Glutathione (γ-L-Glutamyl-L-cysteinylglycine) is a peptide that is produced in the liver from the amino acids, L-cysteine, L-glutamic acid, and glycine. It functions as a powerful antioxidant used in every cell and tissue in the body, that inhibits the formation of, and protects against cellular damage from, free radicals. The 'glutathione system' comprises the enzymes that synthesize glutathione within a cell as well as dedicated enzymes that use glutathione as the means to exert antioxidant effects. It helps to defend the body against damage from cigarette smoking, exposure to radiation, cancer chemotherapy, and toxins, including but not limited to alcohol, glyphosate, and mycotoxins. As a detoxifier of heavy metals and pharmacologic drugs, it aids in the treatment of blood and liver disorders.
Glutathione protects cells in several ways. It neutralizes oxygen molecules before they can harm cells. Together with selenium, glutathione forms the enzyme glutathione peroxidase, which neutralizes hydrogen peroxide. It also is a component of another antioxidant enzyme, glutathione-S-transferase, which is a board-spectrum liver-detoxifying enzyme.
Glutathione protects not only individual cells but also the tissues of the arteries, brain, heart, immune cells, kidneys, lenses of the eyes, liver, lungs, and skin against oxidant damage. It plays a role in preventing cancer, especially liver cancer, and may actually target carcinogens, make them water-soluble (phase-2 detoxification), and then help eliminate them from the body. Because of this mechanism, glutathione may also be considered an antiaging compound. The rate at which humans age is directly correlated with reduced levels of glutathione in cellular fluids; as we grow older, glutathione levels drop, resulting in a decreased ability to deactivate free radicals.
Glutathione protects not only individual cells but also the tissues of the arteries, brain, heart, immune cells, kidneys, lenses of the eyes, liver, lungs, and skin against oxidant damage. It plays a role in preventing cancer, especially liver cancer, and may actually target carcinogens, make them water-soluble (phase-2 detoxification), and then help eliminate them from the body. Because of this mechanism, glutathione may also be considered an antiaging compound. The rate at which humans age is directly correlated with reduced levels of glutathione in cellular fluids; as we grow older, glutathione levels drop, resulting in a decreased ability to deactivate free radicals.
Pharmacologic Mechanisms of action
This tripeptide plays a central role in maintaining cellular health and protecting against oxidative stress, and exerts its beneficial effects through various mechanisms of action, including:
Here is a comprehensive view of the pharmacologic mechanisms of actions with respect to glutathione:
- Free Radical Scavenging: Glutathione acts as a powerful antioxidant by neutralizing free radicals, unstable molecules that can damage cells and contribute to aging and various diseases. It donates electrons to neutralize these radicals, preventing cellular damage.
- Regeneration of Other Antioxidants: Glutathione helps regenerate other antioxidants, such as vitamins C and E. After these antioxidants neutralize free radicals, they become oxidized. Glutathione helps restore them to their active, antioxidant forms.
- Phase II Detoxification: Glutathione plays a vital role in the detoxification process, particularly in phase II of liver detox pathways. It binds to toxins, heavy metals, and harmful substances, making them water-soluble and easier to eliminate from the body.
- Conjugation Reactions: Glutathione conjugates with toxins and facilitates their elimination through urine and bile. This process helps protect cells from the damaging effects of accumulated toxins.
- Immune Cell Function: Glutathione supports the proper functioning of immune cells. It enhances the activity of T cells, which are crucial for the body's defense against infections and abnormal cells.
- Reduction of Oxidative Stress: By reducing oxidative stress, glutathione helps modulate immune responses. Excessive oxidative stress can compromise the immune system's ability to respond effectively.
- DNA Repair: Glutathione contributes to DNA repair processes, helping to maintain the integrity of the genetic material within cells. This is crucial for preventing mutations and maintaining normal cellular function.
- Protein Synthesis: Glutathione plays a role in protein synthesis, supporting the production of enzymes and proteins necessary for various cellular functions.
- Modulation of Inflammation: Glutathione helps regulate inflammation by reducing oxidative stress and inhibiting the activation of inflammatory signaling pathways. This anti-inflammatory effect contributes to overall cellular and tissue health.
