Short Description and History
Glutathione was discovered by J. de Rey-Paihade in 1888 from extracts of yeast and many animal tissues (beef skeletal muscle and liver, fish skeletal muscle, lamb small intestine, and sheep brain) and in fresh egg white.
Glutathione, also known as GSH, is a molecule found naturally in your body. It is produced by the liver and nerve cells in the central nervous system. Glutathione is made up of three amino acids: L-cysteine, glycine, and L-glutamate.
It is an antioxidant, a molecule that helps fight free radicals. Free radicals are unstable molecules that form in response to factors like your diet and the environment. When more free radicals exist than antioxidants, oxidative cell damage occurs. This can lead to inflammation and a variety of health issues ranging from high blood pressure and diabetes to Alzheimer’s disease and more.
Antioxidants are critical as they help keep things in healthy balance. Your body makes some antioxidants, but others come from external sources like your diet or supplements like GSH. Proponents claim that glutathione supplements can help treat and prevent a number of health conditions, from heart disease to Alzheimer’s disease.
Glutathione is readily found in certain foods, such as fruits and vegetables. A study published in Nutrition and Cancer found that dairy products, cereals, and breads are generally low in GSH. Fruits and vegetables have moderate to high amounts of GSH, and freshly prepared meats are relatively high in GSH.
According to limited research, increasing the body’s glutathione through diet or supplements can help with certain health conditions.
What is Glutathione?
Glutathione is a tripeptide (cysteine, glycine, and glutamic acid) found in surprisingly high levels—5 millimolar—concentrations in most cells. As can be seen in the figure below, this is the same concentration in cells as glucose, potassium, and cholesterol! Considering the high level of metabolic activity required to produce glutathione, such a high level underlines its importance.
Figure 1: Concentrations of Molecules in Cells
Glutathione exists in cells in 2 states: reduced (GSH) and oxidized (GSSG). As can be seen in Figure 2 below, oxidized glutathione is actually 2 reduced glutathiones bound together at the sulfur atoms.
Figure 2: Balance Between GSH and GSSG
Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and protein glutathionylation).
Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including kwashiorkor, seizure, Alzheimer’s disease, Parkinson’s disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases.
How does Glutathione work?
Glutathione is involved in the detoxification of both xenobiotic and endogenous compounds. It facilitates excretion from cells (Hg), facilitates excretion from body (POPs, Hg) and directly neutralizes (POPs, many oxidative chemicals). Glutathione facilitates the plasma membrane transport of toxins by at least 4 different mechanisms, the most important of which is formation of glutathione S-conjugates. Low levels of glutathione and/or transferase activity are also associated with chronic exposure to chemical toxins and alcohol, cadmium exposure, AIDS/HIV, macular degeneration, Parkinson’s disease, and other neurodegenerative disorders.
Glutathione directly scavenges diverse oxidants: superoxide anion, hydroxyl radical, nitric oxide, and carbon radicals. Glutathione catalytically detoxifies: hydroperoxides, peroxynitrites, and lipid peroxides. Another way glutathione protects cells from oxidants is through recycling of vitamins C and E.
Figure 3: Glutathione Protection via Recycling
Abbreviations: APx = ascorbate peroxidase; CAT = catalase; DHA = dehydroascorbate; DHAR = dehydroascorbate reductase; MDHA = monodehydroascorbate; MDHAR = monodehydroascorbate reductase; GR = glutathione reductase; GSH = reduced glutathione; GSSG = glutathione disulphide; SOD = superoxide dismutase.
Another indication of the key roles of glutathione in health is that the accumulation of GSSG due to oxidative stress is directly toxic to cells, inducing apoptosis by activation of the SAPK/MAPK pathway. Glutathione depletion triggers apoptosis, although it is unclear whether it is mitochondria or cytosol pools of GSH that are the determining factor.
Perhaps the best indicator of the importance of glutathione is that its cellular and mitochondrial levels directly are highly associated with health and longevity.
What have Research Studies Shown?
Scientific research has revealed that Glutathione can do the following:
• Antioxidant activity
• Prevent cancer progression
• Reduce cell damage in liver disease
• Improve insulin sensitivity
• Reduce symptoms of Parkinson’s disease
• Reduce ulcerative colitis damage
• Treating autism spectrum disorders
• Direct chemical neutralization of singlet oxygen, hydroxyl radicals, and superoxide radicals
• Cofactor for several antioxidant enzymes
• Regeneration of vitamins C and E
• Neutralization of free radicals produced by Phase I liver metabolism of chemical toxins
• One of approximately 7 liver Phase II reactions, which conjugate the activated intermediates produced by Phase I to make them water soluble for excretion by the kidneys
• Transportation of mercury out of cells and the brain
• Regulation of cellular proliferation and apoptosis
• Vital to mitochondrial function and maintenance of mitochondrial DNA (mtDNA)
Glutathione in Research (Expanded)
Antioxidant Activity
An increase in exercise intensity is one of the many ways in which oxidative stress and free radical production has been shown to increase inside our cells. Effective regulation of the cellular balance between oxidation and antioxidation is important when considering cellular function and DNA integrity, as well as the signal transduction of gene expression. Many pathological states, such as cancer, Parkinson’s disease, and Alzheimer’s disease have been shown to be related to the redox state of cells. In an attempt to minimize the onset of oxidative stress, supplementation with various known antioxidants has been suggested. Glutathione is an antioxidant which is quite popular for its ability to minimize oxidative stress and the downstream negative effects thought to be associated with oxidative stress. Glutathione is largely known to minimize the lipid peroxidation of cellular membranes and other such targets that is known to occur with oxidative stress.
