Glutathione (GSH)

Glutathione (GSH) is often referred to as the body's master antioxidant. Composed of three amino acids - cysteine, glycine, and glutamic acid - glutathione can be found in every cell of the human body. The highest concentrations of glutathione are found in the skin and liver, making it critical in the body's detoxification process. Glutathione is used by the liver to detoxify many toxins including formaldehyde, acetaminophen, benzpyrene and many other compounds. It plays a key role in Phase I and Phase II detoxification reactions. Studies have shown those with the highest glutathione live the longest. If there is insufficient glutathione, you will age prematurely, and be prone to lowered ability to detox. Individuals with low glutathione often report an inability to tolerate strong smells and are very prone to inflammatory conditions, especially when this is combined with other variants that cause inflammation. Glutathione is a powerful antioxidant because it neutralizes free radicals and prevents their formation. It has an important role in immune function via white blood cell production and is one of the most potent anti-viral agents known. We all know the benefits of vitamin C, vitamin E and selenium and other antioxidants, however, it’s not well known that as antioxidants donate their electron to the free radical (thus neutralizing the bad free radical), they can become a pro-oxidant and potentially cause damage. However, glutathione recharges other antioxidants so they can continue to do their job. Glutathione easily restores them to their reduced form so they can resume the free radical scavenging activity again. It also has the amazing ability to recycle itself via the enzymes glutathione reductase (GSR). Glutathione Accelerator has NAC and enzyme support, while GSH Assist has glycine when this is needed, or NAC is contraindicated. Nrf2 Accelerator supports the production of Glutathione. Always make sure you have supported Glutathione before giving folate. Methionine → Homocysteine → CBS → Cystathionine → CTH + Pyridoxal 5'-phosphate → Cysteine + Glutamate → GCLM + GCLC → y-GluCys + Glycine → GSS + ATP → GSH → GLRX → GSSG → GSR → GSH

Substantial decreases in Glutathione occur in:

    • Asymptomatic HIV infection
    • Elective abdominal operations
    • Hepatitis C
    • Ulcerative colitis
    • Cancer
    • Cirrhosis
    • Sepsis
    • Under conditions of a glutathione deficiency, a sub lethal dose of TNF became lethal.

Mehionine:

    • Cysteine and methionine are not stored in the body. When you have a deficiency in sulfur amino acids such as methionine, glutathione levels suffer more than more critical processes such as protein synthesis. Any dietary excess is readily oxidized to sulfate, excreted in the urine (or reabsorbed depending on dietary levels) or stored in the form of glutathione (GSH).
    • Glutathione levels are lower in a large number of diseases and following certain medications, which can be reversed by taking methionine.
    • Methionine and sulfur should be able to spare losses of Glutathione associated with dietary deficiencies, increased utilization due to disease or altered immune function.
    • Under conditions of low methionine, synthesis of sulfate and Glutathione will be reduced, which is likely to negatively influence the function of the immune system and of the antioxidant defense mechanisms.
    • Hydrogen peroxide is subject to a number of fates. The enzyme catalase, present in many types of cells, converts it to H2O and O2 (reaction 4). Neutrophils possess a unique enzyme, myeloperoxidase, that uses H2O2 and halides to produce hypohalous acids (reaction 5); this subject is discussed further below. The selenium-containing enzyme glutathione peroxidase will also act on reduced glutathione (GSH) and H2O2 to produce oxidized glutathione (GSSG) and H2O (reaction 6); this enzyme can also use other peroxides as substrates. OH• and OH− can be formed from H2O2 in a nonenzymatic reaction catalyzed by Fe2+ (the Fenton reaction, reaction 7). O2−⋅ and H2O2 are the substrates in the iron-catalyzed Haber-Weiss reaction (reaction
    • Chemical compounds and reactions capable of generating potential toxic oxygen species can be referred to as pro-oxidants. On the other hand, compounds and reactions disposing of these species, scavenging them, suppressing their formation, or opposing their actions are antioxidants and include compounds such as NADPH, GSH, ascorbic acid, and vitamin E. In a normal cell, there is an appropriate pro-oxidant:antioxidant balance. However, this balance can be shifted toward the pro-oxidants when production of oxygen species is increased greatly (eg, following ingestion of certain chemicals or drugs) or when levels of antioxidants are diminished (eg, by inactivation of enzymes involved in disposal of oxygen species and by conditions that cause low levels of the antioxidants mentioned above). This state is called “oxidative stress” and can result in serious cell damage if the stress is massive or prolonged.

Reduced glutathione (GSH) is important in the metabolism of the RBC, in part to counteract the action of potentially toxic peroxides; the RBC can synthesize GSH and requires NADPH to return oxidized glutathione (G-S-S-G) to the reduced state.

Deficiency of Glucose-6-Phosphate Dehydrogenase Is Frequent in Certain Areas & Is an Important Cause of Hemolytic Anemia

    • NADPH, produced in the reaction catalyzed by the X-linked glucose-6-phosphate dehydrogenase (reaction 9) in the pentose phosphate pathway, plays a key role in supplying reducing equivalents in the red cell and in other cells such as the hepatocyte. Because the pentose phosphate pathway is virtually its sole means of producing NADPH, the red blood cell is very sensitive to oxidative damage if the function of this pathway is impaired (eg, by enzyme deficiency). One function of NADPH is to reduce GSSG to GSH, a reaction catalyzed by glutathione reductase (reaction 10).