- Mitochondrial Function: Glutathione supports mitochondrial function, the energy-producing organelles within cells. Healthy mitochondrial function is crucial for overall cellular energy metabolism.
- Neuroprotection: Glutathione is essential for protecting the brain from oxidative damage. It helps maintain the integrity of neurons and supports cognitive function.
Here is a comprehensive view of the pharmacologic mechanisms of actions with respect to glutathione:
Immunomodulatory / Immunostimulatory |
Antioxidant |
Tumor Necrosis Factor (TNF) Alpha Inhibitor |
Calcium Channel Blockers |
Malondialdehyde Down-regulation |
Regenerative |
Neuroprotective Agent |
Anti-Inflammatory Agent |
Cardioprotective |
Chemoprotective Agent |
Detoxifier |
Gastroprotective |
Photoprotective |
Antiviral Agent |
Enzyme Inhibitor |
Heme oxygenase-1 up-regulation |
Nrf2 activation |
Radioprotective |
Glutathione serves as a master antioxidant and cellular defender through its multifaceted actions. By neutralizing free radicals, supporting detoxification, aiding in immune responses, facilitating cellular repair, modulating inflammation, and promoting overall cellular health, glutathione plays a pivotal role in maintaining optimal physiological function and preventing various health issues.
harmony with Melatonin
Recently, scientific inquiry has shed light on the intriguing link between melatonin, the sleep-regulating hormone, and the regulation of glutathione. Unraveling this connection opens up new avenues for understanding how lifestyle and nutrition factors influence not only sleep but also cellular health and resilience.
Melatonin, primarily known for its role in regulating circadian rhythms and promoting restful sleep, showcases a newfound significance in the intricate regulation of glutathione levels. Research suggests that melatonin acts as a potent stimulator of glutathione synthesis within cells, enhancing the antioxidant defense system. This interplay underscores the broader impact of melatonin beyond its conventional association with sleep. The implications of this connection for cellular health include:
While the melatonin-glutathione connection presents a promising avenue for cellular health, certain lifestyle and nutrition factors can impair melatonin production, potentially affecting this delicate balance. Consider the following factors:
The melatonin-glutathione interplay highlights the intricate connections within our body's biochemical network. As we delve deeper into the implications of this relationship, understanding the lifestyle and nutrition factors that influence melatonin production becomes paramount. By adopting healthy sleep habits, ensuring nutrient adequacy, and minimizing disruptive environmental factors, individuals can potentially enhance both their sleep quality and cellular defense mechanisms, paving the way for improved overall well-being.
Melatonin, primarily known for its role in regulating circadian rhythms and promoting restful sleep, showcases a newfound significance in the intricate regulation of glutathione levels. Research suggests that melatonin acts as a potent stimulator of glutathione synthesis within cells, enhancing the antioxidant defense system. This interplay underscores the broader impact of melatonin beyond its conventional association with sleep. The implications of this connection for cellular health include:
- Enhanced Antioxidant Defense: The collaboration between melatonin and glutathione fortifies the cellular defense against oxidative stress. As melatonin boosts glutathione levels, cells become more resilient to the damaging effects of free radicals, contributing to overall health and longevity.
- Detoxification Support: Glutathione is a critical player in cellular detoxification, aiding in the removal of harmful substances. Melatonin's influence on glutathione suggests a potential role in supporting the body's detox processes, highlighting the hormone's multifaceted impact on cellular health.
While the melatonin-glutathione connection presents a promising avenue for cellular health, certain lifestyle and nutrition factors can impair melatonin production, potentially affecting this delicate balance. Consider the following factors:
- Disrupted Sleep Patterns: Irregular sleep patterns and disturbances, often induced by excessive screen time or irregular work schedules, can hinder melatonin production, consequently affecting the regulation of glutathione.
- Nutrient Deficiencies: Adequate levels of nutrients like magnesium, zinc, and vitamin B6 are crucial for melatonin synthesis. Nutrient deficiencies may compromise melatonin production and, subsequently, impact glutathione levels.
- Excessive Artificial Light Exposure: Prolonged exposure to artificial light, especially blue light emitted by electronic devices, can suppress melatonin production. Limiting screen time before bedtime and creating a conducive sleep environment can mitigate this effect.
