This article is not medical or healthcare advice. Before starting on any health related regimen seek the advice of your Primary Care Physician or an M.D.
Glutathione is commonly known as the master antioxidant in the body, and is mostly tightly associated with neutralizing the free radical hydrogen peroxide (which causes lipid peroxidation) to water. It is also involved in conjugation (detoxification) of various chemicals, mycotoxins, and heavy metals.
But how important is it really, and is exogenous supplementation of glutathione helpful ? Well lets go to what the published research says:
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. [1]
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.
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. [2]
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).
Glutathione Associations:
Alzheimers, Parkinsons, and auto immune conditions are associated with low glutathione.
Glutathione modulates antigen presentation to lymphocytes, thereby influencing cytokine production and type of response (cellular or humoral) that develops.
Enhances proliferation of lymphocytes, thereby increasing magnitude of response
Enhances killing activity of cytotoxic T cells and NK cells, and regulating apoptosis, thereby maintaining control of the immune response. [3]
GSH depletion in antigen presenting cells inhibits Th1-associated cytokine production and/or favors Th-2-associated responses. Multiple chemical sensitivities seen are associated with decreased Th-1, increased Th-2 response.
Compromised ability to detoxify environmental toxins and heavy metals, resulting in neurotoxicity
Oxidation of cysteine thiol (SH) groups in proteins; altering function of proteins.
Compromised gut lining, resulting in increased gut permeability and immune reactions
Increased Th2, altered thymic T cell subsets; compromising immune system
Compromises methylation by reducing S-adenosylmethionine synthesis and increased S-adenosylhomocysteine accumulation which inhibits methyltransferase; toxin accumulation.
The rate limiting enzyme for making gluatathione, γ-glutamylcysteine synthetase is down-regulated by Transforming Growth Factor - beta (TGF-beta) and by prolonged oxidant exposure. Mold exposure raises TGF-beta 1.
Low levels of glutathione peroxidase are seen in vitiligo [4], relapsing-remitting multiple sclerosis [5], and type 2 diabetes [6].
Glutathione peroxidase genetic polymorphisms associated with celiac disease. [7]
The toxic effects of acetaminophen, are brought on with excessive doses of this drg. This is associated with rapidly depleted intracellular GSH reserves and can be treated with n-acetylcysteine (NAC) the first 48 hours after overdose.
Glutathione has a central role in a variety of cell functions related to immune defense.
Decreased glutathione in antigen-presenting cells correlates with increased Th2 response.
Decreased glutathione found in macrophage cells from children with chronic asthma has been shown to be related to decreased bacterial phagocytosis. Children with chronic asthma, had decreased glutathione related to Nrf2 mutations.
Decreased glutathione and decreased macrophage defense against intracellular infection with Mycobacterium tuberculosis occurs in the macrophages of individuals with HIV. This was shown to be due to a decrease in the gene expression of glutathione production enzymes.
Restoration of glutathione levels in mycotoxin exposed mice using NAC or glutathione ethyl ester restored IL-12 secretion and prevented airway inflammation/hyperreactivity.
Glutathione restoration using NAC in children with asthma restored phagocytosis.
An increase in urinary excretion of 5-oxoproline, an intermediate of the γ-glutamyl cycle, is a useful indicator of reduced availability of cysteine and/or glycine for GSH synthesis in vivo. Decreased 5-oxoproline in the urine is seen with even mild glutathione synthetase deficiency.
So, yes, glutathione status is important. How can we assess various oxidative stress markers and what they might mean in the future as risk predictors......for various well known diseases, including neuro degeneration diseases:
Oxidative stress is highly linked to aging [8,9]
Alzheimer's is linked to elevated levels of the oxidative stress markers: 4-HNE, MDA, IsoProstanes, 8 OHdG, 8O HG, 3-nitrotyrosine, Ditryrosine. [10,11,12, 13]
Diabetes is linked to elevated 8 OHdG, CML, 8 Isoprostanes [14,15,16]
Hyperlipidemia is linked to elevated F2 Isoprostanes, Dityrosine
Cardiac Heart Disease linked to F2 isoprostanes [17]
Cancer and diabetes are linked to elevated 8 OHdG [18, 19]
Inflammation and cancer are linked to 8 Nitroguanine [20]
H Pylori is linked to elevated 8 nitroguanine [21]
Each of the above markers are not reliant on glutathione status alone, but depending on the situation, other antioxidant systems like Catalase, Thirodoxin, Pirodoxin, Super Oxide Dismutase, NQO1, PON1, B12, Nitric Oxide, and other systems will play a role as well.
References:
Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. By John P Richie Jr, et. al. Europe Journal of Nutrition. Randomized Controlled Trial. 2015 Mar;54(2):251-63. doi: 10.1007/s00394-014-0706-z. Epub 2014 May 5.PMID: 24791752. DOI: 10.1007/s00394-014-0706-z.
Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. By Sinha, et. al. Clinical Nutrition. Published: 30 August 2017. Pages 105–111.
Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. By Peterson, et. al. Proc Natl Acad Sci U S A. 1998 Mar 17; 95(6): 3071–3076. doi: 10.1073/pnas.95.6.3071. PMCID: PMC19696. PMID: 9501217
Low glutathione peroxidase activity levels in patients with vitiligo Hatem Zedan. J Cutan Med Surgury. . 2015 Mar-Apr;19(2):144-8. doi: 10.2310/7750.2014.14076. Epub 2015 Mar 11. PMID: 25775636 DOI: 10.2310/7750.2014.14076
Dietary habits and selenium, glutathione peroxidase and total antioxidant status in the serum of patients with relapsing-remitting multiple sclerosis Katarzyna Socha. Nutriton Journal. . 2014 Jun 18:13:62. doi: 10.1186/1475-2891-13-62. PMID: 24943732. PMCID: PMC4080729. DOI: 10.1186/1475-2891-13-62
Effect of Selenium Supplementation on Glutathione Peroxidase Enzyme Activity in Patients With Chronic Kidney Disease: A Randomized Clinical TrialNephrourol Mon. 2014 May; 6(3): e17945. By Sedighi, et. al. Published online 2014 May 4. doi: 10.5812/numonthly.17945 PMCID: PMC4090673. PMID: 25032143
Evaluation of glutathione peroxidase and superoxide dismutase enzyme polymorphisms in celiac disease patients. ByM Katar. Genetic Molecular Research. 2014 Feb 20;13(1):1030-7. doi: 10.4238/2014.February.20.4. PMID: 24634124. DOI: 10.4238/2014.February.20.4
Oxidative Stress: Mechanisms, Quantification and its role in human aging. Hari Krishnan Krishnamurthy
A Comprehensive Overview of the Complex Role of Oxidative Stress in Aging, The Contributing Environmental Stressors and Emerging Antioxidant Therapeutic Interventions By Evripides Iakovou. Front Aging Neurosci. 2022; 14: 827900. 2022 Jun 13. doi: 10.3389/fnagi.2022.827900. PMCID: PMC9234325. PMID: 35769600
Oxidative Stress and 4-hydroxy-2-nonenal (4-HNE): Implications in the Pathogenesis and Treatment of Aging-related Diseases. By Yanling Li . J Immunol Research. . 2022 Mar 23:2022:2233906. doi: 10.1155/2022/2233906. eCollection 2022.
Nitrative Stress and Tau Accumulation in Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC) in the Kii Peninsula, Japan. January 2018. Frontiers in Neuroscience 11:751. DOI:10.3389/fnins.2017.00751.
Early Detection and Prevention of Alzheimer’s Disease: Role of Oxidative Markers and Natural Antioxidants. By Jamshed Arslan. Front Aging Neurosci. 2020; 12: 231. Published online 2020 Jul 27. doi: 10.3389/fnagi.2020.00231 PMCID: PMC7397955. PMID: 32848710
Nuclear Tau and Its Potential Role in Alzheimer's Disease. By Maina, Serpell, et. al. Biomolecules. . 2016 Jan 7;6(1):9. doi: 10.3390/biom6010009. PMID: 26751496 PMCID: PMC4808803. DOI: 10.3390/biom6010009
Effect of dietary advanced glycation end products on inflammation and cardiovascular risks in healthy overweight adults: a randomised crossover trial. By Estifanos Baye. Sci Rep. . 2017 Jun 23;7(1):4123. doi: 10.1038/s41598-017-04214-6. PMID: 28646140. PMCID: PMC5482825. DOI: 10.1038/s41598-017-04214-6
Urinary Metabolomic Markers of Protein Glycation, Oxidation, and Nitration in Early-Stage Decline in Metabolic, Vascular, and Renal Health. By Masania. Oxid Med Cell Longev. 2019; 2019: 4851323. Published online 2019 Nov 19. doi: 10.1155/2019/4851323 PMCID: PMC6885816. PMID: 31827677
Urinary Oxidative Damage Markers and Their Association with Obesity-Related Metabolic Risk Factors. By Gariballa. Antioxidants (Basel). 2022 May; 11(5): 844. Published online 2022 Apr 26. doi: 10.3390/antiox11050844. PMCID: PMC9138160 PMID: 35624709
F2-isoprostanes as an indicator and risk factor for coronary heart disease Sean S Davies, L Jackson Roberts. Free Radic Biol Medicine. 2011 Mar 1;50(5):559-66. doi: 10.1016/j.freeradbiomed.2010.11.023. Epub 2010 Nov 30. PMID: 21126576 PMCID: PMC3058898. DOI: 10.1016/j.freeradbiomed.2010.11.023
8-hydroxy-2' -deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis. By Athanasios Valavanidis, Thomais Vlachogianni, Constantinos Fiotakis. Journal of Environ Sci Health C Environ Carcinog Ecotoxicol Rev. . 2009 Apr;27(2):120-39. doi: 10.1080/10590500902885684. PMID: 19412858. DOI: 10.1080/10590500902885684
Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. By Lily L Wu, et. al. 2004 Jan;339(1-2):1-9. doi: 10.1016/j.cccn.2003.09.010. PMID: 14687888. DOI: 10.1016/j.cccn.2003.09.010
8-Nitroguanine, a Product of Nitrative DNA Damage Caused by Reactive Nitrogen Species: Formation, Occurrence, and Implications in Inflammation and Carcinogenesis. By Dr. Hiroshi Ohshima. Antioxidants & Redox SignalingVol. 8, No. 5-6. Published Online: 13 June 2006. Antioxidants & Redox Signaling. https://doi.org/10.1089/ars.2006.8.1033
Accumulation of 8-nitroguanine in human gastric epithelium induced by Helicobacter pylori infection. By Ning Ma, et. al. Biochem Biophys Res Commun. . 2004 Jun 25;319(2):506-10. doi: 10.1016/j.bbrc.2004.04.193. PMID: 15178435.