Normally, H2O2 is disposed of by catalase and glutathione peroxidase (reactions 4 and 6),the latter causing increased production of GSSG. GSH is regenerated from GSSG by the action of the enzyme glutathione reductase, which depends on the availability of NADPH (reaction 10). The red blood cells of individuals who are deficient in the activity of glucose-6- phosphate dehydrogenase cannot generate sufficient NADPH to regenerate GSH from GSSG, which in turn impairs their ability to dispose of H2O2 and of oxygen radicals. These compounds can cause oxidation of critical SH groups in proteins and possibly peroxidation of lipids in the membrane of the red cell, causing lysis of the red cell membrane. Some of the SH groups of hemoglobin become oxidized, and the protein precipitates inside the red blood cell, forming Heinz bodies, which stain purple with cresyl violet. The presence of Heinz bodies indicates that red blood cells have been subjected to oxidative stress

    • Decreased regeneration of GSH from GSSG by glutathione reductase (which uses NADPH)
    • Oxidation, due to decreased levels of GSH and increased levels of intracellular oxidants (eg, O2 –• ), of SH groups of Hb (forming Heinz bodies), and of membrane proteins, altering membrane structure and increasing susceptibility to ingestion by macrophages (peroxidative damage to lipids in the membrane also possible)

Glutathione:

    • Scientists speculate that glutathione was essential to the development of life on earth as there are virtually no living organisms on this planet whose cells don't contain glutathione.
    • Glutathione is a compound synthesized from cysteine, important in the body's toxic waste disposal. Like cysteine, glutathione contains the crucial thiol (-SH) group that makes it an effective antioxidant.
    • It conjugates to drugs to make them more soluble for excretion.
    • Involved in protein disulfide bond rearrangement
    • Reduces peroxides
    • Glutathione is important in red and white blood cell formation and throughout the immune system.
    • Important as a hydrophilic molecule that is added to lipophilic toxins and waste in the liver during biotransformation before they can become part of the bile.

Coenzyme:

  • It is a coenzyme in various enzymatic reactions. The most important of these are redox reactions, in which the thiol grouping on the cysteine portion of cell membranes protects against peroxidation; and conjugation reactions, in which glutathione (especially in the liver) binds with toxic chemicals in order to detoxify them.
  • Glutathione participates in leukotriene synthesis and is a cofactor for the enzyme glutathione peroxidase.

Tri-peptide:

  • Consists of 3 amino acids: glutamine, glycine, and cysteine.
  • The amino-terminal glutamate of glutathione, which participates in protein folding and in the metabolism of xenobiotics is linked to cysteine by a non-α peptide bond.

Antioxidant:

  • Prevents damage to important cellular components caused by reactive oxygen species such as free radicals and peroxides.
    • While certain vitamins, minerals, and phytochemicals also act as antioxidants, glutathione is different because it is intracellular and produced inherently within a well-nourished and healthy body.
    • Proper glutathione levels are required so other antioxidants such as vitamins C, E, selenium, and carotenoids, can be properly utilized within the body.

Clinical Uses:

  • Prevention of oxygen toxicity in hyperbaric oxygen therapy
  • Treatment of lead and other heavy metal poisonings
  • Lowering of the toxicity of chemotherapy and radiation in cancer treatments
  • Reversal of cataracts
    • Good for those with GST/GPX gene mutations.
    • To clear harmful chemicals and excess hormones, like estrogen you need to methylate properly. Methylation also affects your ability to produce glutathione, your body's master antioxidant.
    • There is a growing scientific evidence that glutathione helps control inflammation, fight infections, and boost the immune system.
    • It has been used to treat acne and as a skin lightening agent.
    • Regular exercise boosts glutathione production, however athletic over-training may result in lower glutathione.

Glyoxalase System:

  • Glutathione is also needed for the detoxification of methylglyoxal, a toxin produced as a by-product of metabolism. This detoxification reaction is carried out by the glyoxalase system.
  • Glyoxalase I catalyzes the conversion of methylglyoxal and reduced glutathione to S-D-Lactoylglutathione.
  • Glyoxalase II catalyzes the hydrolysis of S-D-Lactoylglutathione to glutathione and D-lactate.

Methyl-donor Deficiency Due To Chemically Induced Glutathione Depletion:

    • Dietary deficiency of methionine (Met) is known to deplete cellular Met and cause DNA hypomethylation, but depletion of Met and impairment in methylation due to chemically induced glutathione (GSH) depletion has escaped recognition. These results provide direct evidence that depletion of GSH leads to Met depletion and also injures the methylation processes.
    • In animal models, levels of glutathione remain constant in females who have suffered a brain injury but drop by as much as 80 percent in males with the same injury. When glutathione levels drop, brain cells die much more quickly. This suggests that boys with brain injuries may require different life-saving treatments than girls.

