GLUTATHIONE SUPPORTS IMMUNE SYSTEM HEALTH AND BODY DETOXIFICATION PROCESSES

 

 

Background

Glutathione (GSH) is a major endogenous intracellular antioxidant with numerous functions. GSH deficiency has been linked with cell damage, lowered immunity, and the progression of ageing. In its reduced form GSH is a linear tripeptide of L-glutamine, L-cysteine and glycine.1 It is found naturally in virtually all human cells with intracellular depletion ultimately resulting in cell death.1 GSH exists in the body in two forms: the reduced form (GSH) and the oxidised form (GSSG).2

Glutathione – Key actions and benefits

Antioxidant to protect against oxidative stress

GSH is an important antioxidant. GSH levels are depleted in response to oxidative stress and ageing. 1,3,4 Cellular damage is associated with ageing as well as the development of chronic disease.5 Plasma GSH has a high turnover with around 85% of the total GSH in plasma normally in the reduced form. Research is also being undertaken into the associations between low GSH status and potential adverse impacts on neurological health, via several proposed mechanisms.6,7,8

GSH depletion at the cellular level initiates extensive damage to the mitochondria, the energy centres of the cell. An increasing number of toxic or pathological states are associated with a marked depletion of mitochondrial GSH.9 GSH levels can quickly become depleted in times of high  oxidative stress associated with illness, infection, trauma or surgery.1 Deficiencies of nutrient precursors and lowered protein intake may additionally lower GSH levels.1

Helps promote skin health

The specific antioxidant potential of GSH was demonstrated in the following animal study along with GSH’s potential to prevent UV-induced melanogenesis.10

Methods: Rodents were allocated to either: a control group, a UVB irradiation group or a UVB-irradiated group and administered an oral GSH dose over 14 days.

Results: GSH was shown to significantly assert its antioxidant potential by reducing lipid peroxidation and superoxide dismutase activity (p<0.05).10 Furthermore, GSH supplemented animals showed inhibited melanin content and tyrosinase functioning (p<0.05) versus the UVB-irradiated group. Upon examination, the basal epidermal layer had a smaller deposit of melanin pigment in the GSH supplemented group, when compared to the UVB-irradiated group. These findings suggest GSH has photoprotective potential against UVB-induced melanogenesis and oxidative stress.10

The anti-melanogenic and anti-ageing effects of glutathione were studied in a 2017.11

Methods: Women aged 20-50 years were administered either 250 mg/day oral GSH, oxidised glutathione (GSSG) or placebo over a 12 week time-frame in this double blind placebo controlled randomized trial.

Results: The melanin index and ultraviolet spots tended to be lower in the glutathione supplemented groups compared to placebo across all sites. Results reached clinical significance in women over 40 years with noted reductions in sun exposed areas such as the right forearm.11 Results suggest benefits may be more pronounced in individuals with increased photo-damage, as seen in the outcomes for middle-aged women.11

Assists natural body detoxification processes

GSH may assist the body in the elimination of toxins and potential carcinogens.12 GSH plays a role in free radical neutralization of chemical toxins manufactured via phase one liver metabolism and assists with the conjugation of intermediate metabolites, rendering them water soluble where excretion can take place via the kidneys.12 Researchers studied the effects of GSH on non-alcoholic fatty liver disease (NAFLD) in a 2017 pilot study. Thirty four participants with NAFLD initially undertook a dietary and lifestyle intervention over 3 months. Supplementation with 300mg of GSH per day was then administered for a further 4 months (29 subjects completed the trial). Alanine aminotransferase (ALT) is an enzyme that indicates liver damage when elevated. ALT levels decreased significantly with GSH supplementation. Ferritin levels, triglycerides and non-esterified fatty acids were also reduced. When subject results were analysed further and split into 2 groups, participants were either noted as ALT responders with reductions of ≥12.9% or ALT non-responders with reductions <12.9%. ALT responders were significantly younger and had lower glycated haemoglobin (HbA1c) levels compared to non-responders.13 Further investigations are warranted.

