Biomarkers of Inflammation and Oxidation: Total Glutathione

Optimal Takeaways  

Glutathione is a tripeptide compound produced endogenously or consumed in the diet or supplement form. It supports vital antioxidant and detoxification functions in the body, including the brain. Glutathione protects against oxidative stress, cellular damage, toxin exposure, and many chronic diseases.

Low glutathione levels are associated with cancer, cardiovascular disease, diabetes, neurodegenerative diseases, and acetaminophen toxicity. High glutathione levels are uncommon but may be associated with resistance to chemotherapy, elevated white blood cells, and myelofibrosis.

Standard Range: Quest: 373 – 838 uM

The ODX Range: 373 – 838 uM

Low total glutathione is associated with chronic disease, e.g., cancer, genitourinary, GI, cardiovascular, and musculoskeletal diseases (Lang 2000), toxin or drug exposure, oxidative stress, cell damage, immune dysfunction, infections, cardiovascular disease, diabetes, arthritis, malnutrition (Richie 2015), inflammation, cognitive impairment, mental health disorders, mitochondrial dysfunction, cystic fibrosis, liver disease, hypertension, lupus, infertility, HIV, aging, fatigue, B12 deficiency, elevated GGT (Minich 2019), pulmonary fibrosis, neurodegenerative disorders, increased risk of multimorbidity (Perez 2020), vitamin C insufficiency (Waly 2015), acetaminophen toxicity (Kalsi 2011), acute respiratory distress syndrome (ARDS), viral infection, severe COVID-19 (Guloyan 2020), impaired mitochondrial electron transport chain function, uremia, rheumatoid arthritis, myocardial infarction (Teskey 2018), heart failure, cardiac structural abnormalities, and increased severity of ventricular dysfunction (Damy 2009).

Neurological disorders associated with low glutathione include compromised DNA repair, impaired myelin maturation, neuroinflammation, Alzheimer’s, Parkinson’s, and other neurodegenerative diseases (Iskusnykh 2022).

High total glutathione is associated with chemotherapy resistance (Traverso 2013), dyserythropoietic disorders (Kobayashi 2022), WBCs above 20x10(9)/L (which can falsely elevate glutathione levels by 25%), myelofibrosis, pyrimidine 5’-nucleotidase deficiency, and riboflavin supplementation (Mayo Clinic).

Overview    

L-gamma-glutamyl-cysteinyl-glycine), known as glutathione (GSH), is a tripeptide compound produced in the body from the amino acids cysteine, glutamic acid, and glycine. It is a major intracellular antioxidant that protects against oxidative stress, supports the detoxification of carcinogens and toxins, regulates protein function, and supports immune function, including activating lymphocytes and supporting natural killer cell activity. Maintaining adequate cell and tissue levels of GSH is vital to disease prevention and healthy aging. Tissue levels can quickly become depleted, such as with an overnight or extended fast. Even subtle GSH depletion contributes to immune dysfunction, toxin susceptibility, oxidative stress, and increased risk of cardiovascular disease, diabetes, arthritis, and cancer. Lack of the rate-limiting amino acid cysteine can impair endogenous GSH production. However, exogenous GSH from food and supplements can help replete blood and tissue levels (Richie 2015).

Glutathione is an integral component of the antioxidant enzyme family glutathione peroxidase (GPx), a selenoprotein that protects RBCs from hemolysis and reduces hydrogen peroxide (H202) to water (H20). Conversion of H202 to H20 oxidizes glutathione to its disulfide form (GSSG). However, the GSSG form can be converted back into GSH by glutathione reductase and NADPH. The GPx4 isoenzyme (PHGPx) protects against lipid peroxidation by reducing toxic lipid and fatty acid hydroperoxides, including derivatives of cholesterol, providing important neuroprotection (Guloyan 2020)

Glutathione is crucial for regulating DNA synthesis and repair, stabilizing cell membranes, protecting cells and proteins from oxidation, modulating cell differentiation, quenching reactive oxygen and nitrogen species, facilitating neurotransmission, and supporting myelin maturation. Glutathione is found in the highest concentration in the brain, especially in the glial cells of the cortex. Glutathione impairment in the brain leads to neuron loss associated with aging and neurological disorders, including stroke, Huntington’s, Parkinson’s, and Alzheimer’s (Iskusnykh 2022).