Glutathione S-transferases enzymes:

    • Has eight classes identified: alpha, kappa, mu, omega, pi, sigma, theta, and zeta. The classes are abbreviated with their first letter (i.e. GSTMA for alpha). These phase II enzymes add a glutathione to toxins in order to detoxify them.
    • GSTs are found in the liver, intestines, and several other places in the body and are responsible for detoxifying a large number of pesticides, herbicides, carcinogens, and chemotherapy drugs.
    • Once a toxic substance has been conjugated with glutathione via the GST specific enzyme, it can be excreted from the body via bile or urine.
    • There are several fairly common polymorphisms that can decrease the function of your GSTs. But, once again, environmental factors also play a huge role in your detox system. So if you have non-functioning genes for a specific enzyme, your body has alternate ways to detox most substances and you can naturally boost those routes through nutrition.
    • One way of inducing GSTs is thought to be through cruciferous vegetable consumption.

Supplementing:

    • Research suggests that glutathione is not orally bioactive, and that very little of oral glutathione tablets or capsules is actually absorbed by the body.
    • Cysteine is also part of the antioxidant glutathione. N-acetyl-L-cysteine (NAC) is a form of cysteine where an acetyl group is attached to cysteine's nitrogen atom and is sold as a dietary supplement.
    • The use of intravenous glutathione injections is becoming popular, albeit controversial.
    • Glutathione supplements are readily available but as always discuss it with your healthcare provider.

Cysteine:

    • Cysteine's antioxidant properties are typically expressed in the tripeptide glutathione, which occurs in humans as well as other organisms.
    • The systemic availability of oral glutathione (GSH) is negligible; so it must be biosynthesized from its constituent amino acids, cysteine, glycine, and glutamic acid.
    • Many nutritional supplements (MSM, N-acetyl cysteine, glutathione) that are good for most people are a problem for those with sulfur problems. While certain aspects of your health will benefit from these agents, they will add to your sulfate/sulfite overload problem, adversely affecting the Methyl Cycle Defect that is the common denominator to all of your health problems.
    • If you have elevated cysteine and you want to convert some to glutathione, take a 2:1 weight ratio of glutamine and glycine (2-500 mg caps of glutamine with 1-500 mg cap of glycine) and your body will do the rest.

T4 to T3 conversion:

    • A major factor has been shown to be the antioxidant Glutathione with a direct correlation between improved T4 to T3 conversion with the use of NADPH as well as Glutathione.

Low Glutathione:

    • Depletion of glutathione may be due to numerous factors, including increases in oxidative stress and cellular toxicity.

Glutathione Deficiency:

    • Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the age-related diseases. Genetic variations (and deletions) in genes (GPX1 GSTP1 GSTT1 GSTM1) lead to lower production and activity of glutathione compromising its detoxification capacity.
    • Glutathione occurs naturally in many foods but its absorption from fruits and vegetables may be low. Adequate amounts of protein increase the production of glutathione in our bodies.

You may need to boost your body's production of glutathione by consuming the following food sources:

    • Beef, pork, poultry, fish, cheese, tofu, legumes. These foods are high in essential amino acids that provide building blocks for producing glutathione.
    • Studies showed that the expression and activity of GSTT1 and GSTM1 genes coding for glutathione can be induced by the consumption of cruciferous vegetables (cauliflower, cabbage, garden cress, bok choy, broccoli, Brussels sprouts).

n-acetyl-p-benzoquinone imine (NAPQI):

  • GSH is known as a substrate in both conjugation reactions and reduction reactions, catalyzed by glutathione S-transferase enzymes in the cytosol, microsomes, and mitochondria. However, it is also capable of participating in non-enzymatic conjugation with some chemicals, as in the case of n-acetyl-p-benzoquinone imine (NAPQI), the reactive cytochrome P450-reactive metabolite formed by acetaminophen, that becomes toxic when GSH is depleted by an overdose (of acetaminophen). Glutathione in this capacity binds to NAPQI as a suicide substrate and in the process detoxifies it, taking the place of cellular protein thiol groups which would otherwise be covalently modified; when all GSH has been spent, NAPQI begins to react with the cellular proteins, killing the cells in the process. The preferred treatment for an overdose of this painkiller is the administration (usually in atomized form) of N-acetylcysteine, which is used by cells to replace spent GSSG and renew the usable GSH pool. It conjugates to drugs to make them more soluble for excretion, is a cofactor for some enzymes, is involved in protein disulfide bond rearrangement and reduces peroxides.

Supplement recommendations for antioxidants:

    • Glutathione Power
    • NAC (N-Acetyl Cysteine) 20 mg
    • SAMe
    • L-Methionine
    • Whey
    • DIM Detox
    • Nrf2 Detox
    • Liposomal Glutathione
    • Ascorbic Acid 1 gram 250's
    • Selenium (selenomethionine) 180's

Redox molecule:

    • It undergoes a cycle of oxidation and reduction. When glutathione (GSH) gets used, it loses electrons and becomes glutathione disulfide (GSSH). It can regain electrons, and be converted back into a reusable form, but only in the presence of an electron donor. The primary electron donor is NADPH (nicotinamide adenine dinucleotide phosphate).