Free radicals may contribute to aging and some diseases. Antioxidants help to counteract free radicals and protect the body from their damaging effects. Glutathione is a very strong antioxidant, partly because high concentrations can be found in every cell in the body.
Glutathione: Antioxidant Properties Dedicated to Nanotechnologies
“Since its discovery, GSH has been shown to play ubiquitous roles in most living cells, from prokaryotic to eukaryotic organisms. GSH was defined as the intracellular redox buffer, and its major function, either free or associated to proteins, is tightly connected to redox reactions, mainly acting as a reductant versus oxygen and its derived reactive species. From physio-chemical and biochemical points of view, GSH redox properties are well defined and act in cell signaling through post-translational modifications. Disturbance of redox homeostasis related to the depletion of GSH has been shown more and more to be implicated in many pathophysiological states, opening a means for its use as a drug. Glutathione has clearly penetrated fields other than biology, such as therapeutics, with associated nanotechnology approaches for improving its bioavailability and targeting ability. Indeed, growing research considers GSH not only as a drug, but also as a tool for stimuli responsive in drug delivery systems.”
Preventing Cancer Progression
Some research has shown that glutathione has a role in preventing the progression of cancer. However, the same research indicates that glutathione may make tumors less sensitive to chemotherapy, which is a common cancer treatment. Determining the effects of glutathione on cancer will require more research.
However, glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and disturbances in GSH homeostasis are involved in the etiology and progression of many human diseases including cancer. While GSH deficiency, or a decrease in the GSH/glutathione disulfide (GSSG) ratio, leads to an increased susceptibility to oxidative stress implicated in the progression of cancer, elevated GSH levels increase the antioxidant capacity and the resistance to oxidative stress as observed in many cancer cells. The review below highlights the role of GSH and related cytoprotective effects in the susceptibility to carcinogenesis and in the sensitivity of tumors to the cytotoxic effects of anticancer agents.
Role of Glutathione in Cancer Progression and Chemoresistance
The modulation of cellular GSH is a double-edged sword, both sides of which have been exploited for potential therapeutic benefits. Enhancing the capacity of GSH and its associated enzymes, in order to protect cells from redox-related changes or environmental toxins, represents a persistent aim in the search for cytoprotective strategies against cancer. On the contrary, the strategy of depleting GSH and GSH-related detoxification pathways is aimed at sensitizing cancer cells to chemotherapy, the so-called chemo sensitization. In this context, it has been reported that GSH and GSH enzyme-linked systems may be a determining factor for the sensitivity of some tumors to various chemotherapeutic agents. In particular, GST is a relevant parameter for chemotherapy response, and it may be utilized as a useful biomarker for selecting tumors potentially responsive to chemotherapeutic regimens.
However, the attempts to deplete GSH have been limited by the nonselective effects of BSO and have stimulated the research of new GCL inhibitors.
Since it is well known that GSH depletion leads to the upregulation of antioxidant genes, many of which are under Nrf2 control and, that in several types of tumors, Nrf2 is constitutively activated, a new and indirect approach for cancer therapy may be used to modulate the Nrf2-ARE pathway. Based on this, Nrf2 creates a new paradigm in cryoprotection, cancer prevention, and drug resistance.
In summary, the involvement of GSH in the carcinogenesis and in the drug resistance of tumor cells is clear, but further studies, aimed at understanding the GSH-driven molecular pathways, might be crucial to design new therapeutic strategies to fight cancer progression and overcome chemoresistance.”
Reducing Cell Damage in Liver Disease
Hepatitis, alcohol abuse, and fatty liver disease all damage the cells of the liver. The liver plays a critical role in metabolism and detoxification of ingested and blood-borne substances. Many drugs, environmental toxicants and selected dietary components have the potential to cause liver damage by inducing oxidative stress. Pathophysiological consequences of hepatic oxidative damage include dysregulation of lipid metabolism (steatosis), impaired liver function (hepatocyte degeneration and death), and activation of the immune response (inflammation and fibrosis/cirrhosis) (Pessayre et al. 2004).
These conditions become manifest in liver diseases of various etiologies––such as non-alcoholic fatty liver disease (NAFLD) (Pessayre et al. 2002), alcoholic liver disease (ALD) (Albano 2008), and drug-induced liver injury (DILI) (Pessayre et al. 2012).
Under physiological conditions, the liver is protected from oxidative stress by the capacity of its hepatocytes to synthesize GSH.
Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study
Glutathione plays crucial roles in the detoxification and antioxidant systems of cells and has been used to treat acute poisoning and chronic liver diseases by intravenous injection. This is a first study examining the therapeutic effects of oral administration of glutathione in patients with nonalcoholic fatty liver disease (NAFLD).
The study was an open label, single arm, multicenter, pilot trial. Thirty-four NAFLD patients diagnosed using ultrasonography were prospectively evaluated. All patients first underwent intervention to improve their lifestyle habits (diet and exercise) for 3 months, followed by treatment with glutathione (300 mg/day) for 4 months. Researchers evaluated their clinical parameters before and after glutathione treatment. Researchers also quantified liver fat and fibrosis using vibration-controlled transient elastography. The primary outcome of the study was the change in alanine aminotransferase (ALT) levels.
Study Flow Chart showing Patient Allocation
Twenty-nine patients finished the protocol. ALT levels significantly decreased following treatment with glutathione for 4 months. In addition, triglycerides, non-esterified fatty acids, and ferritin levels also decreased with glutathione treatment. Following dichotomization of ALT responders based on a median 12.9% decrease from baseline, researchers found that ALT responders were younger in age and did not have severe diabetes compared with ALT non-responders. The controlled attenuation parameter also decreased in ALT responders. 
Alanine aminotransferase (ALT) levels before and after treatment with glutathione in a ALT responders and b ALT non-responders
This pilot study demonstrates the potential therapeutic effects of oral administration of glutathione in a practical dose for patients with NAFLD. Large-scale clinical trials are needed to verify its efficacy.
Improving Insulin Sensitivity
Insulin resistance can result in the development of type 2 diabetes. The production of insulin causes the body to move glucose (sugar) from the blood and into cells that use it for energy.
A small 2018 study indicates that people with insulin resistance tend to have lower glutathione levels, particularly if they have experienced complications, such as neuropathy or retinopathy. A 2013 study reaches similar conclusions.
Glutathione metabolism in type 2 diabetes and its relationship with microvascular complications and glycemia
Researchers hypothesized that there is decreased synthesis of glutathione (GSH) in type 2 diabetes (T2DM) especially in the presence of microvascular complications, and this is dependent on the degree of hyperglycemia.
Compared to the controls, T2DM patients had lower erythrocyte GSH concentrations (0.90 ± 0.42 vs. 0.35 ± 0.30 mmol/L; P = 0.001) and absolute synthesis rates (1.03 ± 0.55 vs. 0.50 ± 0.69 mmol/L/day; P = 0.01), but not fractional synthesis rates (114 ± 45 vs. 143 ± 82%/day; P = 0.07). The magnitudes of changes in patients with complications were greater for both GSH concentrations and absolute synthesis rates (P-values ≤ 0.01) compared to controls. There were no differences in GSH concentrations and synthesis rates between T2DM patients with and without complications (P-values > 0.1). Fasting glucose and HbA1c did not correlate with GSH concentration or synthesis rates (P-values > 0.17).
Compared to non-diabetic controls, patients with T2DM have glutathione deficiency, especially if they have microvascular complications. This is probably due to reduced synthesis and increased irreversible utilization by non-glycemic mechanisms.
The relationship between the level of glutathione, impairment of glucose metabolism and complications of diabetes mellitus
Here researchers investigated whether there is a difference between the subjects with new-onset type 2 diabetes mellitus (DM), impaired glucose tolerance (IGT) and normal fasting blood glucose levels with respect to the level of glutathione (GSH) and the relationship between the presence of complication of diabetes and the level of GSH.
Oral Glucose Tolerance Test (OGTT) was performed in IFG patients, with no episode of drug use, who were admitted to hospital. According to the results of the application 30 subjects with type 2 DM, 30 subjects with IGT and 28 subjects with normal blood glucose level were included in the study. Anthropometric measurements and blood pressure values of all subjects were recorded. The biochemical parameters of subjects were studied in the biochemistry laboratory by utilizing Olympus AV-2700. The subjects with diabetic retinopathy and nephropathy were established subsequent to the examination of the retina and 24-hour urine collection test performed to subjects with diagnosis of DM. Levels of GSH in all subjects were measured by enzymatic recycling method.
The mean levels of GSH in subjects with DM were significantly reduced compared with IGT or normal subjects (respectively p=0.02 and p<0.001). Besides, lower levels of GSH were acquired in subjects with IGT compared to normal subjects (p<0.001). The mean levels of GSH in subjects with diabetic retinopathy were lower than the subjects with no established diagnosis of diabetic retinopathy (p<0.001). Similarly, lower levels of GSH (p<0.001) were obtained in microalbuminuria subjects than normoalbuminuric subjects.
At the end of the study, researchers came to the conclusion that GSH deficiency was of great significance in the pathogenesis of Diabetes Mellitus.
References:
Pizzorno J. (2014). Glutathione!. Integrative medicine (Encinitas, Calif.), 13(1), 8–12.
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