Glutathione is instrumental in the breakdown and excretion of industrial toxins, including mercury and persistent organic pollutants (POPs). Endogenous production of GSH can be negatively affected by genetic factors, malnutrition, protein insufficiency, hypochlorhydria, and increased exposure to toxins in the environment (Minich 2019). The association between glutathione and lead is more complex as GSH levels may be higher in those with lead toxicity (Gurer-Orhan 2004). However, the GSH to oxidized GSSG ratio can decrease with lead exposure, indicating increasing oxidative stress and glutathione depletion. Lead exposure is also associated with increased oxidative stress markers malondialdehyde (MDA) and GGT and decreased antioxidant markers, including serum carotenoids, vitamin C, and vitamin E (Vacchi-Suzzi 2018). Paracetamol (acetaminophen) can deplete glutathione, leading to potentially fatal hepatotoxicity, especially in individuals with low baseline intrahepatic glutathione status, including those with HIV, chronic hepatitis C, cystic fibrosis, malnutrition, and anorexia nervosa (Kalsi 2011).

Targeted nutrition support can promote glutathione levels. A randomized, double-blind, placebo-controlled study of oral GSH was conducted on 54 healthy non-smoking adults over six months, using a dose of 250 or 1000 mg/day compared to placebo. GSH levels were measured in whole blood, red blood cells, plasma, lymphocytes, and buccal mucosal cells. Most GSH is concentrated in RBCs, but small amounts are found in plasma, primarily in the oxidized forms of GSH disulfide (GSSG) and GSH protein mixed disulfides (GSSP). Measuring total GSH takes into account both oxidized and reduced GSH. Results from the study found (Richie 2015):

• Whole blood GSH increased significantly in both treatment groups starting at one month, while no increase was observed in the placebo group.
• RBC GSH increased significantly in the high-dose group after one month of supplementation but not until six months in the low-dose group.
• Lymphocyte GSH levels increased significantly in the high-dose group after one, three, and six months of supplementation but only after six months in the low-dose group. No changes occurred in the placebo group.
• Natural killer cell cytotoxicity increased significantly in the high-dose group and non-significantly in the low-dose group after three months of supplementation.
• The oxidized to reduced glutathione ratio decreased significantly in both the high and low-dose groups after six months, suggesting reduced oxidative stress.
• GSH levels decreased in both treatment groups after a 1-month washout period but remained significantly higher than baseline in the high-dose group.
• Long-term consistent dosing is recommended for optimizing glutathione levels

Consuming supplemental amino acid precursors of GSH can increase its production in the body. A two-week randomized controlled trial of GSH precursors N-acetylcysteine (NAC) and glycine found that total whole blood GSH increased in the subset of subjects with a significantly higher baseline level of oxidative stress. More significant oxidative stress was characterized by higher malondialdehyde, oxidized glutathione, and total cysteine, an indicator of higher oxidized cysteine (Lizzo 2022). The NAC form of cysteine or obtaining cysteine from whey is preferred as cysteine itself can be poorly absorbed. Consuming supplemental SAMe, alcohol-free beer, and almonds have also been found to promote GSH production. Meditation is also associated with higher glutathione levels (Pizzorno 2014).

Glutathione metabolism and endogenous production can be supported by vitamins B2, B12, pantothenic acid, C, and E, as well as selenium, alpha lipoic acid, omega-3s, and a variety of phytonutrients from fruits, vegetables, and green tea. Adequate intake of protein, especially cysteine from whey, can support endogenous GSH production. Glutathione can also be consumed in whole foods such as asparagus, avocado, green beans, and cucumbers. A Mediterranean-style diet is associated with less oxidized plasma glutathione. For individuals with impaired protein digestion and absorption, glutathione can be administered intravenously, sublingually, and in liposomal form (Minich 2019).

Glutathione can be recycled endogenously due to the action of gamma-glutamyl transferase (GGT). The GGT enzyme breaks down oxidized glutathione (GSSG) to provide cysteine for de novo GSH synthesis. Blood levels of GGT increase with oxidative stress and the need for GSH. Levels of GGT decrease with supplemental NAC or whey protein, reducing the need to recycle GSH (Pizzorno 2014).

Glutathione reductase (GR) is another enzyme that reduces oxidized GSSG to GSH. Higher GR levels are found in those with higher cognitive functioning and a lower risk of developing Alzheimer's disease. Researchers suggest GR be considered a potentially protective biomarker against cognitive decline and Alzheimer's (Park 2023). A significant increase in GSSG can be seen with diabetes and age-related macular degeneration, though low total glutathione may only be seen with diabetes (Samiec 1998).  

