, cysteine is severely depleted, and NAC helps to restore cellular glutathione levels to homeostasis by providing a source of cysteine. However, no clinical trials have been reported that provide any evidence of its effectiveness for raising the chronically low homeostatic level of glutathione that occurs in primary mitochondrial diseases [1, 11]. Additionally, in the context of lowered ATP production, which is a hallmark of mitochondrial diseases, it is important to note that NAC, essentially only being a form of cysteine, will require 2 ATP molecules to be converted to glutathione. This is because cysteine is at the very beginning of the two-step cellular synthesis of glutathione (see Figure 1). For a detailed explanation, read our article on NAC https://www.glutathionereporter.com/n-acetylcysteine-nac-cannot-increase-cellular-glutathione-levels/.

Figure 1. The two sequential ATP-dependent reactions by which glutathione is synthesized inside cells, with the enzyme catalyzing the reaction and the number of ATP molecules required for the reaction to occur, displayed above and below the arrows respectively.

Unlike NAC, dietary supplementation with gamma-glutamylcysteine (GGC), the immediate precursor to glutathione, can elevate intracellular glutathione levels above homeostasis [12]. This increased glutathione pool may help contend with the increased flow of free radicals from dysfunctional mitochondria. Moreover, the conversion of GGC to glutathione only requires 1 molecule of ATP as it is the product of the first step in glutathione synthesis, as shown in Figure 1. This low energy feature of GGC may be particularly useful for overcoming the ATP inadequacy that occurs in mitochondrial diseases. Finally, GGC may be capable of acting as an antioxidant in its own right by removing key ROS such as hydrogen peroxide and superoxide anions independently of glutathione [13]. This may be advantageous in severe cases of mitochondrial diseases where there could be insufficient ATP available to synthesize glutathione from GGC.

In summation, GGC’s potential to elevate intracellular glutathione levels above homeostasis in an energy-efficient manner, makes it a promising candidate as a potential therapeutic for mitochondrial diseases.

Reference

1. Schapira, AHV 2006, ‘Mitochondrial Disease’, The Lancet, vol. 368, no. 9529, pp. 70-82. 
2. Jones, M, Fosbery, R, Gregory, J, Taylor, D 2014, Cambridge International AS and A Level Biology Coursebook, 4^th edn, Cambridge University Press, United Kingdom.
3. Atkuri, KR, Cowan, TM, Kwan, T, Ng, A, Herzenberg, LA, Herzenberg, LA, Enns, GM 2009, ‘Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia’, Proceedings of the National Academy of Sciences, vol. 106, no. 10, pp. 3941-3945.
4. Enns, GM, Moore, T, Le, A, Atkuri, K, Shah, MK, Cusmano-Ozog, K, Niemi, AK, Cowan, TM 2014, ‘Degree of Glutathione Deficiency and Redox Imbalance Depend on Subtype of Mitochondrial Disease and Clinical Status’, The Public Library of Science One, vol. 9, no. 6.
5. Baertling, F, Rodenburg, RJ, Schaper, J, Smeitink, JA, Koopman, WJH, Mayatepek, E, Morava, E, Distelmaier, F 2014, ‘A guide to diagnosis and treatment of Leigh syndrome’, Journal of Neurology, Neurosurgery & Psychiatry, vol. 85, no. 3, pp. 257-265.
6. Saneto, RP, Cohen, BH, Copeland, WC, Naviaux, RK 2013, ‘Alpers-Huttenlocher Syndrome’, Pediatric Neurology, vol. 48, no. 3, pp. 167-178.
7. El-Hattab, AW, Adesina, AM, Jones, J, Scaglia, F 2015, ‘MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options’, Molecular genetics and metabolism, vol. 106, no. 1-2, pp. 4-12.
8. Hargreaves, IP, Sheena, Y, Land, JM, Heales, SJR 2005, ‘Glutathione deficiency in patients with mitochondrial disease: Implications for pathogenesis and treatment’, Journal of Inherited Metabolic Disease, vol. 28, no. 1, pp. 81-88.
9. Chinnery, PF, Turnbull, DM 2001, ‘Epidemiology and treatment of mitochondrial disorders’, American Journal of Medical Genetics, vol. 106, no. 1, pp. 94-101.
10. Gorman, GS, Chinnery, PF, DiMauro, S, Hirano, M, Koga, Y, McFarland, R, Suomalainen, A, Thorburn, DR, Zeviani, M, Turnbull, DM 2016, ‘Mitochondrial diseases’, Nature Reviews Disease Primers, vol. 2, no. 26080, pp. 1-22.
11. Enns, GM, Cowan, TM 2017, ‘Glutathione as a Redox Biomarker in Mitochondrial Disease – Implications for Therapy’, Journal of Clinical Medicine, vol. 6, no. 5, pp. 50.
12. Zarka, MH, Bridge, WJ 2017, ‘Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study’, Redox Biology, vol. 11, pp. 631-636.
13. Quintana-Cabrera, R, Fernandez-Fernandez, S, Bobo-Jimenez, V, Escobar, J, Sastre, J, Almeida, A, Bolaños, JP 2012, ‘γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor’, Nature Communications, vol. 3, no. 718, pp. 1-8.

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A biological antioxidant is defined as “any substance that, when present at low concentrations, significantly delays or prevents the oxidation of oxidizable substrates” [1]. Oxidizable substrates in the body, such as DNA and proteins, can incur damage by accepting electrons from unstable reactive oxygen species (ROS), which are generated by exogenous and endogenous means. Ultra-violet radiation (UVR) is a type of ionizing radiation that significantly increases ROS formation as its short wavelength and high frequency possesses enough energy to knock electrons out of oxygen molecules. This makes them highly unstable. Everyday UVR exposure often leads to sunburn, and long-term repeated exposure can additionally result in substantial skin and DNA damage that may lead to the development of melanoma and other skin cancers [2].

