Glutathione

Glutathione Research

What is the research background of Glutathione?

The discovery and structural determination of glutathione: In 1888, glutathione was first discovered in yeast. In 1921, scientists further determined its chemical structure. It is a tripeptide formed by the condensation of glutamic acid, cysteine, and glycine through peptide bonds.

Recognition of its important roles in living organisms: Since the 1930s, people have gradually recognized that glutathione has a variety of important functions in living organisms. It participates in the redox reactions within cells, playing a key role in maintaining the stability of the intracellular environment and protecting cells from oxidative damage. At the same time, it also plays an important role in physiological processes such as amino acid transport and regulation of enzyme activity. These discoveries have laid a theoretical foundation for the application of glutathione in the medical field.

Research on sources driven by medical application demands: With the deepening of research on the physiological functions of glutathione, its potential application value in the medical field has become increasingly prominent. It is used to treat a variety of diseases, such as liver diseases and eye diseases, and can also be used as an antioxidant. In order to meet the large demand for glutathione in clinical applications, researchers began to devote themselves to exploring efficient and stable sources of glutathione, which has promoted in-depth research on its sources.

What is the mechanism of action of Glutathione?

1. Antioxidant effect

Glutathione (GSH) is an effective antioxidant that participates in the antioxidant defense system within cells. It can directly react with reactive oxygen species (ROS) such as hydrogen peroxide (H₂O₂) and reduce them to harmless substances (Reddy V N. 1990; Sinha R, 2018). For example, through the glutathione redox cycle, glutathione reacts with H₂O₂ and converts it into water, thereby protecting cells from oxidative damage. In this process, glutathione is oxidized to oxidized glutathione (GSSG), but the glutathione reductase in the cell can reduce GSSG back to GSH, maintaining the antioxidant capacity of the cell.

Glutathione can also protect the -SH groups on the cell membrane, which play an important role in cation transport and membrane permeability. By maintaining the reduced state of the membrane -SH groups, glutathione helps to maintain the stability and normal function of the cell membrane^[1].

2. Detoxification effect

Glutathione plays an important role in the detoxification process. It can bind to toxins to form non-toxic or low-toxic compounds and promote their excretion from the body. For example, in the liver, glutathione binds to various harmful substances and is excreted from the body through bile or urine, protecting liver cells from the damage of toxins. The liver is the main detoxification organ of the human body, and the role of glutathione in it is crucial.

3. Influence on the immune system

Glutathione has important functions in immune cells. In macrophages, natural killer cells, and T cells, for example, it can regulate cell activation, metabolism, appropriate cytokine release, redox activity, and free radical levels^[2]. Immune cells play a key role in combating pathogens and maintaining the health of the body. Glutathione enhances the body's immune ability by regulating the functions of these cells.

Glutathione can stabilize redox activity, shift the cytokine profile towards a Th1-type response, and enhance the function of T lymphocytes, thus playing an important immunomodulatory and antioxidant role^[2]. Th1-type cytokines are mainly involved in cellular immune responses against pathogens such as viruses, bacteria, and tumor cells. Glutathione enhances the body's immune defense ability by regulating the balance of cytokines.

4. Role in the reproductive system

Glutathione plays an important role in the male and female germ cells of mammals as well as in the early stages of embryonic development. In male and female gametes, GSH is involved in protecting these cells from oxidative damage^[3]. For example, during spermatogenesis, the concentration of glutathione gradually decreases, and during oocyte maturation, the synthesis of glutathione is regulated by gonadotropins, and its concentration also changes. Glutathione is also related to maintaining the morphology of the meiotic spindle of the oocyte. After fertilization, it plays a positive role in the formation of the male pronucleus and the development of the early embryo to the blastocyst stage. In addition, cumulus cells also play an important role in the synthesis of glutathione.

What are the applications of Glutathione?

1. Application in alcoholic liver disease

Alcoholic liver disease (ALD) is a serious disease characterized by severe oxidative stress. Chronic alcohol use can trigger oxidative stress and inflammation, damaging liver cells. Glutathione (GSH), a tripeptide composed of γ-glutamylcysteineylglycine containing a thiol group, participates in redox reactions and is the main free radical scavenger within cells. In the liver, the concentration of GSH is relatively high, but in patients with ALD, its endogenous level decreases, exacerbating the condition.

Intravenous supplementation of GSH has shown good effects in patients with ALD, being able to improve liver function and reduce fibrosis markers^[4].

