Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Clinical nutrition

Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function

Abstract

Background/Objectives:

Glutathione (GSH) is the most abundant endogenous antioxidant and a critical regulator of oxidative stress. Maintenance of optimal tissues for GSH levels may be an important strategy for the prevention of oxidative stress-related diseases. We investigated if oral administration of liposomal GSH is effective at enhancing GSH levels in vivo.

Subjects/Methods:

A 1-month pilot clinical study of oral liposomal GSH administration at two doses (500 and 1000 mg of GSH per day) was conducted in healthy adults. GSH levels in whole blood, erythrocytes, plasma and peripheral blood mononuclear cells (PBMCs) were assessed in 12 subjects at the baseline and after 1, 2 and 4 weeks of GSH administration.

Results:

GSH levels were elevated after 1 week with maximum increases of 40% in whole blood, 25% in erythrocytes, 28% in plasma and 100% in PBMCs occurring after 2 weeks (P<0.05). GSH increases were accompanied by reductions in oxidative stress biomarkers, including decreases of 35% in plasma 8-isoprostane and 20% in oxidized:reduced GSH ratios (P<0.05). Enhancements in immune function markers were observed with liposomal GSH administration including Natural killer (NK) cell cytotoxicity, which was elevated by up to 400% by 2 weeks (P<0.05), and lymphocyte proliferation, which was elevated by up to 60% after 2 weeks (P<0.05). Overall, there were no differences observed between dose groups, but statistical power was limited due to the small sample size in this study.

Conclusions:

Collectively, these preliminary findings support the effectiveness of daily liposomal GSH administration at elevating stores of GSH and impacting the immune function and levels of oxidative stress.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Lu SC . Regulation of hepatic glutathione synthesis: current concepts and controversies. FASEB J 1999; 13: 1169–1183.

    Article  CAS  Google Scholar 

  2. Meister A, Anderson ME . Glutathione. Annu Rev Biochem 1983; 52: 711–760.

    Article  CAS  Google Scholar 

  3. Vina J . Glutathione: Metabolism and Physiological Functions. CRC Press: Boca Raton, 1990.

    Google Scholar 

  4. Giustarini D, Rossi R, Milzani A, Colombo R, Dalle-Donne I . S-glutathionylation: from redox regulation of protein functions to human diseases. J Cell Mol Med 2004; 8: 201–212.

    Article  CAS  Google Scholar 

  5. Forman HJ, Zhang H, Rinna A . Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med 2009; 30: 1–12.

    Article  CAS  Google Scholar 

  6. Droge W, Breitkreutz R . Glutathione and immune function. Proc Nutr Soc 2000; 59: 595–600.

    Article  CAS  Google Scholar 

  7. Hamilos DL, Zelarney P, Mascali JJ . Lymphocyte proliferation in glutathione-depleted lymphocytes: direct relationship between glutathione availability and the proliferative response. Immunopharmacology 1989; 18: 223–235.

    Article  CAS  Google Scholar 

  8. Griffith OW . Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radic Biol Med 1999; 27: 922–935.

    Article  CAS  Google Scholar 

  9. Zhang H, Forman HJ . Glutathione synthesis and its role in redox signaling. Semin Cell Dev Biol 2012; 23: 722–728.

    Article  CAS  Google Scholar 

  10. Vogt BL, Richie JP Jr. . Fasting-induced depletion of glutathione in the aging mouse. Biochem Pharmacol 1993; 46: 257–263.

    Article  CAS  Google Scholar 

  11. Jaeschke H, Wendel A . Diurnal fluctuation and pharmacological alteration of mouse organ glutathione content. Biochem Pharmacol 1985; 34: 1029–1033.

    Article  CAS  Google Scholar 

  12. Jollow DJ . Glutathione thresholds in reactive metabolite toxicity. Arch Toxicol Suppl 1980; 3: 95–110.

    Article  CAS  Google Scholar 

  13. Ellouk-Achard S, Levresse V, Martin C, Pham-Huy C, Dutertre-Catella H, Thevenin M et al. Ex vivo and in vitro models in acetaminophen hepatotoxicity studies. Relationship between glutathione depletion, oxidative stress and disturbances in calcium homeostasis and energy metabolism. Arch Toxicol Suppl 1995; 17: 209–214.

    Article  CAS  Google Scholar 

  14. Townsend DM, Tew KD, Tapiero H . The importance of glutathione in human disease. Biomed Pharmacother 2003; 57: 145–155.

    Article  CAS  Google Scholar 

  15. Nuttall SL, Martin U, Sinclair AJ, Kendall MJ . Glutathione: in sickness and in health. Lancet 1998; 351: 645–646.

    Article  CAS  Google Scholar 

  16. Julius M, Lang CA, Gleiberman L, Harburg E, DiFranceisco W, Schork A . Glutathione and morbidity in a community-based sample of elderly. J Clin Epidemiol 1994; 47: 1021–1026.