When the body’s antioxidant defence system becomes overwhelmed due to an influx of ROS, a cascade of oxidative damage can occur. If the DNA or membrane of a cell is irreversibly damaged, it will be marked for programmed cell death (apoptosis). This process releases inflammatory markers such as prostaglandins, which are responsible for inducing the symptoms of sunburn: Vasodilation, swelling and pain [3]. Oxidative damage can accumulate over time if UVR exposure is frequent, accelerating photoaging and consequently increasing the appearance of wrinkles, pigmentation and blotchiness.  The Skin Cancer Foundation states that photoaging is responsible for 90% of visible changes to the skin [4]. The symptoms of photoaging occur due to the oxidation of dermal collagen fibre bundles, which are proteins responsible for providing strength and elasticity to our skin [5]. Since the body produces less collagen as we age, the symptoms of photoaging will naturally accumulate over time. Long-term UVR exposure evidently hastens this process.

Depending on its wavelength, UVR is categorized intoUVA (315-400 nm), UVB (280-315 nm) and UVC (100-280 nm). Each type differs in their biological activity and ability to penetrate our skin. Of the UVR entering the atmosphere, 90% of UVA, 10% of UVB, and none of the UVC radiation reaches the Earth’s surface. For this reason, the only possible routes of UVC exposure are from man-made devices such as tanning beds and lasers. Radiation in the UVA spectrum is primarily responsible for ROS generation and sunburn, while UVB can directly damage DNA by inducing the formation of thymine-thymine cyclobutane dimers, which can lead to mutation, and potentially skin cancers if not repaired [6]. Considerable levels of OH• (hydroxyl radical) and H₂O₂ (hydrogen peroxide) are produced within 15 minutes of UVR exposure and continue for up to 60 minutes afterwards [2].

Glutathione (GSH) has been shown to play a protective role during UVR exposure via three mechanisms. The primary function of GSH is to neutralize the oxidation capacity of H₂O₂ by converting it to water (see Reaction 1 below). In this process, catalyzed by the enzyme glutathione peroxidase, reduced glutathione (GSH) is oxidized to (GSSG), which the cell then recycles back to the reduced form using the enzyme glutathione reductase (see Reaction 2 below).

Reaction 1. H₂O₂ + 2GSH     —->    2H₂O + GSSG

Reaction 2. GSSG + NADPH + H⁺   —->    2GSH + NADP⁺

Melanin is a skin pigment that acts as a photoprotector by absorbing UVR. The production of melanin in the epidermis (melanogenesis) is accelerated during UVR exposure, which concurrently generates ROS [7]. The second function of GSH is to downregulate UVR-induced melanogenesis, which consequently lowers the increased level of ROS production [7]. Lastly, GSH also supports the activity of DNA repair enzymes [8], lowering the incidence of mutations which are a precursor to skin cancer, as well as apoptosis which leads to sunburn [9].

GSH is only able to protect cells against UVR if there is a sufficient concentration within the cells to address the onslaught of UVR induced ROS.  This can be an issue, as UVA exposure has been shown to deplete GSH in the dermis and epidermis skin tissue [10]. Studies have shown that a diminished GSH pool stimulates apoptosis and leads to increased UVR sensitization and sunburn [11,12]. Research suggests that during UVR exposure, GSH in affected cells is progressively depleted due to inhibition of cysteine transport as well as decreased activity of the enzyme gamma-glutamate cysteine ligase (GCL) [13]. The product of GCL is gamma-glutamylcysteine (GGC), which is an essential precursor to GSH. Taking GGC supplements bypasses the need for GCL to be working at its maximal rate, allowing GSH to be continually produced and hence withstand depletion inside cells.

The risk of cellular oxidative stress can be lowered by limiting exposure to UVR and/or by strategies that increase the cellular GSH pool to provide a buffer against the UVR-induced acute increase in ROS production [10]. During long or acute periods of UVR exposure, the antioxidant defense system will eventually become overwhelmed, as the rate of GSH synthesis is outcompeted by the accumulation of ROS. Supplemental GGC has been shown to increase the intracellular GSH pool [14] and, if consumed before UVR exposure, there is great potential for the skin to further withstand oxidative stress through a heightened GSH antioxidant buffer. Supplements should always be used in conjunction with additional measures such as sunscreen and protective clothing to achieve a decreased risk of sunburn, photoaging and skin cancer.