2. Role in delaying aging

In a randomized, double-blind, placebo-controlled, parallel, three-arm study of healthy female subjects, the melanin index and ultraviolet spots on the face and arms of subjects taking GSH or GSSG were often lower than those of the placebo group. In some areas, the wrinkles of subjects taking GSH were significantly reduced, and compared with the placebo group, the skin elasticity of the GSH and GSSG groups showed a tendency to increase. This study indicates that glutathione has a positive effect on delaying skin aging^[5].

2. Application in Parkinson's disease

Parkinson's disease (PD) is a neurological disorder. Research shows that glutathione (GSH) may have a certain therapeutic effect on PD. Through a systematic search of multiple databases and meta-analysis, it was found that there was a statistically significant difference in the Unified Parkinson's Disease Rating Scale (UPDRS) III between GSH and the control group, and there was also a significant difference in glutathione peroxidase. However, there were no statistically significant differences between the two groups in UPDRS I and UPDRS II scores and side effects. In addition, subgroup analysis showed that the dose (300mg vs 600mg) was a factor affecting UPDRS III. This indicates that GSH may slightly improve the motor scores of PD without increasing the occurrence of adverse events^[6].

3. Application in cardiovascular diseases

Prevention of cardiovascular diseases: In cardiovascular diseases such as coronary artery obstruction, hypertensive heart disease, and stroke, many cardiovascular pathologies generate a state of oxidative stress during their development, leading to the deterioration of patients' conditions, which is related to the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Reduced glutathione (GSH), as an important antioxidant, can participate in combating the oxidation of active substances. GSH is synthesized in the heart and liver and is of great significance for preventing or reducing the harmful ROS effects in cardiovascular diseases^[7].

In cardiovascular diseases: Lower circulating glycine levels are associated with cardiovascular disease (CVD). Studies have found that glycine deficiency enhances the development of atherosclerosis, while glycine supplementation weakens it. DT-109 is a glycine-based compound with dual lipid-lowering/glucose-lowering properties and has a significant protective effect against atherosclerosis. Studies on patients with coronary heart disease, atherosclerotic mice, and macrophages have shown that glycine has a pathogenic role in atherosclerosis, and glycine-based treatment can alleviate atherosclerosis through the antioxidant effect of inducing glutathione biosynthesis ^[8].

Source:PubMed^[8]

4. Application in the prevention and treatment of eye diseases

Prevention and treatment of cataracts: In ophthalmology, glutathione can be used for the prevention and treatment of cataracts. Research shows that the occurrence of cataracts is closely related to oxidative damage in the lens. As an antioxidant, glutathione can reduce the impact of oxidative damage on lens cells and maintain the normal function of the lens. For example, in a study, eye drops containing glutathione were used to treat cataract patients, and it was observed that the degree of lens opacity of the patients was reduced, and their vision was improved to a certain extent ^[9].

Prevention and treatment of retinopathy: Retinopathy is a common eye disease, and its occurrence is related to factors such as oxidative stress and inflammatory response. Glutathione can, through its antioxidant effect, reduce the oxidative damage of the retinal tissue, inhibit the inflammatory response, and thus protect retinal cells. In addition, glutathione can also promote the metabolic function of retinal cells and enhance the self-repair ability of the retina^[9].

5. Application in multiple sclerosis

In multiple sclerosis, neuronal degeneration is related to oxidative stress. Dimethyl fumarate (DMF) is an effective oral treatment option that has been proven to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. DMF can activate the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), leading to an increase in the synthesis of the main cellular antioxidant glutathione (GSH), and has a significant neuroprotective effect in vitro. Studies have found that DMF does induce glutathione reductase (GSR), increasing the recycling of glutathione by inducing GSR^[10].

6. Application in Alzheimer's disease

In Alzheimer's disease, amyloid β peptide (Aβ) is considered one of the important causes of Alzheimer's disease (AD). Ferroptosis is a newly recognized mechanism of oxidative cell death that is highly related to AD. Tetrahydroxystilbene glucoside (TSG) is beneficial in relieving learning and memory in AD and aged mouse models. Studies have found that TSG resists the neurotoxic death of nerve cells caused by Aβ by regulating ferroptosis-related proteins and enzymes in APP/PS1 mice, alleviates cellular oxidative stress and inflammatory damage, and promotes the activation of the GSH/GPX4/ROS and Keap1/Nrf2/ARE signaling pathways. In addition, TSG also reduces the expression of markers related to ferroptosis and enhances the ability to resist oxidative stress ^[11].