Enhances immune system defence

Glutathione (GSH) is a key thiol antioxidant that plays a critical role in supporting immunity, particularly the innate immune system.14,15 The innate immune system is regarded as the body’s first line of defence against infection.16 In addition GSH also plays an integral role in T-cell lymphocyte function.17 A basic research premise suggests reactive oxygen species cause oxidative stress in the presence of issues such as infection, thereby inducing inflammation, GSH is a demonstrated antioxidant that may reduce free radical damage to body cells. However, this view is now seen by some researchers to be too simplistic.15 Diotallevi et al, investigated endogenous GSH’s role within the innate immune system in a rodent cell line study.15 In redox regulation, GSH/GSSG (also known as oxidized glutathione), demonstrates potential signalling molecule actions, separate to GSH’s antioxidant capacity.15 These signalling molecules regulate protein function, suggesting GSH is necessary in a “small pattern of genes” that map to general immunity and anti- viral actions. In this study, endogenous GSH did not appear to impact inflammatory genes when inhibited.15

GSH also has an important role to play in adaptive immunity. GSH is necessary for the reduction of  di-sulfide bonds, required in one of the initial stages of processing and degradation of antigens. Poor glutathione status is associated with an elevated risk of infection in several adverse health states.18

Absorption

Human studies

Several studies provide important insights into how oral glutathione supplementation can increase body stores of glutathione. Oral GSH absorption in humans was demonstrated in a six month, double-blind, randomized, placebo controlled trial by Richie et al, at daily dose rates of either 250 mg  or 1000 mg.17  Although blood GSH levels have not changed in other studies,19 oral GSH supplementation was shown to significantly increase GSH content in the protein-bound fraction of plasma.20 Honda et al, also suggest GSH supplementation may raise protein-bound glutathione incorporation into the liver or potentially decrease excretion.13

Animal studies

Oral GSH has also been shown to effectively increase GSH tissue concentrations in areas of the kidney, heart, lung, brain, small intestine and skin in GSH depleted mice.21,22 Research shows GSH is effectively absorbed in the gastrointestinal tract of rats via a specialised uptake mechanism.1,23,24,25 A study on rats conducted by Favilli et al demonstrated the jejunum, lung and brain absorbed GSH  mostly intact whereas the GSH uptake in the liver was initiated by the breakdown by y-GT activity followed by resynthesis. Both mechanisms may be involved in increasing GSH levels in the heart.23

GSH & Vitamin C

  • GSH and Vitamin C are key intracellular
  • GSH activity is enhanced by vitamin C, a prominent antioxidant nutrient that has the ability to modulate GSH 26,27
  • Chronic vitamin C deficiency states are associated with depleted GSH and an enhanced risk of oxidative 5,28
  • Vitamin C supplementation can assist GSH concentrations to help maintain overall antioxidant protection.29
  • Vitamin C is an antioxidant nutrient that must be derived from dietary, or supplemental sources as the human body lacks a key enzyme necessary for biosynthesis of this vitamin.

Precautions & Considerations

  • Not recommended for use by pregnant or breastfeeding women.
  • Take away from meals or as directed by your healthcare practitioner.

References

1. No authors listed. Glutathione, reduced (GSH). Monograph. Altern Med Rev. 2001 Dec;6(6):601-7.

2. Kidd, P. Glutathione: systemic protectant against oxidative and free radical damage. Alternative Medicine Review. 2(3):155-176. 1997.

3. Julius M, Lang CA, Gleiberman L, et al. Glutathione and morbidity in a community-based sample of elderly. J Clin Epidemiol. 1994 Sep;47(9):1021-6.

4. Lang CA, Naryshkin S, Schneider DL, et al. Low blood glutathione levels in healthy aging adults. J Lab Clin Med. 1992 Nov;120(5):720-5.

5. Henning SM, Zhang JZ, McKee RW, et al. Glutathione blood levels and other oxidant defence indices in men fed diets low in vitamin C. J Nutri. 1991 Dec;121(12):1969-75

6. Dringen R. Metabolism and functions of glutathione in brain. Prog Neurobiol. 2000 Dec;62(6):649-71.

7. Singh I, Pahan K, Khan M, et al. Cytokine-mediated Induction of Ceramide Production Is Redox-sensitive. J Biol Chem, Vol. 273, Issue 32, 20354-20362, August 7, 1998.

8. Baranczyk-Kuzma A, Ku?ma M, Gutowicz M, et al. Glutathione S-transferase pi as a target for tricyclic antidepressants in human brain. Acta Biochim Pol. 2004;51(1):207-12.

9. Lash LH. Mitochondrial Glutathione Transport: Physiological, Pathological and Toxicological Implications. Chem Biol Interact. 2006 Oct 27;163(1-2):54-67. Epub 2006 Apr 4.

10. Nagapan, T. S., Lim, W. N., Basri, D. F., & Ghazali, A. R. (2019). Oral supplementation of L-glutathione prevents UVB-induced melanogenesis and oxidative stress in BALB/c mice. Experimental Animals. https://doi.org/10.1538/expanim.19-0017.

11. Weschawalit S., Thonghip T., Phutrakool P., Asawanonda P. (2017) Glutathione and its antiaging and antimelanogenic effects, Clinical Cosmetic and Investigational Dermatology, 10, 147 – 153.