References

1. Halliwell, B. and Gutteridge, J.M.C. (1999). Free radicals in biology and medicine. Journal of Free Radicals in Biology & Medicine, 1(4), 331–332, DOI: 10.1016/0748-5514(85)90140-0
2. Chen, L., Hu, J.Y. and Wang, S.Q. (2012). The role of antioxidants in photoprotection: A critical review. Journal of the American Academy of Dermatology, 67(5), 1013–1024, DOI: 10.1016/j.jaad.2012.02.009
3. Guerra, K.C., Urban, K. and Crane, J.S. (2021). Sunburn. StatPearls Publishing. PMID: 30521258.
4. Grabel, A. (2019). Photoaging: What You Need to Know About the Other Kind of Aging – The Skin Cancer Foundation. [online] The Skin Cancer Foundation. Available at: https://www.skincancer.org/blog/photoaging-what-you-need-to-know/.
5. Edwards, C., Pearse, A., Marks, R., Nishimori, Y., Matsumoto, K. and Kawai, M. (2001). Degenerative Alterations of Dermal Collagen Fiber Bundles in Photodamaged Human Skin and UV-Irradiated Hairless Mouse Skin: Possible Effect on Decreasing Skin Mechanical Properties and Appearance of Wrinkles. Journal of Investigative Dermatology, 117(6), pp.1458–1463, DOI: 10.1038/jid.2001.2
6. Adamiec, M. and Skonieczna, M. (2019). UV radiation in HCT 116 cells influences intracellular H2O2 and glutathione levels, antioxidant expression, and protein glutathionylation. Acta Biochimica Polonica, 66(4), 605-610, DOI: 10.18388/abp.2019_2892
7. Nagapan, T.S., Lim, W.N., Basri, D.F. and Ghazali, A.R. (2019). Oral supplementation of L-glutathione prevents ultraviolet B-induced melanogenesis and oxidative stress in BALB/c mice. Experimental Animals, 68(4), 541–548, DOI: 10.1538/expanim.19-0017
8. Schenk, H., Klein, M., Erdbrugger, W., Droge, W. and Schulze-Osthoff, K. (1994). Distinct effects of thioredoxin and antioxidants on the activation of transcription factors NF-kappa B and AP-1. Proceedings of the National Academy of Sciences, 91(5), 1672–1676, DOI: 10.1073/pnas.91.5.1672
9. Godic, A., Poljšak, B., Adamic, M. and Dahmane, R. (2014). The Role of Antioxidants in Skin Cancer Prevention and Treatment. Oxidative Medicine and Cellular Longevity, 2014, 1–6, DOI: 10.1155/2014/860479
10. Connor, M.J. and Wheeler, L.A. (1987). Depletion of cutaneous glutathione by ultraviolet radiation. Photochemistry and Photobiology, 46(2), 239–245, DOI: 10.1111/j.1751-1097.1987.tb04762.x
11. Friesen, C., Kiess, Y. and Debatin, K-M. (2004). A critical role of glutathione in determining apoptosis sensitivity and resistance in leukemia cells. Cell Death & Differentiation, 11(S1), S73–S85, DOI: 10.1038/sj.cdd.4401431
12. Tyrrell, R.M. and Pidoux, M. (1988). Correlation between endogenous glutathione content and sensitivity of cultured human skin cells to radiation at defined wavelengths in the solar ultraviolet range. Photochemistry and Photobiology, 47(3), 405–412, DOI: 10.1111/j.1751-1097.1988.tb02744.x
13. Zhu, M. and Bowden, G.T. (2007). Molecular Mechanism(s) for UV-B Irradiation-Induced Glutathione Depletion in Cultured Human Keratinocytes. Photochemistry and Photobiology, 80(2), 191–196, DOI: 10.1111/j.1751-1097.2004.tb00070.x
14. Bridge, W.J. and Zarka, M.H. (2017). Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study. Redox Biology, 11, 631–636, DOI: 10.1016/j.redox.2017.01.014

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Osteoporosis is a debilitating skeletal condition characterized by low bone density, causing bone fragility and increased risk of bone fractures ^[1]. The body constantly renews bone tissue by absorbing old tissue and regenerating new tissue. As we get older, these two processes become unbalanced, resulting in increased bone resorption and decreased bone formation ^[2]. This is a contributing factor for the gradual loss in bone density and strength as we age. Other factors impacting bone health may include cellular changes, genetic damage due to complex age-related changes as well as nutritional deficiencies of calcium and vitamin D. Oxidative stress can also negatively affect bone health ^[2].

Oxidative stress occurs due to excessive reactive oxygen species (ROS) paired with inadequate levels of antioxidants, in particular glutathione ^[3]. The level of ROS in the body increases with age and as a result of negative lifestyle factors such as smoking ^[4] and obesity ^[5]. This progressively weakens the maintenance of functional tissues ^[6] and further negatively impacts the balance of bone formation and bone resorption ^[7-8].

The body has a finely tuned antioxidant system which neutralizes ROS. This includes the group of antioxidant vitamins such as C & E, but in particular glutathione, which is the most powerful antioxidant in its own right. Glutathione also recycles Vitamins C & E and is therefore the cornerstone of our complex antioxidant response ^[9].

The importance of glutathione is well recognized in the medical community ^[9]. We also know that the body’s production of glutathione slows down as we age and is negatively affected by stress, toxins and illness ^[10]. Even strenuous exercise can temporarily reduce cellular glutathione below optimal. Strategies to enhance glutathione have been explored, but they have been met with very limited success. Supplements such as n-acetylcysteine (NAC), herbal remedies or even glutathione itself do not have the ability to increase glutathione within our cells and, although popular, fail to achieve their objective. For a supplement to be effective, it also needs to be able to increase cellular glutathione above homeostasis, or the natural set point determined by the enzymatic production of glutathione in our cells. This set point progressively becomes lower as we age resulting in suboptimal glutathione production.

Another contributing factor to bone health is Vitamin D, a deficiency of which has long been associated with weak bone formation. Rickets is a disease of the bone directly caused by low levels of Vitamin D as well as dietary calcium. A deficiency in Vitamin D also hinders the absorption of calcium and promotes the release of calcium from the bones, which can lead to the development of osteoporosis. This can significantly weaken bone strength and flexibility, leading to a reduced ability to withstand stress ^[11]. Recent studies have shown a strong correlation between glutathione depletion and the bioavailability of both vitamin D and dietary calcium ^[12-13]. Vitamin D supplements are therefore not successful unless glutathione status is at optimal levels ^[12]. Additionally, it has been shown that decreased glutathione, and the consequent increase in ROS levels, results in a decline of calcium absorption, hindering the effective mineralization of the skeleton ^[13].

Hence, it would be beneficial to have increased glutathione levels in order to ensure optimal Vitamin D absorption and minimal oxidative stress. Supplementation with gamma-glutamylcysteine has shown to increase cellular glutathione levels above homeostasis ^[14] and therefore proves to have potential value as a preventative therapy for osteoporosis by reducing oxidative stress and optimizing Vitamin D and calcium absorption.