Make NADPH and Glutathione:

    • By improving methylation cycle function, it is possible to improve the synthesis of glutathione.
    • The sulfur-containing amino acid cysteine is a very important constituent of the glutathione molecule. Cysteine is made from cystathionine and homocysteine.
    • Vitamin B-6 and the amino acid L-serine participate in the activation of the sulfuration pathway. Hence B-6’s importance in glutathione formation. B-6 also is critical to activate the gamma-glutamyl cycle (via the GGT enzyme), a pathway that brings cysteine, glycine, and glutamine together in the cytoplasm of cells to form glutathione.

The following nutrients are critical for increasing glutathione synthesis:

    • Vitamin B-6/P5P
    • Vitamin B-12
    • Zinc
    • Magnesium
    • Selenium
    • Amino acids: cysteine (or NAC), glutamine and glycine
    • Possibly the use of low molecular weight antioxidants: lipoic acid and Vitamins C and E

Disease Inference Score:

    • Prostatic Neoplasms 142.43
    • Liver Cirrhosis, Experimental 117.87
    • Hepatocellular carcinoma 103.07
    • Diabetes Mellitus, Experimental 100.73
    • Breast carcinoma 90.12
    • Reperfusion Injury 88.35
    • Diabetes Mellitus, Type 2 80.6
    • Brain Ischemia 80.56
    • Lung Neoplasms 74.48
    • Colorectal cancer 67.31
    • Squamous cell carcinoma 65.65
    • Myocardial Ischemia 64.09
    • Stomach Neoplasms 60.89
    • Dermatitis, Contact 59.19
    • Obesity 54.78
    • Hypertension 54.25
    • Carcinoma 53.55
    • Neoplasm Invasiveness 51.35
    • Mesothelioma, Malignant 50.17
    • Colonic neoplasm 48.44
    • Pulmonary Fibrosis 47.6
    • Drug-induced liver injury 47.04
    • Neoplasm Metastasis 47.04
    • Inflammation 45.35
    • Brain Injuries 44.38
    • Disease Progression 43.78
    • Carcinoma, Non-Small-Cell Lung 43.73
    • Rheumatoid arthritis 42.01
    • Parkinson's disease 41.36
    • Arthritis, Experimental 41.29
    • Alzheimer's Disease 40.23
    • Atherosclerosis 40.15
    • Kidney Failure, Chronic 40.1
    • Asthma 39.93
    • Autism 39.39
    • Neurodegenerative Diseases 38.34
    • Cell Transformation, Neoplastic 38.3
    • Disease Models, Animal 37.7
    • Esophageal squamous cell carcinoma 37.43
    • Glioblastoma multiforme 37.34
    • Urinary Bladder Neoplasms 37.15
    • Mammary Neoplasms, Experimental 37.01
    • Adenocarcinoma 36.94
    • Myocardial infarction 36.79
    • Alcoholic liver cirrhosis 36.75
    • Heart failure 36.2
    • Nerve Degeneration 34.83
    • Carcinoma, squamous cell of head and neck 34.71
    • Infarction, Middle Cerebral Artery 33.94
    • Acute kidney injury 33.4
    • Renal cell carcinoma 32.57
    • Ulcerative colitis 32.17
    • Mouth Neoplasms 30.57
    • Osteosarcoma 29.94
    • Radiation Injuries, Experimental 29.85
    • Ovarian Neoplasms 29.31
    • Manganese Poisoning 28.86
    • Cardiomyopathies 28.79
    • Psoriasis 28.69
    • Esophageal Neoplasms 28.49
    • Mammary Neoplasms, Animal 28.3
    • Myocardial Reperfusion Injury 28.13
    • Skin Neoplasms 27.65
    • Status Epilepticus 27.63
    • Hepatitis, Autoimmune 27.35
    • Pneumonia 26.89
    • Amyotrophic lateral sclerosis 1 26.8
    • Colitis 26.77
    • Non-alcoholic fatty liver disease 26.03
    • Multiple myeloma 25.71
    • Pulmonary Emphysema 25.6
    • Chronic obstructive pulmonary disease 25.59
    • Fatty Liver 25.54
    • Pancreatic carcinoma 25.36
    • Liver Cirrhosis 25.19
    • Thyroid carcinoma 25.16
    • Hepatitis, Chronic 24.75
    • Leishmaniasis, Cutaneous 24.74
    • Diabetes Mellitus, Type 1 24.0
    • Diabetic retinopathy 23.93
    • Sepsis 23.79
    • Heat Stroke 23.67
    • Hernia, Diaphragmatic 23.43
    • Marfan Syndrome 22.94
    • Atopic eczema 22.82
    • Lung Injury 22.74
    • Precancerous Conditions 22.7
    • Male infertility 22.66
    • Liver Diseases 22.56
    • Burns 22.44
    • Cardiac hypertrophy 22.43
    • Hepatolenticular Degeneration 22.31
    • Arthritis, Juvenile 22.17
    • Trigeminal Neuralgia 22.13
    • Allergy 21.97
    • Necrosis 21.93
    • Calcinosis 21.71
    • Abortion, Spontaneous 21.06
    • Brain Neoplasms 20.65
    • Glomerulonephritis 20.59
    • Oral Submucous Fibrosis 20.59
    • Acute coronary syndrome 20.53
    • HIV Infections 20.12
    • Carotid Artery Diseases 19.55
    • Liver Neoplasms, Experimental 19.53