Summary of nutrients and foods for support of glutathione levels

Source: Minich, Deanna M, and Benjamin I Brown. “A Review of Dietary (Phyto)Nutrients for Glutathione Support.” Nutrients vol. 11,9 2073. 3 Sep. 2019, doi:10.3390/nu11092073. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

References  

Damy, Thibaud et al. “Glutathione deficiency in cardiac patients is related to the functional status and structural cardiac abnormalities.” PloS one vol. 4,3 (2009): e4871. doi:10.1371/journal.pone.0004871

Gurer-Orhan, Hande et al. “Correlation between clinical indicators of lead poisoning and oxidative stress parameters in controls and lead-exposed workers.” Toxicology vol. 195,2-3 (2004): 147-54. doi:10.1016/j.tox.2003.09.009

Kalsi, Sarbjeet S et al. “A review of the evidence concerning hepatic glutathione depletion and susceptibility to hepatotoxicity after paracetamol overdose.” Open access emergency medicine : OAEM vol. 3 87-96. 23 Dec. 2011, doi:10.2147/OAEM.S24963

Karkhanei, B et al. “Evaluation of oxidative stress level: total antioxidant capacity, total oxidant status and glutathione activity in patients with COVID-19.” New microbes and new infections vol. 42 (2021): 100897. doi:10.1016/j.nmni.2021.100897

Kobayashi, Akie et al. “Dyserythropoietic anaemia with an intronic GATA1 splicing mutation in patients suspected to have Diamond-Blackfan anaemia.” EJHaem vol. 3,1 163-167. 10 Jan. 2022, doi:10.1002/jha2.374 

Lang, Calvin A et al. “High blood glutathione levels accompany excellent physical and mental health in women ages 60 to 103 years.” The Journal of laboratory and clinical medicine vol. 140,6 (2002): 413-7. doi:10.1067/mlc.2002.129504

Lizzo, Giulia et al. “A Randomized Controlled Clinical Trial in Healthy Older Adults to Determine Efficacy of Glycine and N-Acetylcysteine Supplementation on Glutathione Redox Status and Oxidative Damage.” Frontiers in aging vol. 3 852569. 7 Mar. 2022, doi:10.3389/fragi.2022.852569 

Mayo Clinic, Glutathione, Blood. https://www.mayocliniclabs.com/test-catalog/overview/608409#Clinical-and-Interpretive

Minich, Deanna M, and Benjamin I Brown. “A Review of Dietary (Phyto)Nutrients for Glutathione Support.” Nutrients vol. 11,9 2073. 3 Sep. 2019, doi:10.3390/nu11092073

Park, Sang-A et al. “A Preliminary Study on the Potential Protective Role of the Antioxidative Stress Markers of Cognitive Impairment: Glutathione and Glutathione Reductase.” Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology vol. 21,4 (2023): 758-768. doi:10.9758/cpn.23.1053

Perez, Laura M et al. “Glutathione Serum Levels and Rate of Multimorbidity Development in Older Adults.” The journals of gerontology. Series A, Biological sciences and medical sciences vol. 75,6 (2020): 1089-1094. doi:10.1093/gerona/glz101

Pizzorno, Joseph. “Glutathione!.” Integrative medicine (Encinitas, Calif.) vol. 13,1 (2014): 8-12.

Richie, John P Jr et al. “Randomized controlled trial of oral glutathione supplementation on body stores of glutathione.” European journal of nutrition vol. 54,2 (2015): 251-63. doi:10.1007/s00394-014-0706-z

Traverso, Nicola et al. “Role of glutathione in cancer progression and chemoresistance.” Oxidative medicine and cellular longevity vol. 2013 (2013): 972913. doi:10.1155/2013/972913

Vacchi-Suzzi, Caterina et al. “Low levels of lead and glutathione markers of redox status in human blood.” Environmental geochemistry and health vol. 40,4 (2018): 1175-1185. doi:10.1007/s10653-017-0034-3

Waly, Mostafa I et al. “Low Nourishment of Vitamin C Induces Glutathione Depletion and Oxidative Stress in Healthy Young Adults.” Preventive nutrition and food science vol. 20,3 (2015): 198-203. doi:10.3746/pnf.2015.20.3.198