    Article  CAS  Google Scholar 

  17. Flagg EW, Coates RJ, Eley JW, Jones DP, Gunter EW, Byers TE et al. Dietary glutathione intake in humans and the relationship between intake and plasma total glutathione level. Nutr Cancer 1994; 21: 33–46.

    Article  CAS  Google Scholar 

  18. Flagg EW, Coates RJ, Jones DP, Byers TE, Greenberg RS, Gridley G et al. Dietary glutathione intake and the risk of oral and pharyngeal cancer. Am J Epidemiol 1994; 139: 453–465.

    Article  CAS  Google Scholar 

  19. Favilli F, Marraccini P, Iantomasi T, Vincenzini MT . Effect of orally administered glutathione on glutathione levels in some organs of rats: role of specific transporters. Br J Nutr 1997; 78: 293–300.

    Article  CAS  Google Scholar 

  20. Kariya C, Leitner H, Min E, van Heeckeren C, van Heeckeren A, Day BJ . A role for CFTR in the elevation of glutathione levels in the lung by oral glutathione administration. Am J Physiol Lung Cell Mol Physiol 2007; 292: L1590–L1597.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Hagen TM, Wierzbicka GT, Sillau AH, Bowman BB, Jones DP . Bioavailability of dietary glutathione: effect on plasma concentration. Am J Physiol 1990; 259: G524–G529.

    CAS  PubMed  Google Scholar 

  23. Vina J, Perez C, Furukawa T, Palacin M, Vina JR . Effect of oral glutathione on hepatic glutathione levels in rats and mice. Br J Nutr 1989; 62: 683–691.

    Article  CAS  Google Scholar 

  24. Hunjan MK, Evered DF . Absorption of glutathione from the gastro-intestinal tract. Biochim Biophys Acta 1985; 815: 184–188.

    Article  CAS  Google Scholar 

  25. Furukawa T, Meydani SN, Blumberg JB . Reversal of age-associated decline in immune responsiveness by dietary glutathione supplementation in mice. Mech Ageing Dev 1987; 38: 107–117.

    Article  CAS  Google Scholar 

  26. Cai J, Chen Y, Seth S, Furukawa S, Compans RW, Jones DP . Inhibition of influenza infection by glutathione. Free Radic Biol Med 2003; 34: 928–936.

    Article  CAS  Google Scholar 

  27. Novi AM . Regression of aflatoxin B1-induced hepatocellular carcinomas by reduced glutathione. Science 1981; 212: 541–542.

    Article  CAS  Google Scholar 

  28. Trickler D, Shklar G, Schwartz J . Inhibition of oral carcinogenesis by glutathione. Nutr Cancer 1993; 20: 139–144.

    Article  CAS  Google Scholar 

  29. Schwartz JL, Shklar G . Glutathione inhibits experimental oral carcinogenesis, p53 expression, and angiogenesis. Nutr Cancer 1996; 26: 229–236.

    Article  CAS  Google Scholar 

  30. Shklar G, Schwartz J, Trickler D, Cheverie SR . The effectiveness of a mixture of beta-carotene, alpha-tocopherol, glutathione, and ascorbic acid for cancer prevention. Nutr Cancer 1993; 20: 145–151.

    Article  CAS  Google Scholar 

  31. Richie JP Jr, Nichenametla S, Neidig W, Calcagnotto A, Haley JS, Schell TD et al. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Eur J Nutr 2015; 54: 251–263.

    Article  CAS  Google Scholar 

  32. Kleinman WA, Richie JP Jr . Status of glutathione and other thiols and disulfides in human plasma. Biochem Pharmacol 2000; 60: 19–29.

    Article  CAS  Google Scholar 

  33. Rahman I, Kode A, Biswas SK . Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nat Protoc 2006; 1: 3159–3165.

    Article  CAS  Google Scholar 

  34. Muscat JE, Kleinman W, Colosimo S, Muir A, Lazarus P, Park J et al. Enhanced protein glutathiolation and oxidative stress in cigarette smokers. Free Radic Biol Med 2004; 36: 464–470.

    Article  CAS  Google Scholar 

  35. Drabkin DL . The standardization of hemoglobin measurements. Am J Med Sci 1949; 217: 711–714.

    Google Scholar 

  36. Schell TD, Mylin LM, Georgoff I, Teresky AK, Levine AJ, Tevethia SS . Cytotoxic T-lymphocyte epitope immunodominance in the control of choroid plexus tumors in simian virus 40 large T antigen transgenic mice. J Virol 1999; 73: 5981–5993.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Hamilos DL, Wedner HJ . The role of glutathione in lymphocyte activation. I. Comparison of inhibitory effects of buthionine sulfoximine and 2-cyclohexene-1-one by nuclear size transformation. J Immunol 1985; 135: 2740–2747.

    CAS  PubMed  Google Scholar 

  38. Gmunder H, Droge W . Differential effects of glutathione depletion on T cell subsets. Cell Immunol 1991; 138: 229–237.