- Poor Dietary Choices: Diets lacking in antioxidant-rich foods may impair the body's ability to produce glutathione effectively. A balanced and nutrient-dense diet contributes to optimal glutathione synthesis.
The melatonin-glutathione interplay highlights the intricate connections within our body's biochemical network. As we delve deeper into the implications of this relationship, understanding the lifestyle and nutrition factors that influence melatonin production becomes paramount. By adopting healthy sleep habits, ensuring nutrient adequacy, and minimizing disruptive environmental factors, individuals can potentially enhance both their sleep quality and cellular defense mechanisms, paving the way for improved overall well-being.
Boosting glutathione
While lower levels of this powerful antioxidant can contribute to many health issues – including conditions more likely to develop in older people – there are many ways you can help ensure the body has the glutathione it needs.
The body naturally produces glutathione; however, diet plays an important role – if you eat the right foods. Focusing on unprocessed antioxidant- and sulfur-rich foods is key to building your glutathione levels. On the other hand, the modern American diet with its high levels of seed oils wreak havoc on your glutathione levels. It will be vital for you to lower your seed oils and linoleic acid intake by avoiding all processed foods, only cooking with ghee or beef tallow as an oil and avoiding chicken, pork and nearly all restaurant food.
The body naturally produces glutathione; however, diet plays an important role – if you eat the right foods. Focusing on unprocessed antioxidant- and sulfur-rich foods is key to building your glutathione levels. On the other hand, the modern American diet with its high levels of seed oils wreak havoc on your glutathione levels. It will be vital for you to lower your seed oils and linoleic acid intake by avoiding all processed foods, only cooking with ghee or beef tallow as an oil and avoiding chicken, pork and nearly all restaurant food.
- Eat a sulfur-rich diet: You need sulfur for your body to make glutathione. The best food sources of sulfur include cruciferous vegetables, including but not limited to broccoli, Brussels sprouts, cauliflower, garlic and onions, as well as the proteins beef, fish and poultry.
- Exercise: Although exercise can cause oxidative stress, it leads to the production of more glutathione. Researchers have found that adults who exercised regularly had higher levels of glutathione. Even sedentary individuals had improved levels once they started working out. Aerobic training combined with circuit weight training produced the greatest benefit.
- Get enough restful sleep: A good night’s sleep increases the body’s ability to produce more glutathione. Plus, studies show that people who have high levels of glutathione fall asleep faster and wake up feeling more refreshed.
- Reduce or eliminate alcohol: Alcohol is known to deplete glutathione, which boosts free radical damage and weakens immune function, and allows toxins to accumulate in the body.
- Expose your skin to near infrared light: By exposing the skin to near infrared light, you increase melatonin levels, which causes your body to produce glutathione. You can do this with sunshine or near infrared bulbs on the bare skin.
- Supplement with molecular hydrogen: Supplemental molecular hydrogen increases the body's glutathione levels through its effects on genetic expression that produce glutathione and other antioxidants.
- Try glutathione-boosting supplements: Supplements like milk thistle, whey protein, N-Acetyl Cysteine (NAC) and turmeric or curcumin can help boost and maintain glutathione levels.
Supplementation
Supplementation of glutathione is thought to support this pool of glutathione in a cell and thus maintain the efficacy of the entire glutathione system. Despite the pervasive role of glutathione in cell biology, it currently has a limited role in nutritional supplementation due to the following pharmacokinetic properties:
Although oral glutathione supplementation does not efficiently increase intracellular glutathione levels for the above reasons, it can be absorbed intact into the blood stream. Since increased glutathione levels in the blood have been shown to slow the breakdown of nitric oxide, glutathione supplementation may be useful to augment nitric oxide boosters such as L-citrulline or L-arginine.
Perhaps the most effective route of administration with respect to absorption of glutathione is nebulization. The production of glutathione by the body can be boosted by taking other supplemental compounds including dehydroepiandrosterone (DHEA), a hormone; and N-acetylcysteine. Some suggest supplementing with these precursors may be better than taking glutathione orally.
- There may be some absorption of glutathione intact from the intestines, but it cannot enter cells intact. It must be metabolized to form L-cystine (two molecules of L-cysteine bound together) before being taken up.