12. Pizzorno J. Glutathione! The Path Ahead, Integrative Medicine. 2013 Apr; 13(1):8-12.

13. Honda, Y., Kessoku, T., Sumida, Y., Kobayashi, T., Kato, T., Ogawa, Y., Tomeno, W., Imajo, K., Fujita, K., Yoneda, M., Kataoka, K., Taguri, M., Yamanaka, T., Seko, Y., Tanaka, S., Saito, S., Ono, M., Oeda, S., Eguchi, Y., Aoi, W., … Nakajima, A. (2017). Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study. BMC gastroenterology, 17(1), 96. https://doi.org/10.1186/s12876-017-0652-3.

14. Asher BF, Guilford FT. Oxidative Stress and Low Glutathione in Common Ear, Nose, and Throat Conditions: A Systematic Review. Altern Ther Health Med. 2016 Sep;22(5):44-50. PMID: 27622960.

15. Diotallevi, M., Checconi, P., Palamara, A. T., Celestino, I., Coppo, L., Holmgren, A., Abbas, K., Peyrot, F., Mengozzi, M., & Ghezzi, P. (2017). Glutathione Fine-Tunes the Innate Immune Response toward Antiviral Pathways in a Macrophage Cell Line Independently of Its Antioxidant Properties. Frontiers in immunology, 8, 1239. https://doi.org/10.3389/fimmu.2017.01239.

16. InformedHealth.org [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. The innate and adaptive immune systems. [Updated 2020 Jul 30]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279396.

17. Richie JP Jr, Nichenametla S, Neidig W, Calcagnotto A, Haley JS, Schell TD, Muscat JE. Eur J Nutr. 2014 May 5. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Department of Public Health Sciences, Penn State Cancer Institute, H069, Penn State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA.

18. Morris, D., Khurasany, M., Nguyen, T., Kim, J., Guilford, F., Mehta, R., Gray, D., Saviola, B., & Venketaraman, V. (2013). Glutathione and infection. Biochimica et biophysica acta, 1830(5), 3329–3349. https://doi.org/10.1016/j.bbagen.2012.10.012

19. Allen, J., & Bradley, R. D. (2011). Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. Journal of alternative and complementary medicine (New York, N.Y.), 17(9), 827–833. https://doi.org/10.1089/acm.2010.0716.

20. Park, E. Y., Shimura, N., Konishi, T., Sauchi, Y., Wada, S., Aoi, W., Nakamura, Y., & Sato, K. (2014). Increase in the protein-bound form of glutathione in human blood after the oral administration of glutathione. Journal of agricultural and food chemistry, 62(26), 6183–6189. https://doi.org/10.1021/jf501338z.

21. Aw TY, Wierzbicka G, Jones DP. Oral glutathione increases tissue glutathione in vivo. Chem Biol Interact. 1991;80(1):89-97.

22. Chirag Kariya, Heather Leitner, Elysia Min, Christiaan van Heeckeren,Anna van Heeckeren and Brian J. Day. A role for CFTR in the elevation of glutathione levels in the lung by oral glutathione administration., Am J Physiol Lung Cell Mol Physiol 292: L1590–L1597, 2007.

23. Vincenzini MT, Favilli F, Iantomasi T. Intestinal uptake and transmembrane transport systems of intact GSH; characteristics and possible biological role. Biochim Biophys Acta. 1992 Mar 26;1113(1):13-23.

24. Favilli F, Marraccini P, Iantomasi T, et al. Effect of orally administered glutathione on glutathione levels in some organs of rats: role of specific transporters. Br J Nutr. 1997 Aug;78(2):293-300.

25. Mårtensson J, Jain A, Meister A. Glutathione is required for intestinal function. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1715-9.

26. Lenton KJ, Therriault H, Cantin AM, et al. Direct correlation of glutathione and ascorbate and their dependence on age and season in human lymphocytes. Am J Clin Nutr. 2000 May;71(5):1194-1200.

27. Lenton KJ, Sané AT, Therriault H, et al. Vitamin C augments lymphocyte glutathione in subjects with ascorbate deficiency. Am J Clin Nutr. 2003 Jan;77(1):189-95.

28. Lenton KJ, Therriault H, Fülöp T, et al. Glutathione and ascorbate are negatively correlated with oxidative DNA damage in human lymphocytes. Carcinogenesis. 1999 Apr;20(4):607-13.

29. Johnston CS, Meyer CG, Srilakshmi JC. Vitamin C elevates red blood cell glutathione in healthy adults. Am J Clin Nutr. 1993 Jul;58(1):103-5ading.