References

1. Sozen, T.; Ozisik, L.; Calik Basaran, N. An Overview And Management Of Osteoporosis. European Journal of Rheumatology 2017, 4 (1), 46-56.
2. Corrado, A.; Cici, D.; Rotondo, C.; Maruotti, N.; Cantatore, F. Molecular Basis Of Bone Aging. International Journal of Molecular Sciences 2020, 21 (10), 3679.
3. Zhou X, Wang Z, Ni Y, Yu Y, Wang G, Chen L. Suppression effect of N-acetylcysteine on bone loss in ovariectomized mice. Am J Transl Res. 2020;12(3):731-742.
4. Kamceva, G.; Arsova-Sarafinovska, Z.; Ruskovska, T.; Zdravkovska, M.; Kamceva-Panova, L.; Stikova, E. Cigarette Smoking And Oxidative Stress In Patients With Coronary Artery Disease. Open Access Macedonian Journal of Medical Sciences 2016, 4 (4), 636-640.
5. Matsuda, M.; Shimomura, I. Increased Oxidative Stress In Obesity: Implications For Metabolic Syndrome, Diabetes, Hypertension, Dyslipidemia, Atherosclerosis, And Cancer. Obesity Research & Clinical Practice 2013, 7 (5), e330-e341.
6. Cui, H.; Kong, Y.; Zhang, H. Oxidative Stress, Mitochondrial Dysfunction, And Aging. Journal of Signal Transduction 2012, 2012, 1-13.
7. Almeida M, Han L, Martin-Millan M, Plotkin LI, Stewart SA, Roberson PK, Kousteni S, O’Brien CA, Bellido T, Parfitt AM, Weinstein RS, Jilka RL, Manolagas SC. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem. 2007;282:27285–27297.
8. Domazetovic V, Marcucci G, Iantomasi T, Brandi ML, Vincenzini MT. Oxidative stress in bone remodeling: role of antioxidants. Clin Cases Miner Bone Metab. 2017;14:209–216. 
9. Pizzorno, J. Glutathione!. Integrative Medicine: A Clinician’s Journal 2014, 1 (13), 8-12.
10. Mosoni, L.; Breuillé, D.; Buffière, C.; Obled, C.; Mirand, P. Age-Related Changes In Glutathione Availability And Skeletal Muscle Carbonyl Content In Healthy Rats. Experimental Gerontology 2004, 39 (2), 203-210.
11. Laird, E.; Ward, M.; McSorley, E.; Strain, J.; Wallace, J. Vitamin D And Bone Health; Potential Mechanisms. Nutrients 2010, 2 (7), 693-724.
12. Jain, S.K., R. Parsanathan, A.E. Achari, P. Kanikarla-Marie, and J.A. Bocchini, Jr., Glutathione Stimulates Vitamin D Regulatory and Glucose-Metabolism Genes, Lowers Oxidative Stress and Inflammation, and Increases 25-Hydroxy-Vitamin D Levels in Blood: A Novel Approach to Treat 25-Hydroxyvitamin D Deficiency. Antioxid Redox Signal, 2018. 29(17): p. 1792-1807
13. Moine, L., M. Rivoira, G. Díaz de Barboza, A. Pérez, and N. Tolosa de Talamoni, Glutathione depleting drugs, antioxidants and intestinal calcium absorption. World J Gastroenterol, 2018. 24(44): p. 4979-4988.
14. Zarka, M.H. and W.J. Bridge, Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomized human trial pilot study. Redox Biology, 2017. 11: p. 631-636.

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Not long after COVID-19 became synonymous with the collapse of tourism, businesses and overburdened health systems, reports of people surfaced who suffered from a condition that became known as Long Covid. In essence, Long Covid is a lingering illness in people who have contracted COVID-19 and then presumably recovered because the virus was no longer detectable. Regardless of how severe the initial onset of COVID-19 manifested itself, a significant proportion of patients report debilitating symptoms long after the virus has been eliminated from their body ^[1].

An Irish study found that over 50% of patients with COVID-19 reported persistent fatigue more than 10 weeks after initial symptoms ^[2]. Likewise, researchers in Italy confirmed troublesome symptoms sixty days after initial onset ^[3]. The US Centers for Disease Control and Prevention similarly concluded ongoing symptoms such as fatigue and cough. They found this to be more prevalent in older people or those suffering from chronic diseases.

But is this a hallmark of SARS-CoV-2 and entirely unexpected? The short answer is no, because there is a range of viruses that cause post-infectious fatigue syndrome. Similar conditions have been reported for Ross River virus, Ebola virus, Dengue Fever virus and SARS coronavirus ^[1], just to name a few. Although the progression of disease and the organ damage they cause is quite different, chronic fatigue is a lingering condition they all share. Interestingly, the symptoms of post-infectious chronic fatigue are remarkably similar to those experienced by people who have Myalgic Encephalomyelitis, commonly known as Chronic Fatigue Syndrome . In fact, Dr Anthony Fauci, the Director of the National Institute for Allergy and Infectious Diseases, reported that patients who had COVID-19 often develop a post-viral syndrome that is remarkably like Chronic Fatigue Syndrome ^[4]. It is too early to tell how long this condition will last post-COVID-19.

The indirect cost of Chronic Fatigue Syndrome is staggering, up to 836 000 and 2.5 million individuals are affected in the United States alone before COVID-19 struck ^[5]. It remains to be seen how many additional cases will be added as a result of this pandemic.

