Randomized controlled trial of oral glutathione supplementation on body stores of glutathione
- 2k Downloads
Glutathione (GSH), the most abundant endogenous antioxidant, is a critical regulator of oxidative stress and immune function. While oral GSH has been shown to be bioavailable in laboratory animal models, its efficacy in humans has not been established. Our objective was to determine the long-term effectiveness of oral GSH supplementation on body stores of GSH in healthy adults.
A 6-month randomized, double-blinded, placebo-controlled trial of oral GSH (250 or 1,000 mg/day) on GSH levels in blood, erythrocytes, plasma, lymphocytes and exfoliated buccal mucosal cells was conducted in 54 non-smoking adults. Secondary outcomes on a subset of subjects included a battery of immune markers.
GSH levels in blood increased after 1, 3 and 6 months versus baseline at both doses. At 6 months, mean GSH levels increased 30–35 % in erythrocytes, plasma and lymphocytes and 260 % in buccal cells in the high-dose group (P < 0.05). GSH levels increased 17 and 29 % in blood and erythrocytes, respectively, in the low-dose group (P < 0.05). In most cases, the increases were dose and time dependent, and levels returned to baseline after a 1-month washout period. A reduction in oxidative stress in both GSH dose groups was indicated by decreases in the oxidized to reduced glutathione ratio in whole blood after 6 months. Natural killer cytotoxicity increased >twofold in the high-dose group versus placebo (P < 0.05) at 3 months.
These findings show, for the first time, that daily consumption of GSH supplements was effective at increasing body compartment stores of GSH.
KeywordsGlutathione Supplementation Antioxidant Immune function
We thank Ashley Knipe for her technical assistance with sample processing and Nate Sheaffer in the Penn State Hershey Flow Cytometry Core Facility. We thank Mr. Yoichiro Sugimura (deceased) and Ms. Erika Hashizume for their support in the design and implementation of this trial. This work was supported by Kyowa Hakko Bio Co., Ltd (JR). Glutathione (Setria®) supplements and placebo were provided by Kyowa Hakko Bio Co., Ltd. Kyowa Hakko Bio Co., Ltd had no role in the conduct, collection, management, analysis and interpretation of the data, or writing of the manuscript. Immunological analyses were supported in part by the Penn State Hershey Cancer Institute through the Clinical Correlative Immunology Laboratory (TS and JH).
Conflict of interest
JPR received research support for this study and travel funds to present previous research findings from Kyowa Hakko Bio Co., Ltd. Kyowa Hakko Bio Co., Ltd is a biotechnology and fermentation company that provides glutathione (Setria®). None of the other authors have any conflicts of interest to disclose.
- 1.Lu SC (1999) Regulation of hepatic glutathione synthesis: current concepts and controversies. Faseb J 13:1169–1183Google Scholar
- 3.Vina J (1990) Glutathione: metabolism and physiological functions. CRC Press, Boca RatonGoogle Scholar
- 10.Ellouk-Achard S, Levresse V, Martin C, Pham-Huy C, Dutertre-Catella H, Thevenin M, Warnet JM, Claude JR (1995) 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 17:209–214CrossRefGoogle Scholar
- 17.Flagg EW, Coates RJ, Jones DP, Byers TE, Greenberg RS, Gridley G, McLaughlin JK, Blot WJ, Haber M, Preston-Martin S et al (1994) Dietary glutathione intake and the risk of oral and pharyngeal cancer. Am J Epidemiol 139:453–465Google Scholar
- 21.Hagen TM, Wierzbicka GT, Sillau AH, Bowman BB, Jones DP (1990) Bioavailability of dietary glutathione: effect on plasma concentration. Am J Physiol 259:G524–G529Google Scholar
- 35.Hamilos DL, Wedner HJ (1985) 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 135:2740–2747Google Scholar
- 38.Richie JP Jr, Skowronski L, Abraham P, Leutzinger Y (1996) Blood glutathione concentrations in a large-scale human study. Clin Chem 42:64–70Google Scholar
- 41.Drabkin DL (1949) The standardization of hemoglobin measurements. Am J Med Sci 217:711–714Google Scholar
- 42.Nichenametla SN, Ellison I, Calcagnotto A, Lazarus P, Muscat JE, Richie JP Jr (2008) Functional significance of the GAG trinucleotide-repeat polymorphism in the gene for the catalytic subunit of gamma-glutamylcysteine ligase. Free Radic Biol Med 45:645–650. doi: 10.1016/j.freeradbiomed.2008.05.012 CrossRefGoogle Scholar
- 43.Gaitonde MK (1967) A spectrophotometric method for the direct determination of cysteine in the presence of other naturally occurring amino acids. Biochem J 104:627–633Google Scholar
- 45.Lozzio CB, Lozzio BB (1975) Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood 45:321–334Google Scholar
- 46.Schell TD, Mylin LM, Georgoff I, Teresky AK, Levine AJ, Tevethia SS (1999) Cytotoxic T-lymphocyte epitope immunodominance in the control of choroid plexus tumors in simian virus 40 large T antigen transgenic mice. J Virol 73:5981–5993Google Scholar
- 53.Nichenametla SN, Muscat JE, Liao JG, Lazarus P, Richie JP Jr (2012) A functional trinucleotide repeat polymorphism in the 5′-untranslated region of the glutathione biosynthetic gene GCLC is associated with increased risk for lung and aerodigestive tract cancers. Mol Carcinog. doi: 10.1002/mc.21923 Google Scholar
- 58.Liang CM, Lee N, Cattell D, Liang SM (1989) Glutathione regulates interleukin-2 activity on cytotoxic T-cells. J Biol Chem 264:13519–13523Google Scholar
- 59.Vojdani A, Mumper E, Granpeesheh D, Mielke L, Traver D, Bock K, Hirani K, Neubrander J, Woeller KN, O’Hara N, Usman A, Schneider C, Hebroni F, Berookhim J, McCandless J (2008) Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15. J Neuroimmunol 205:148–154. doi: 10.1016/j.jneuroim.2008.09.005 CrossRefGoogle Scholar
- 63.Michelet F, Gueguen R, Leroy P, Wellman M, Nicolas A, Siest G (1995) Blood and plasma glutathione measured in healthy subjects by HPLC: relation to sex, aging, biological variables, and life habits. Clin Chem 41:1509–1517Google Scholar
- 65.Nguyen D, Hsu JW, Jahoor F, Sekhar RV (2014) Effect of increasing glutathione with cysteine and glycine supplementation on mitochondrial fuel oxidation, insulin sensitivity, and body composition in older HIV-infected patients. J Clin Endocrinol Metab 99:169–177. doi: 10.1210/jc.2013-2376 CrossRefGoogle Scholar