    Article  CAS  Google Scholar 

  39. Morris D, Khurasany M, Nguyen T, Kim J, Guilford F, Mehta R et al. Glutathione and infection. Biochim Biophys Acta 2013; 1830: 3329–3349.

    Article  CAS  Google Scholar 

  40. Galter D, Mihm S, Droge W . Distinct effects of glutathione disulphide on the nuclear transcription factor kappa B and the activator protein-1. Eur J Biochem 1994; 221: 639–648.

    Article  CAS  Google Scholar 

  41. Suthanthiran M, Anderson ME, Sharma VK, Meister A . Glutathione regulates activation-dependent DNA synthesis in highly purified normal human T lymphocytes stimulated via the CD2 and CD3 antigens. Proc Natl Acad Sci USA 1990; 87: 3343–3347.

    Article  CAS  Google Scholar 

  42. Hargrove ME, Wang J, Ting CC . Regulation by glutathione of the activation and differentiation of IL-4-dependent activated killer cells. Cell Immunol 1993; 149: 433–443.

    Article  CAS  Google Scholar 

  43. Liang CM, Lee N, Cattell D, Liang SM . Glutathione regulates interleukin-2 activity on cytotoxic T-cells. J Biol Chem 1989; 264: 13519–13523.

    CAS  PubMed  Google Scholar 

  44. Vojdani A, Mumper E, Granpeesheh D, Mielke L, Traver D, Bock K et al. Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15. J Neuroimmunol 2008; 205: 148–154.

    Article  CAS  Google Scholar 

  45. Huang HY, Helzlsouer KJ, Appel LJ . The effects of vitamin C and vitamin E on oxidative DNA damage: results from a randomized controlled trial. Cancer Epidemiol Biomark Prev 2000; 9: 647–652.

    CAS  Google Scholar 

  46. Jacob RA, Aiello GM, Stephensen CB, Blumberg JB, Milbury PE, Wallock LM et al. Moderate antioxidant supplementation has no effect on biomarkers of oxidant damage in healthy men with low fruit and vegetable intakes. J Nutr 2003; 133: 740–743.

    Article  CAS  Google Scholar 

  47. Ottestad I, Vogt G, Retterstol K, Myhrstad MC, Haugen JE, Nilsson A et al. Oxidised fish oil does not influence established markers of oxidative stress in healthy human subjects: a randomised controlled trial. Br J Nutr 2012; 108: 315–326.

    Article  CAS  Google Scholar 

  48. Stewart RJ, Askew EW, McDonald CM, Metos J, Jackson WD, Balon TW et al. Antioxidant status of young children: response to an antioxidant supplement. J Am Diet Assoc 2002; 102: 1652–1657.

    Article  CAS  Google Scholar 

  49. Patrignani P, Panara MR, Tacconelli S, Seta F, Bucciarelli T, Ciabattoni G et al. Effects of vitamin E supplementation on F(2)-isoprostane and thromboxane biosynthesis in healthy cigarette smokers. Circulation 2000; 102: 539–545.

    Article  CAS  Google Scholar 

  50. Nemzer BV, Rodriguez LC, Hammond L, Disilvestro R, Hunter JM, Pietrzkowski Z . Acute reduction of serum 8-iso-PGF2-alpha and advanced oxidation protein products in vivo by a polyphenol-rich beverage; a pilot clinical study with phytochemical and in vitro antioxidant characterization. Nutr J 2011; 10: 67.

    Article  CAS  Google Scholar 

  51. Trebble TM, Wootton SA, Miles EA, Mullee M, Arden NK, Ballinger AB et al. Prostaglandin E2 production and T cell function after fish-oil supplementation: response to antioxidant cosupplementation. Am J Clin Nutr 2003; 78: 376–382.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge the support of the staff of the Pennsylvania State University College of Medicine Clinical Research Center and Investigational Pharmacy. This work was supported by Research Nutritionals, LLC. Liposomal glutathione preparations (Tri-Fortify Orange) were provided by Researched Nutritionals, LLC (Los Olivos, CA, USA). Immunological analyses were supported in part by the Penn State Cancer Institute through the Clinical Correlative Immunology Laboratory (TDS, JPH). The project described was supported in part by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant 1UL1TR002014-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to R Sinha or J P Richie Jr.

Ethics declarations

Competing interests

RS and JPR received research funding for this study from Researched Nutritionals, LLC. Researched Nutritionals, LLC is a nutraceutical company that provides liposomal glutathione (Tri-Fortify Orange) to health care professionals. Other than providing research funding and liposomal GSH, Researched Nutritionals, LLC did not play a role in the design of the study, collection and analysis of the data and the decision to publish. There were no personal financial interests between any of the authors with Researched Nutritionals, LLC.

Additional information

Supplementary Information accompanies this paper on European Journal of Clinical Nutrition website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sinha, R., Sinha, I., Calcagnotto, A. et al. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. Eur J Clin Nutr 72, 105–111 (2018). https://doi.org/10.1038/ejcn.2017.132

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ejcn.2017.132

This article is cited by

Search

Quick links