So, what causes post-infectious chronic fatigue? We know that viruses such as SARS-CoV-2 can damage the heart, lungs or kidneys, and the impaired function of these organs would be sufficient to produce chronic fatigue.  Also, patients who have been on ventilators can suffer from post-traumatic stress disorder. Others may develop depression due to their reduced quality of life post-infection. It is highly likely that these psychiatric disorders also lead to chronic fatigue. However, many patients do not present with either physiological symptoms, such as organ damage, or psychiatric conditions and still suffer from post-infectious chronic fatigue ^[1].

To study this further, we can look at earlier research conducted on sufferers of Chronic Fatigue Syndrome. Even back in 1999, it was suspected that Chronic Fatigue Syndrome may have its roots in oxidative stress ^[6]. That lead to the conclusion that acute glutathione depletion may be involved. Some studies have revealed that glutathione is chronically depleted in some sufferers ^[7].

The role of glutathione in preventing oxidative stress is well understood. As an antioxidant, it performs many vital functions inside the cell. In the case of chronic fatigue, there appears to be a tug of war for this critical molecule. The immune system places great demands on glutathione when challenged, as is the case in Chronic Fatigue Syndrome. This can lead to competition for glutathione precursors since the muscular system also relies on glutathione for aerobic muscular contraction ^[8]. As the immune system takes priority in survival, insufficient glutathione may express itself as fatigue since skeletal muscles cannot sustain normal aerobic metabolism.

Time will tell how post-infectious chronic fatigue will progress in COVID-19 patients. It is hoped that further research will identify specific causes that lead to effective treatments. This may ultimately also relieve the symptoms of Chronic Fatigue Syndrome. Glutathione will most likely play a significant role in these studies, and an effective way to supplement cellular glutathione will be needed. Supplementation with gamma-glutamylcysteine has been demonstrated in a human clinical trial to increase cellular glutathione levels regardless of its initial (basal) concentration. And, most importantly, this increase occurred rapidly (within hours) ^[9]. With other supplements, a slight increase in glutathione (GSH) could only be observed after many months of daily supplementation. The recent commercial availability of gamma-glutamylcysteine means that researchers are now able to successfully test the effectiveness of increasing cellular glutathione (GSH) in treating the symptoms of Long Covid and Chronic Fatigue Syndrome.

References

1. Komaroff, A.L. and L. Bateman, Will COVID-19 Lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Frontiers in Medicine, 2021. 7(1132)
   https://www.frontiersin.org/article/10.3389/fmed.2020.606824
2. Townsend, L., A.H. Dyer, K. Jones, J. Dunne, A. Mooney, F. Gaffney, L. O’Connor, D. Leavy, K. O’Brien, J. Dowds, J.A. Sugrue, D. Hopkins, I. Martin-Loeches, C. Ni Cheallaigh, P. Nadarajan, A.M. McLaughlin, N.M. Bourke, C. Bergin, C. O’Farrelly, C. Bannan, and N. Conlon, Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS One, 2020. 15(11): p. e0240784.
   https://doi.org/10.1371/journal.pone.0240784
3. Carfì, A., R. Bernabei, and F. Landi, Persistent Symptoms in Patients After Acute COVID-19. Jama, 2020. 324(6): p. 603-605. 10.1001/jama.2020.12603.
4. Topol, E. and A. Verghese, Fauci to Medscape:‘We’re All In It Together and We’re Gonna Get Through It’. 2020, Medscape.
5. Clayton, E.W., Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An IOM Report on Redefining an Illness. JAMA, 2015. 313(11): p. 1101-1102.
   https://doi.org/10.1001/jama.2015.1346
6. Bounous, G. and J. Molson, Competition for glutathione precursors between the immune system and the skeletal muscle: pathogenesis of chronic fatigue syndrome. Med Hypotheses, 1999. 53(4): p. 347-9. 10.1054/mehy.1998.0780
7. Shungu, D.C., N. Weiduschat, J.W. Murrough, X. Mao, S. Pillemer, J.P. Dyke, M.S. Medow, B.H. Natelson, J.M. Stewart, and S.J. Mathew, Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed, 2012. 25(9): p. 1073-87. 10.1002/nbm.2772
8. JAMMES, Y., J.G. STEINBERG, O. MAMBRINI, F. BRÉGEON, and S. DELLIAUX, Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. Journal of Internal Medicine, 2005. 257(3): p. 299-310.
   https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2005.01452.x
9. 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.
   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5284489/pdf/main.pdf

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Gamma-glutamylcysteine (GGC) is essential to mammalian life. Mice that have had the glutamate-cysteine ligase (GCL) gene knocked out do not develop beyond the embryo stage and die before birth ^[5]. This is because gamma-glutamylcysteine (GGC) is vital for the biosynthesis of glutathione (GSH). Since the production of cellular gamma-glutamylcysteine (GGC) in humans slows down with age, as well as during the progression of many chronic diseases, it has been postulated that supplementation with gamma-glutamylcysteine (GGC) could offer health benefits. Other benefits of gamma-glutamylcysteine (GGC) supplementation may extend to situations where glutathione (GSH) has been acutely lowered below optimum such as following strenuous exercise, and during trauma or episodes of poisoning.

Several review articles have been published regarding the therapeutic potential of gamma-glutamylcysteine (GGC) to replenish glutathione in age-related ^[6] and chronic disease states such as Alzheimer’s disease ^[7]. Gamma-glutamylcysteine (GGC) is also capable of being a powerful antioxidant in its own right ^[8-10].

A human clinical study in healthy, non-fasting adults demonstrated that orally administered gamma-glutamylcysteine (GGC) can significantly increase lymphocyte glutathione (GSH) levels indicating systemic bioavailability, validating the therapeutic potential of gamma-glutamylcysteine (GGC) ^[16].