- Provision of L-cysteine within the cell is all that is needed to increase glutathione synthesis, and N-Acetylcysteine does this efficiently at a lower financial cost than glutathione.
Although oral glutathione supplementation does not efficiently increase intracellular glutathione levels for the above reasons, it can be absorbed intact into the blood stream. Since increased glutathione levels in the blood have been shown to slow the breakdown of nitric oxide, glutathione supplementation may be useful to augment nitric oxide boosters such as L-citrulline or L-arginine.
Perhaps the most effective route of administration with respect to absorption of glutathione is nebulization. The production of glutathione by the body can be boosted by taking other supplemental compounds including dehydroepiandrosterone (DHEA), a hormone; and N-acetylcysteine. Some suggest supplementing with these precursors may be better than taking glutathione orally.
Supplements to consider
Too little glutathione may be a major driver of the oxidative stress and mitochondrial dysfunction that lead to age-related degeneration. As mentioned, oral glutathione supplementation is not considered optimal. However, researchers have observed that glutathione in liposomal form offers three times greater intestinal absorption, compared to regular, non-liposomal glutathione.
Liposomal delivery is an advanced technology that allows nutrients to reach your body effectively without being broken down by the digestive system. Supplements encapsulated with liposomes enhance the ability of that substance to integrate into the fatty membranes that line each cell in our bodies. Liposomes can be likened as little bubbles that protect the nutrients until they reach your intestines, ensuring that your body absorbs them properly.
Here is a great supplement to glutathione, secondary to glutathione in the nebulized form:
Liposomal delivery is an advanced technology that allows nutrients to reach your body effectively without being broken down by the digestive system. Supplements encapsulated with liposomes enhance the ability of that substance to integrate into the fatty membranes that line each cell in our bodies. Liposomes can be likened as little bubbles that protect the nutrients until they reach your intestines, ensuring that your body absorbs them properly.
Here is a great supplement to glutathione, secondary to glutathione in the nebulized form:
references
Aukrust P, Svardal AM, Müller F, Lunden B, Berge RK, Frøland SS. Decreased levels of total and reduced glutathione in CD4+ lymphocytes in common variable immunodeficiency are associated with activation of the tumor necrosis factor system: possible immunopathogenic role of oxidative stress. Blood. 1995 Aug 15;86(4):1383-91. PMID: 7632946.
Di Loreto S, Falone S, Caracciolo V, Sebastiani P, D'Alessandro A, Mirabilio A, Zimmitti V, Amicarelli F. Fifty hertz extremely low-frequency magnetic field exposure elicits redox and trophic response in rat-cortical neurons. J Cell Physiol. 2009 May;219(2):334-43. doi: 10.1002/jcp.21674. PMID: 19115234.
Kaur P, Aschner M, Syversen T. Glutathione modulation influences methyl mercury induced neurotoxicity in primary cell cultures of neurons and astrocytes. Neurotoxicology. 2006 Jul;27(4):492-500. doi: 10.1016/j.neuro.2006.01.010. Epub 2006 Mar 2. PMID: 16513172.
Schulz JB, Lindenau J, Seyfried J, Dichgans J. Glutathione, oxidative stress and neurodegeneration. Eur J Biochem. 2000 Aug;267(16):4904-11. doi: 10.1046/j.1432-1327.2000.01595.x. PMID: 10931172.
García-Giménez JL, Romá-Mateo C, Pérez-Machado G, Peiró-Chova L, Pallardó FV. Role of glutathione in the regulation of epigenetic mechanisms in disease. Free Radic Biol Med. 2017 Nov;112:36-48. doi: 10.1016/j.freeradbiomed.2017.07.008. Epub 2017 Jul 10. PMID: 28705657.
Kwon DH, Lee H, Park C, Hong SH, Hong SH, Kim GY, Cha HJ, Kim S, Kim HS, Hwang HJ, Choi YH. Glutathione Induced Immune-Stimulatory Activity by Promoting M1-Like Macrophages Polarization via Potential ROS Scavenging Capacity. Antioxidants (Basel). 2019 Sep 18;8(9):413. doi: 10.3390/antiox8090413. PMID: 31540482; PMCID: PMC6770173.