    • Arsenic Poisoning 19.07
    • Visceral leishmaniasis 18.88
    • Autoimmune disease 18.87
    • Pneumonia, Pneumococcal 18.68
    • Copper-Overload Cirrhosis 18.67
    • Keratosis 18.66
    • Schizophrenia 18.48
    • Lung adenocarcinoma 18.39
    • Respiratory Hypersensitivity 18.37
    • Crohn's disease 18.02
    • Genetic Predisposition to Disease 17.9
    • Tongue Neoplasms 17.9
    • Diabetic nephropathy 17.79
    • Intracerebral hemorrhage 17.65
    • Plasmodium Falciparum Blood Infection Level 17.47
    • Papilloma 17.42
    • Insulin resistance 17.29
    • Wounds and Injuries 17.27
    • Liver Neoplasms 17.23
    • Cardiovascular disease 17.01
    • Retinal Diseases 16.65
    • Turner Syndrome 16.64
    • Fibrosis 16.6
    • Hyperalgesia 16.49
    • Glioma 16.37
    • Cholestasis 16.36
    • Pleural Diseases 16.33
    • Thrombosis 16.25
    • Primary biliary cirrhosis 16.23
    • Occupational Diseases 16.22
    • Down syndrome 16.08
    • Asbestosis 16.04
    • Diabetic Neuropathies 15.98
    • Asphyxia Neonatorum 15.96
    • Mesothelioma 15.84
    • Kidney disease 15.75
    • Hyperthyroidism 15.43
    • Skin Diseases 15.43
    • Entamoebiasis 15.39
    • Head and Neck Neoplasms 15.32
    • Amyotrophic lateral sclerosis 15.22
    • Gallbladder neoplasm 15.03
    • Shock, Hemorrhagic 15.01
    • Pleurisy 14.99
    • Silicosis 14.9
    • Parkinsonian Disorders 14.86
    • Stroke 14.86
    • Amphetamine-Related Disorders 14.84
    • Dermatitis, Allergic Contact 14.83
    • Carcinoma, Transitional Cell 14.81
    • Endometriosis 14.81
    • Neoplasm Recurrence, Local 14.72
    • Stomach Ulcer 14.72
    • Spinocerebellar Ataxia 17 14.53
    • Drug-Related Side Effects and Adverse Reactions 14.45
    • Ischemia 14.44
    • Metabolic Syndrome X 14.36
    • Osteoporosis, Postmenopausal 14.34
    • Diabetes mellitus 14.27
    • Endometrial neoplasm 14.25
    • Hypertension, Essential 14.2
    • Neoplasms, Experimental 14.2
    • Hemangiosarcoma 14.19
    • Ceroid lipofuscinosis, neuronal 1, infantile 14.17
    • Cholangiocarcinoma 13.84
    • Cachexia 13.79
    • Berylliosis 13.73
    • Hyperplasia 13.62
    • Premature Birth 13.39
    • Aortic Diseases 12.99
    • Kidney Neoplasms 12.91
    • Inflammatory bowel disease 12.9
    • Hemolytic-Uremic Syndrome 12.89
    • Acute lymphoblastic leukemia 12.86
    • Hyperoxia 12.83
    • Bronchial Hyperreactivity 12.81
    • Leukemia, Myeloid, Acute 12.77
    • Osteoporosis 12.75
    • Hyperoxaluria 12.6
    • Melanoma 12.6
    • Peripheral neuropathy 12.57
    • Lymphoma, Large B-Cell, Diffuse 12.44
    • Acute Lung Injury 12.39
    • Muscular Atrophy 12.35
    • Osteoarthritis 12.34
    • Multiple sclerosis 12.19
    • Protein Deficiency 12.15
    • Dilated cardiomyopathy 12.08
    • Leukemia-Lymphoma, Adult T-Cell 12.07
    • Uterine Cervical Neoplasms 12.01
    • Barrett's esophagus 11.93
    • Coronary artery disease 11.9
    • Hypersensitivity, Immediate 11.81
    • Ureteral Calculi 11.73
    • Listeriosis 11.72
    • Leukemia 11.67
    • Adenoma 11.62
    • Hypoglycemia 11.62
    • Infertility, Female 11.55
    • Lewy body dementia 11.09
    • HIV Wasting Syndrome 11.06
    • Gliosarcoma 11.04
    • Micronuclei, Chromosome-Defective 11.03
    • Nasopharyngeal carcinoma 10.86
    • MELAS Syndrome 10.8
    • Adrenoleukodystrophy 10.79
    • Lung Diseases 10.79
    • Nervous System Diseases 10.74
    • Urticaria 10.69
    • Systemic lupus erythematosus 10.54
    • Liver Failure, Acute 10.52
    • Enterocolitis, Necrotizing 10.49
    • Adrenocortical Carcinoma 10.47
    • Ophthalmoplegia, Chronic Progressive External 10.47
    • Urologic Neoplasms 10.45
    • Adenomatous Polyposis Coli 10.42
    • Age-related macular degeneration 10.36
    • Behcet's syndrome 10.29
    • Leishmaniasis 10.13
    • Maturity-Onset Diabetes of the Young, Type 1 10.07
    • Nephrosis 10.05
    • Azoospermia 9.99
    • Hypercholesterolemia 9.93
    • Cerebral amyloid angiopathy 9.92
    • Pregnancy Complications, Cardiovascular 9.87
    • Eye Infections, Bacterial 9.86
    • Diabetic Cardiomyopathies 9.83
    • Emphysema 9.82
    • Angina, Stable 9.7
    • Hemochromatosis 9.7
    • Appendicitis 9.69
    • Weight Gain 9.66
    • Chloracne 9.65
    • Ceroid Lipofuscinosis, Neuronal, 6 9.46
    • Cardiomyopathy, Hypertrophic 9.43