Animal model studies with gamma-glutamylcysteine (GGC) have supported it’s potential therapeutic role in both the reduction of oxidant stress-induced damage in tissues including the brain ^[17] and as a treatment for sepsis ^[18].

Supplementation with glutathione (GSH) is incapable of increasing cellular glutathione (GSH) since the glutathione (GSH) concentration found in the extracellular environment is much lower than that found intracellularly by about a thousand-fold. This large difference means that there is an insurmountable concentration gradient that prohibits extracellular glutathione entering cells. Although currently unproven, gamma-glutamylcysteine (GGC) may be the pathway intermediate of glutathione transportation in multicellular organisms ^{[19, 20]}.

References

1. Orlowski, M. and A. Meister, The gamma-glutamyl cycle: a possible transport system for amino acids. Proc Natl Acad Sci U S A, 1970. 67(3): p. 1248-55.
2. Meister, A. and M.E. Anderson, Glutathione. Annu Rev Biochem, 1983. 52: p. 711-60.
3. Anderson, M.E. and A. Meister, Transport and direct utilization of gamma-glutamylcyst(e)ine for glutathione synthesis. Proceedings of the National Academy of Sciences of the United States of America., 1983. 80(3): p. 707-11.
4. Mårtensson, J., Method for determination of free and total glutathione and γ-glutamylcysteine concentrations in human leukocytes and plasma. Journal of Chromatography B: Biomedical Sciences and Applications, 1987. 420(0): p. 152-157.
5. Dalton, T.P., et al., Genetically altered mice to evaluate glutathione homeostasis in health and disease. Free Radical Biology and Medicine, 2004. 37(10): p. 1511-1526.
6. Ferguson, G. and W. Bridge, Glutamate cysteine ligase and the age-related decline in cellular glutathione: The therapeutic potential of γ-glutamylcysteine. Archives of Biochemistry and Biophysics, 2016. 593: p. 12-23.
7. Cao, P., et al., Therapeutic approaches to modulating glutathione levels as a pharmacological strategy in Alzheimer’s disease. Curr Alzheimer Res, 2015. 12(4): p. 298-313.
8. Quintana-Cabrera, R. and J.P. Bolanos, Glutathione and gamma-glutamylcysteine in the antioxidant and survival functions of mitochondria. Biochemical Society Transactions, 2013. 41: p. 106-110.
9. Quintana-Cabrera, R., et al., γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor. Nat Commun, 2012. 3: p. 718.
10. Nakamura, Y.K., M.A. Dubick, and S.T. Omaye, γ-Glutamylcysteine inhibits oxidative stress in human endothelial cells. Life Sciences, 2011(0).
11. 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.
12. 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.
13. Yang, Y., et al., γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level. Redox Biology, 2019. 20: p. 157-166.
14. Wu, G., et al., Glutathione metabolism and its implications for health. Journal of Nutrition, 2004. 134(3): p. 489-92.
15. Stark, A.A., et al., The role of gamma-glutamyl transpeptidase in the biosynthesis of glutathione. Biofactors, 2003. 17(1-4): p. 139-49.
16. Chandler, S.D., et al., Safety assessment of gamma-glutamylcysteine sodium salt. Regulatory Toxicology and Pharmacology, 2012. 64(1): p. 17-25.
17. Braidy, N., et al., The Precursor to Glutathione (GSH), γ-Glutamylcysteine (GGC), Can Ameliorate Oxidative Damage and Neuroinflammation Induced by Aβ40 Oligomers in Human Astrocytes. Frontiers in Aging Neuroscience, 2019. 11(177).
18. Yang, Y., et al., γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level. Redox Biology, 2019. 20: p. 157-166.
19. Wu, G., et al., Glutathione metabolism and its implications for health. Journal of Nutrition, 2004. 134(3): p. 489-92.
20. Stark, A.A., et al., The role of gamma-glutamyl transpeptidase in the biosynthesis of glutathione. Biofactors, 2003. 17(1-4): p. 139-49.
21. Chandler, S.D., et al.,Safety assessment of Gamma-glutamylcysteine sodium salt. Regulatory Toxicology and Pharmacology, 2012. 64(1): p. 17-25.
22. Braidy, N., et al., The Precursor to Glutathione (GSH), γ-Glutamylcysteine (GAMMA-GLUTAMYLCYSTEINE), Can Ameliorate Oxidative Damage and Neuroinflammation Induced by Aβ40 Oligomers in Human Astrocytes. Frontiers in Aging Neuroscience, 2019. 11(177).

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The resulting treated samples are usually then centrifuged to remove solids and the supernatant stored frozen prior to analysis. There are many methods available in the scientific literature for the analysis of glutathione (GSH) but none, however, are particularly reliable or simple. This is reflected in the literature values of blood glutathione (GSH) analysis which often vary greatly between laboratories using what seem to be similar methods ^[2]. Methods include HPLC, HPLC-MS/MS and capillary electrophoresis ^[3]. One of the most commonly used is a spectroscopic method based on the glutathione (GSH) reductase enzyme recycling assay first described in ^[4].

Sampling blood and measuring GSH in either red blood cells (RBC) or plasma would seem like an acceptable method of determining glutathione (GSH) status, however, both present unique technical difficulties and are open to artefacts. In the case of RBC’s, their metabolism, physiology and structure are not considered representative of most cell types in the body as they lack a nucleus and most organelles. In addition, the acid pre-treatment of the RBC’s releases a large amount of iron that can oxidize glutathione (GSH) even under acidic conditions. In the case of blood plasma, there exists an approximate thousand-fold difference between intracellular glutathione (GSH) (mM range) to extracellular or plasma concentration (µM range). Thus, a small amount of RBC lysis in the sample even by using too small a needle to draw blood can result in erroneously high estimates of plasma glutathione (GSH).