7. Adjuvant treatment of respiratory diseases

Adjuvant treatment of chronic obstructive pulmonary disease (COPD): For patients with chronic obstructive pulmonary disease, airway inflammation and oxidative stress are important factors leading to the progression of the disease. Glutathione can alleviate airway inflammation and improve respiratory function through its antioxidant effect. It can scavenge free radicals in the airway, reduce the damage of oxidative stress to airway epithelial cells, and thus relieve airway inflammation. In addition, glutathione can also regulate immune function and enhance the body's resistance to pathogens ^[12].

8. Application in islet diseases

The glutathione reductase and glutathione peroxidase were evaluated in the serum of patients with islet diseases and diabetic patients. Research shows that in this disease, the imbalance of the ratio of oxidants to antioxidants may be related to the condition, and the specific mechanism remains to be further studied^[13].

Conclusions

As a tripeptide compound composed of glutamic acid, cysteine, and glycine, glutathione plays a variety of key roles in living organisms, such as antioxidation, detoxification, immune regulation, and influence on the reproductive system. Since its discovery, with the deepening of research, its application value in the medical field has been continuously highlighted, showing positive effects in the treatment or prevention of a variety of diseases such as alcoholic liver disease, Parkinson's disease, cardiovascular diseases, and eye diseases. Although the application mechanisms in some aspects and the details of its roles in certain diseases remain to be further explored, glutathione is of great significance in maintaining the health of the body and preventing and treating diseases.

Relevant Citations

[1]  Reddy V N. Glutathione and its function in the lens-an overview.[J]. Experimental Eye Research, 1990,50(6):771-778.DOI:10.1016/0014-4835(90)90127-G.

[2]  Abnousian A, Vasquez J, Sasaninia K, et al. Glutathione Modulates Efficacious Changes in the Immune Response against  Tuberculosis[J]. Biomedicines, 2023,11(5).DOI:10.3390/biomedicines11051340.

[3]  Ogunfolaju E. Glutathione[M]. 2020.https://www.researchgate.net/publication/344526535_Glutathione.

[4]  Ck D A. Intravenous Glutathione: A Promising Therapy for the Alcoholic Liver Disease[J]. Journal of Medical Science and Clinical Research, 2024.

[5]  Weschawalit S, Thongthip S, Phutrakool P, et al. Glutathione and its antiaging and antimelanogenic effects[J]. Clinical Cosmetic and Investigational Dermatology, 2017,10:147-153.DOI:10.2147/CCID.S128339.

[6]  Wang H, Zhang J, Li Y, et al. Potential use of glutathione as a treatment for Parkinson's disease[J]. Experimental and Therapeutic Medicine, 2021,21(2):125.DOI:10.3892/etm.2020.9557.

[7]  Matuz-Mares D, Riveros-Rosas H, Vilchis-Landeros M M, et al. Glutathione Participation in the Prevention of Cardiovascular Diseases[J]. Antioxidants, 2021,10(8).DOI:10.3390/antiox10081220.

[8]  Rom O, Liu Y, Finney A C, et al. Induction of glutathione biosynthesis by glycine-based treatment mitigates  atherosclerosis[J]. Redox Biology, 2022,52:102313.DOI:10.1016/j.redox.2022.102313.

[9]  Ganeshpurkar A, Bhadoriya S S, Pardhi P, et al. In vitro prevention of cataract by Oyster Mushroom Pleurotus florida extract on  isolated goat eye lens[J]. Indian Journal of Pharmacology, 2011,43(6):667-670.DOI:10.4103/0253-7613.89823.

[10] Hoffmann C, Dietrich M, Herrmann A, et al. Dimethyl Fumarate Induces Glutathione Recycling by Upregulation of Glutathione Reductase[J]. Oxidative Medicine and Cellular Longevity, 2017,2017.DOI:10.1155/2017/6093903.

[11] Gao Y, Li J, Wu Q, et al. Tetrahydroxy stilbene glycoside ameliorates Alzheimer's disease in APP/PS1 mice  via glutathione peroxidase related ferroptosis[J]. International Immunopharmacology, 2021,99:108002.DOI:10.1016/j.intimp.2021.108002.

[12] Dewan B, Shinde S. Glutathione an Effective Adjuvant Therapy for Acute Respiratory Distress Syndrome Associated with COVID-19 Infection[J]. Journal of Advances in Medicine and Medical Research, 2022.DOI: https://doi.org/10.4103/jrms.jrms_777_20.

[13] Khaki L, Vaezi G, Ayatollahi A, et al. Evaluation of Glutathione Reductase and Glutathione Peroxidase in the Serum of Iranian Patients with Alopecia Areata: A Case-control Study[J]. Iranian Journal of Allergy Asthma and Immunology, 2020,19(6):676-678.DOI:10.18502/ijaai.v19i6.4937.