Related Pathways:

    • Wnt signaling pathway
    • Viral myocarditis
    • VEGF signaling pathway
    • Vascular smooth muscle contraction
    • Type II diabetes mellitus
    • Type I diabetes mellitus
    • Tuberculosis
    • Tryptophan metabolism
    • Transmembrane transport of small molecules
    • TRAF6 Mediated Induction of proinflammatory cytokines
    • Toxoplasmosis
    • Toll-like receptor signaling pathway
    • Tight junction
    • Thyroid cancer
    • TGF-beta signaling pathway
    • Asthma
    • Autoimmune thyroid disease
    • Axon guidance
    • B cell receptor signaling pathway
    • Bile secretion
    • Binding and Uptake of Ligands by Scavenger Receptors
    • Bladder cancer
    • Caffeine metabolism
    • Cell adhesion molecules (CAMs)
    • Cell cycle
    • Cell Cycle
    • Cellular responses to stress
    • Chagas disease (American trypanosomiasis)
    • Chemokine signaling pathway
    • Chronic myeloid leukemia
    • Colorectal cancer
    • Complement and coagulation cascades
    • Cytokine-cytokine receptor interaction
    • Cytosolic DNA-sensing pathway
    • Developmental Biology
    • Disease
    • Drug metabolism - cytochrome P450
    • Drug metabolism - other enzymes
    • Endocytosis
    • Endometrial cancer
    • Epithelial cell signaling in Helicobacter pylori infection
    • ErbB signaling pathway
    • Extracellular matrix organization
    • Fatty acid metabolism
    • Fc epsilon RI signaling pathway
    • Fc gamma R-mediated phagocytosis
    • Focal adhesion
    • Gap junction
    • Glioma
    • Glutathione metabolism
    • GnRH signaling pathway
    • Graft-versus-host disease
    • Hematopoietic cell lineage
    • Hemostasis
    • Hepatitis C
    • Huntington's disease
    • Immune System
    • Innate Immune System
    • Insulin signaling pathway
    • Intestinal immune network for IgA production
    • Jak-STAT signaling pathway
    • Leishmaniasis
    • Leukocyte transendothelial migration
    • Linoleic acid metabolism
    • Long-term depression
    • Long-term potentiation
    • Malaria
    • MAPK signaling pathway
    • Measles
    • Melanogenesis
    • Melanoma
    • Metabolic pathways
    • Metabolism
    • Metabolism of proteins
    • Metabolism of xenobiotics by cytochrome P450
    • mTOR signaling pathway
    • Mus musculus biological processes
    • Natural killer cell mediated cytotoxicity
    • Neurotrophin signaling pathway
    • NOD-like receptor signaling pathway
    • Non-small cell lung cancer
    • Oocyte meiosis
    • Osteoclast differentiation
    • Other types of O-glycan biosynthesis
    • p53 signaling pathway
    • Pancreatic cancer
    • Parkinson's disease
    • Pathways in cancer
    • Pentose and glucuronate interconversions
    • Peroxisome
    • Glutathione Health Effects
    • Angiotensin converting enzyme inhibitor
    • Anti cytotoxic
    • Antidote
    • Anti eczemic
    • Anti hepatitic
    • Antioxidant
    • Cancer preventive

Gene Interactions:

    • GSTP1
    • ABCC1
    • TNF
    • NFE2L2
    • HMOX1
    • GSTM1
    • CYP3A4
    • GSTA1
    • GCLM
    • CXCL8
    • AS3MT
    • MAPK1
    • TYR
    • RELA
    • CASP3
    • KEAP1
    • NQO1
    • SOD2
    • TP53
    • SOD1
    • MGST1
    • ALB
    • CAT
    • IFNG
    • ABCC2
    • GSTA3
    • CFTR
    • CYP2E1
    • GGT1
    • CYP2C9
    • GSTA2
    • MAPK8
    • AKR1B1
    • CYP1A1
    • GSTT1
    • ATG5
    • MPO
    • PTGS2
    • FN1
    • CCL5
    • GLRX
    • MMP9
    • IKBKB
    • SLC31A1
    • FAS
    • JUN
    • IL6
    • MTR
    • BCL2
    • SIRT1
    • LPO
    • STAT1
    • ABCG2
    • STAT3
    • CXCL1
    • VCAM1
    • CYP3A5
    • CD86
    • IL13
    • TXNRD1
    • CYP1B1
    • ABCG2
    • PYGM
    • TPO
    • TGFB1
    • CHUK
    • SLC25A10
    • NGF
    • NOS2
    • PRKCD
    • ABCC5
    • HIF1A
    • CYP2B6
    • HRAS
    • GPX1
    • JAK2
    • AGT
    • SELE
    • UCHL1
    • UCP2
    • IGF1
    • MTF1
    • CYCS
    • IGFALS
    • CYP2C18
    • IGFBP3
    • ATP7B
    • IAPP
    • CYP2C19
    • PARP1
    • ODC1
    • RXRA
    • DUSP1
    • ABCC4
    • CD36
    • HSPA5
    • FYN
    • SP1
    • RB1
    • TALDO1
    • EPAS1
    • ICAM1
    • UCP1
    • CNTF
    • EPO
    • NFKB1
    • TOP2A