These problems were addressed in the study by selecting the lymphocyte fraction of blood ^[5]. These nucleated cells were considered more representative of the body’s cells and could be easily isolated by high speed fluorescence activated cell sorting (FACS) which allowed the collection of a million lymphocytes in less than 5 minutes. The resulting million cells were acid treated and analysed for glutathione (GSH) content using the glutathione (GSH) reductase enzyme recycling assay.

References

1. Monostori, P., et al., Determination of glutathione and glutathione disulfide in biological samples: An in-depth review  Journal of Chromatography B, 2009. 877: p. 3331.
2. Rossi, R., et al., Blood glutathione disulfide: In vivo factor or in vitro artifact? Clinical Chemistry, 2002. 48(5): p. 742-753.
3. Iwasaki, Y., et al., Chromatographic and mass spectrometric analysis of glutathione in biological samples  Journal of Chromatography B, 2009. 877(28): p. 3309.
4. Tietze, F., Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: Applications to mammalian blood and other tissues. Analytical Biochemistry, 1969. 27(3): p. 502-522.
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.

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The first reaction is rate limiting and is catalyzed by the enzyme glutamate-cysteine ligase (GCL, EC 6.3.2.2; formerly γ-glutamylcysteine synthetase). GCL is composed of a heavy catalytic subunit (GCLC, MW ~ 73,000) and a light modifier (GCLM, MW ~ 30,000) subunit. GCL is the key control point for the homeostasis of cellular GSH and is regulated at multiple levels. Its regulation at a genetic level (both transcriptional and translational) and at a biochemical level (post-translational) are incredibly complex.

The light modifier subunit GCLM is enzymatically inactive but plays an important regulatory function by lowering the Km of GCLC for glutamate and raising the Ki for glutathione (GSH) ^{[7, 8]}. The resulting holoenzyme dimer comprising the two subunits is catalytically more efficient and less subject to inhibition by glutathione (GSH) than GCLC alone. In rats, GCLC has a Km for glutamate that is about 10-fold higher than that of the GCL holoenzyme, which is higher than the cellular glutamate concentration in most tissues

GCL is specific for the glutamyl moiety and is regulated physiologically by: (a) non-allosteric feedback competitive inhibition by glutathione (GSH) (Ki = 2.3 mM) which involves binding of GSH to the glutamate and another site on the enzyme ^{[8, 9]} and (b) availability of its precursor, cysteine ^[1]. The apparent Km values of GCL for glutamate and cysteine are 1.8 and 0.1–0.3 mM, respectively ^[9]. The intracellular glutamate concentration is nearly 10-fold higher than the Km value, but intracellular cysteine concentrations approximate the apparent Km value ^[10] indicating that cysteine may be a limiting substrate for GCL. This has led to the false assumption that the cause of glutathione (GSH) depletion associated with so many chronic diseases must be from an under supply of cysteine in the diet. This is an unlikely scenario as the developed world dietary intake of sulfur amino acids is generally adequate. For example, the typical American diet supplies much more than the recommended required quantity of cysteine ^[11]. Interestingly, this has not discouraged multiple research groups testing cysteine prodrugs, such as N-acetylcysteine (NAC), as supplements to increase glutathione (GSH) levels. Unsurprisingly, most clinical trials with NAC have demonstrated a lack of efficacy ^[12-16]. However, NAC has been shown to restore glutathione levels in cases such as acetaminophen overdose where an acute depletion of glutathione is observed ^[17]. In these cases, glutathione (GSH) levels are well below the normal concentration and therefore feedback inhibition of GCL is absent. To this date, the only medically recognized use of NAC in increasing cellular glutathione is in acetaminophen poisoning.

Our proposition is that the suboptimal glutathione levels associated with so many chronic diseases are not due to a cysteine undersupply but an impairment in one of the multiple control mechanisms of the GCL enzyme. Again, this impairment can be effectively bypassed by supplementation with gamma-glutamylcysteine (GGC) which can be transported into cells where it will be rapidly converted to glutathione by the enzyme Glutathione Synthase (GS).

The second step in glutathione (GSH) synthesis is catalyzed by the enzyme Glutathione Synthase (GS, EC 6.3.2.3, formerly known as GSH synthetase). GS is constitutively expressed in all cells and has not been studied as extensively as GCL ^[5]. It is not subject to feedback inhibition by glutathione (GSH) and its substrates gamma-glutamylcysteine (GGC) and glycine are rapidly ligated to form glutathione (GSH). The intracellular concentration of gamma-glutamylcysteine (GGC) is extremely low (~ 5 uM) when GS is present, thus GCL is considered the rate-limiting enzyme ^[6]. In support of this observation, over expression of GS in a yeast model failed to increase glutathione (GSH) levels whereas over expression of GCL did ^[18].

The intracellular concentration of glutathione (GSH) is in the millimolar range and the extracellular concentration is in the micromolar range. This steep glutathione (GSH) concentration gradient from inside the cell to outside the cell drives the export of glutathione (GSH) from the cell. This concentration gradient of glutathione (GSH) makes transport of glutathione (GSH) from outside the cell to inside the cell thermodynamically unfavorable. It is not surprising then that most attempts to increase intracellular glutathione (GSH) by glutathione supplementation have been unsuccessful ^{[19, 20]}. Once outside the cell, glutathione (GSH) degradation occurs exclusively in the extracellular space, and only on the surface of cells that express the ectoenzyme γ-glutamyl transferase. This enzyme catalyzes the transfer of the γ-glutamyl moiety of glutathione (GSH) to another amino acid to produce a γ-Glu-AA and cysteinyl-glycine. These γ-Glu-AAs can be transported back into cells, where they become substrates for the enzyme γ-glutamyl cyclotransferase. This enzyme generates 5-oxoproline and releases the amino acid or peptide that is bound to glutamate. 5-Oxoproline is converted to glutamate by the ATP-requiring enzyme 5-oxoprolinase. The other part of the hydrolyzed glutathione (GSH) molecule cysteinyl-glycine is transported back inside the cell and broken down further by nonspecific dipeptidases into cysteine and glycine ready providing substrates for glutathione (GSH) resynthesis. This process allows for the release of cysteine from glutathione (GSH) which can then be used in protein synthesis. In this case, glutathione (GSH) is functioning as a storage mechanism for cysteine which is otherwise unstable in its free form.