Liao N, Shi Y, Zhang C, Zheng Y, Wang Y, Zhao B, Zeng Y, Liu X, Liu J. Antioxidants inhibit cell senescence and preserve stemness of adipose tissue-derived stem cells by reducing ROS generation during long-term in vitro expansion. Stem Cell Res Ther. 2019 Oct 17;10(1):306. doi: 10.1186/s13287-019-1404-9. PMID: 31623678; PMCID: PMC6798439.
Sinha R, Sinha I, Calcagnotto A, Trushin N, Haley JS, Schell TD, Richie JP Jr. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. Eur J Clin Nutr. 2018 Jan;72(1):105-111. doi: 10.1038/ejcn.2017.132. Epub 2017 Aug 30. PMID: 28853742; PMCID: PMC6389332.
H. Limon-Pacheco, Jorge, and Maria E. Gonsebatt. “The Glutathione System and Its Regulation by Neurohormone Melatonin in the Central Nervous System.” Central Nervous System Agents in Medicinal Chemistry, vol. 10, no. 4, 1 Dec. 2010, pp. 287–297, https://doi.org/10.2174/187152410793429683.
Di Loreto S, Falone S, Caracciolo V, Sebastiani P, D'Alessandro A, Mirabilio A, Zimmitti V, Amicarelli F. Fifty hertz extremely low-frequency magnetic field exposure elicits redox and trophic response in rat-cortical neurons. J Cell Physiol. 2009 May;219(2):334-43. doi: 10.1002/jcp.21674. PMID: 19115234.
Kaur P, Aschner M, Syversen T. Glutathione modulation influences methyl mercury induced neurotoxicity in primary cell cultures of neurons and astrocytes. Neurotoxicology. 2006 Jul;27(4):492-500. doi: 10.1016/j.neuro.2006.01.010. Epub 2006 Mar 2. PMID: 16513172.
Schulz JB, Lindenau J, Seyfried J, Dichgans J. Glutathione, oxidative stress and neurodegeneration. Eur J Biochem. 2000 Aug;267(16):4904-11. doi: 10.1046/j.1432-1327.2000.01595.x. PMID: 10931172.
García-Giménez JL, Romá-Mateo C, Pérez-Machado G, Peiró-Chova L, Pallardó FV. Role of glutathione in the regulation of epigenetic mechanisms in disease. Free Radic Biol Med. 2017 Nov;112:36-48. doi: 10.1016/j.freeradbiomed.2017.07.008. Epub 2017 Jul 10. PMID: 28705657.
Kwon DH, Lee H, Park C, Hong SH, Hong SH, Kim GY, Cha HJ, Kim S, Kim HS, Hwang HJ, Choi YH. Glutathione Induced Immune-Stimulatory Activity by Promoting M1-Like Macrophages Polarization via Potential ROS Scavenging Capacity. Antioxidants (Basel). 2019 Sep 18;8(9):413. doi: 10.3390/antiox8090413. PMID: 31540482; PMCID: PMC6770173.
Liao N, Shi Y, Zhang C, Zheng Y, Wang Y, Zhao B, Zeng Y, Liu X, Liu J. Antioxidants inhibit cell senescence and preserve stemness of adipose tissue-derived stem cells by reducing ROS generation during long-term in vitro expansion. Stem Cell Res Ther. 2019 Oct 17;10(1):306. doi: 10.1186/s13287-019-1404-9. PMID: 31623678; PMCID: PMC6798439.
Sinha R, Sinha I, Calcagnotto A, Trushin N, Haley JS, Schell TD, Richie JP Jr. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. Eur J Clin Nutr. 2018 Jan;72(1):105-111. doi: 10.1038/ejcn.2017.132. Epub 2017 Aug 30. PMID: 28853742; PMCID: PMC6389332.
H. Limon-Pacheco, Jorge, and Maria E. Gonsebatt. “The Glutathione System and Its Regulation by Neurohormone Melatonin in the Central Nervous System.” Central Nervous System Agents in Medicinal Chemistry, vol. 10, no. 4, 1 Dec. 2010, pp. 287–297, https://doi.org/10.2174/187152410793429683.