GSTM1, GSTP, GSTP1:

    • Glutathione S-transferases (GSTs) are a family of enzymes that play an important role in detoxification.
    • These genes are involved in supporting glutathione-s-transferase, which is responsible for healthy levels and function of glutathione.

GSTM1 – Glutathione S-transferase mu 1:

    • Glutathione S-transferase M1 (cytoplasm) (GSTM1) is in the mu class of enzymes functioning in the detoxification of the cytoplasm of cells.
    • Functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione.
    • Null mutations of this class mu gene have been linked with an increase in a number of cancers, likely due to an increased susceptibility to environmental toxins and carcinogens.
    • This polymorphism reduces the clearance of chemical toxins and increases the individual's susceptibility to carcinogens, chemical toxins, anesthesia and affect the toxicity of certain drugs.
    • Although there are a few SNPs in the GSTM1 gene, the main polymorphism of interest is the null allele - in other words, some individuals are lacking one or even both copies of the GSTM1 gene. Individuals with fewer copies of GSTM1 may be somewhat more prone to allergies, asthma, and certain cancers, especially if they are missing copies of other GST family genes such as GSTP1 or GSTT1.
    • GSTM1 (Glutathione S-Transferase Mu 1) has been shown in several studies to interact with phthalates.

Gene SNPs:

Rs74837985:

    • Also known as rs1065411. 46% of people have the variant allele C and 53% have the wild type (typical) allele G.

Rs7483:

Rs113846795:

Rs366631:

    • SNP that has been correlated with a deletion in GSTM1 with little or no GSTM1 expression. There is a higher risk of some cancers with non-functioning GSTM1 gene, but the association is modified for some by diet and environment. This mutation should encourage people to eat healthy and not smoke!
    • For those with GSTM1 null genotypes and phthalate exposure, the risk of fibroids is about 5 times greater.
    • The AA genotype corresponds to null and is present in about 50% of the population.

rs1056806:

    • (D) DELETION-The D (deleted) version of the GSTM1 gene which means that no GSTM1 enzyme is produced. Those with deletions can compensate by adding extra portions of cruciferous vegetables and consume on average at least 3-4 portions per week. It is also recommended to add frequent consumption of allium vegetables (garlic, onions,etc) to the diet.

Glutathione-S-transferase enzymes:

    • Detoxify many water soluble environmental toxins, including many solvents, polycyclic aromatic hydrocarbons, steroids, herbicides, fungicides, lipid peroxidases and heavy metals such as mercury, cadmium and lead.
    • Decreased glutathione conjugation capacity may increase toxic burden and increase oxidative stress.
    • Copy Number Variations in the GSTT1 and GSTM1 enzymes are associated with less effective detoxification of potential carcinogens may confer an increased susceptibility to some cancers.
    • If either or both the GSTT1 or GSTM1 enzymes are ABSENT they are assigned a Null genotype. If either copy is present, it is termed PRESENT. The GSTP1 gene encodes for an enzyme, glutathione S-transferase P1 (GSTP1) located in brain tissue, skin tissue and lung tissue which is involved in Phase II detoxification of carcinogens, xenobiotics, steroids, heavy metals and products of oxidative stress.
    • The GSTP1 rs1695 polymorphism produces a variant enzyme with lower activity and less capability of effective detoxification.
    • The glutathione S-transferase genes code for enzymes that are involved in the metabolism of a variety of carcinogens and environmental toxins. Two of the genes, GSTM1 and GSTT1, have been extensively studied for the effects of carcinogens and toxins on the fairly common null polymorphisms that involve a deletion on the genes. The deletion is fairly common with 50 – 78% of people, depending on ethnic group, having the null genotype for GSTM1.

GSTT1 NULL/GSTM1 NULL:

    • This individual has NOT inherited any copies of the GSTT1 or GSTM1 enzymes. NULL genotypes are associated with less effective detoxification of potential carcinogens. In the liver, when there is reduced glutathione capacity the mercapturic acid pathway is utilised. Mercapturic acid is a condensation product formed from the coupling of cysteine with aromatic compounds. It is formed as a conjugate in the liver and is excreted in the urine. Glutathione-S-transferase adducts lose glutamate and glycine portions, and are acetylated to form mercapturic acids, which are excreted. Levels of mercapturic in the urine may be used as an indicator of exposure to, ethylene dibromide and acrylamide for example.