Glutathione (GSH) is a cofactor, coenzyme, and/or substrate for a number of enzymes, and can participate in a number of redox and conjugation reactions. Within the cell, it exists mainly (98%) in the thiol-reduced form glutathione (GSH), but some is also present as glutathione disulfide (GSSG). This ratio of GSH:GSSG is maintained by the action of the enzyme GSSG reductase (also known as glutathione reductase) which requires NADPH+ as the reducing cofactor. Glutathione (GSH) can react with many electrophilic compounds to generate glutathione S-conjugates. Free radicals are neutralized and other oxidants are reduced by the direct action of glutathione (GSH) and indirectly via enzyme glutathione peroxidase, which used glutathione (GSH) as a cofactor.   

References

1. Meister, A. and M.E. Anderson, Glutathione. Annu Rev Biochem, 1983. 52: p. 711-60.
2. Ferguson, G. and W. Bridge, Glutamate cysteine ligase and the age-related decline in cellular glutathione: The therapeutic potential of γ-glutamylcysteine. Archives of Biochemistry and Biophysics, 2016. 593: p. 12-23.
3. Franklin, C.C., et al., Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase. Molecular Aspects of Medicine, 2009. 30(1-2): p. 86-98.
4. Ballatori, N., et al., Glutathione dysregulation and the etiology and progression of human diseases. Biological Chemistry, 2009. 390(3): p. 191-214.
5. Lu, S.C., Glutathione synthesis. Biochimica et Biophysica Acta (BBA) – General Subjects, 2013. 1830(5): p. 3143-3153.
6. Dalton, T.P., et al., Genetically altered mice to evaluate glutathione homeostasis in health and disease. Free Radical Biology and Medicine, 2004. 37(10): p. 1511-1526.
7. Huang, C.S., M.E. Anderson, and A. Meister, Amino acid sequence and function of the light subunit of rat kidney gamma-glutamylcysteine synthetase. J Biol Chem, 1993. 268(27): p. 20578-83.
8. Huang, C.S., et al., Catalytic and regulatory properties of the heavy subunit of rat kidney gamma-glutamylcysteine synthetase. J Biol Chem, 1993. 268(26): p. 19675-80.
9. Richman, P.G. and A. Meister, Regulation of gamma-glutamyl-cysteine synthetase by nonallosteric feedback inhibition by glutathione. J Biol Chem, 1975. 250(4): p. 1422-6.
10. Bannai, S. and N. Tateishi, Role of membrane transport in metabolism and function of glutathione in mammals. J Membr Biol, 1986. 89(1): p. 1-8.
11. Lang, C.A., The impact of glutathione on health and longevity. Journal of Anti Aging Medicine, 2001. 4(2): p. 137-144.
12. Aitio, M.-L., N-acetylcysteine – passe-partout or much ado about nothing? British Journal of Clinical Pharmacology, 2006. 61(1): p. 5-15.
13. Ashworth, A. and S.T. Webb, Does the prophylactic administration of N-acetylcysteine prevent acute kidney injury following cardiac surgery? Interact CardioVasc Thorac Surg, 2010. 11(3): p. 303-308.
14. Sochman, J., N-Acetylcysteine Somewhere Between Scylla and Charybdis. J Am Coll Cardiol, 2010. 56(13): p. 1067-a-.
15. Wang, G., et al., N-acetylcysteine in Cardiac Surgery: Do the Benefits Outweigh the Risks? A Meta-Analytic Reappraisal. Journal of cardiothoracic and vascular anesthesia, 2011. 25(2): p. 268-275.
16. Coles, L.D., et al., Repeated-Dose Oral N-Acetylcysteine in Parkinson’s Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress. The Journal of Clinical Pharmacology, 2018. 58(2): p. 158-167.
17. Rushworth, G.F. and I.L. Megson, Existing and potential therapeutic uses for N-acetylcysteine: The need for conversion to intracellular glutathione for antioxidant benefits. Pharmacology & Therapeutics, 2014. 141(2): p. 150-159.
18. Grant, C.M., F.H. MacIver, and I.W. Dawes, Glutathione synthetase is dispensable for growth under both normal and oxidative stress conditions in the yeast Saccharomyces cerevisiae due to an accumulation of the dipeptide gamma-glutamylcysteine. Mol Biol Cell, 1997. 8(9): p. 1699-707.
19. Witschi, A., et al., The systemic availability of oral glutathione. European Journal of Clinical Pharmacology, 1992. 43(6): p. 667-669.
20. 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.

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The importance of glutathione is highlighted by the fact that all cells produce their own glutathione. It comes as no surprise that glutathione has been the subject of more than 80,000 papers published in peer-reviewed scientific journals all over the world during the last two decades. No other molecule, other than possibly water and oxygen, has been studied more extensively by research scientists.

Maintaining cellular glutathione levels is essential to good health. Unfortunately, for most diseases and disorders and during aging itself, our bodies lose the capacity to produce glutathione at homeostatic levels that are high enough to fight off the ravages of oxidative stress.

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