Actions for this Genotype:

    • Consume cruciferous vegetables to support the Glutathionylation pathway.
    • To increase glutathione capacity it is important to ensure availability of precursors and co-factors.
    • Glutathione depletion can be supported with a-lipoic acid, taurine or milk thistle.
    • Look at exposure to water soluble environmental toxins, including many solvents, herbicides, fungicides, lipid peroxidases and heavy metals such as mercury, cadmium and lead. If the exposure to environmental toxins is increased then risk reduction needs to be assessed.

Fruits and Vegetables:

    • Drinking 480 ml (about 16 oz) of grape juice per day for 8 weeks for smokers could decrease diastolic blood pressure, but that the effect can be higher in those with GSTM1-null.
    • The GSTM1-null genotype had a greater increase in antioxidant effects with an increase in gamma-tocopherol.
    • A higher vegetable intake decreased the risk of bladder cancer with an even more protective effect for those carrying GSTM1 null with an even lower risk of bladder cancer associated with high cruciferous vegetable intake.
    • Having a GSTM1 null genotype can benefit from eating even more servings of broccoli than those with a present gene in terms of prostate cancer. In other words, those with GSTM1 present may benefit from broccoli a few times a week, while those with the null genotype should add in another serving or two.

GSTP1 I105V:

    • Glutathione S-transferase Pi 1 (GSTP1) is an enzyme with an important antioxidant role and is encoded for by the GSTP1 gene.
    • Is involved in estrogen metabolism.
    • GSTP1 is located primarily in the brain and lungs.
    • GSTP1 polymorphisms are associated with either higher or lower enzyme activity, depending on the exposure.
    • This GSTP1 polymorphism is associated with increased risk of various cancers, risk that is compounded by exposure
    • to cigarette smoke.
    • Minimize exposure to cigarette smoke, charred food, herbicides, fungicides, insect sprays, industrial solvents, and toxic metals. Ensure availability of glutathione (GSH) precursors and cofactors: methionine, N-acetylcysteine, glutamine, glycine, magnesium, and pyridoxal-5-phosphate (B6).
    • GSH depletion may be offset by alpha lipoic acid, milk thistle, and taurine. Allium vegetables (e.g., onions, leeks, garlic) and crucifers(e.g., broccoli, cauliflower, cabbage, kale, Brussels sprouts, radish sprouts) can increase GST activity and reduce cancer risk.
    • Consume an antioxidant-rich diet to prevent oxidative stress.
    • Glutathione can act indecently to neutralize reactive oxygen species, it often requires the action of GSTP1 in order to neutralize xenobiotic reactive oxygen species. Xenobiotics are molecules which are not normally produced, or expected to be present in the body and xenobiotic reactive oxygen species include a diverse range of environmental factors including herbicides, pesticides and several drugs.
    • There is one SNP in the GSTP1 gene associated with poor health outcomes, rs1695 or A313G.

GSTP1 SNPs:

    • The glutathione S-transferase pi gene (GSTP1) functions in chemical clearance and anti-inflammatory properties.
    • High concentrations of GST-p are found in the skin, lungs, sinuses, bladder and the intestinal tract.
    • Polymorphisms of this enzyme allow for increased inflammatory activity in these areas that include eczema, asthma, chronic sinusitis, IBS, "leaky" gut and interstitial cystitis.
    • Detoxifies polyaromatic hydrocarbons (PAHs).
    • A tumor suppressor gene and is involved in detoxification and metabolism reactions, which can prevent genome damage to cells and cancer initiation.
    • The binding site of GSTP is highly shape specific for the substrates it processes: some chemicals readily bind, whereas others are more slowly conjugated due to their unwieldy shape.

Influencers:

    • Acetaminophen, Hep C or influenza infection, endotoxemia/LPS h Aflatoxins, butyrate, glucocorticoids, EGCG, brassica vegetables, garlic and onions, soy, lycopene, spirulina, and selenium.

Rs1695 Ile105Val:

    • The G allele is associated with an increased risk of developing asthma dependant on different populations.
    • Glutathione is a potent antioxidant which can act alone or in conjunction with GSTP1 to remove harmful oxidative species.
    • Glutathione supplementation can be recommended for carriers of either allele especially those who live in areas with a high level of atmospheric ozone.
    • Carnosic acid (found in rosemary) up-regulates the GSTP enzyme.
    • GSTP-null can have less weight gain on a high fat diet.
    • Less acetaminophen toxicity in GSTP-null.
    • A mutation increases enzyme expression and alters the binding site geometry which can increase cancer risk as there is an increased procarcinogenic clearance in the blood which can cause damage.
    • AA: normal
    • AG: somewhat reduced GSTP1 activity, greater improvements in VO2 max in response to aerobic training, possible detoxification problems.
    • GG: somewhat reduced GSTP1 activity, Greater improvements in VO2 max in response to aerobic training. 3.5x asthma risk in certain populations, possible detoxification problems.
    • Associated Symptoms And Conditions:
      • Acute lymphocytic leukemia (Arab children)
      • Asthma
      • Bladder cancer
      • Eczema
      • IBS
      • Interstitial cystitis
      • Leaky gut
      • Mandibular osteoradionecrosis after radiotherapy of head and neck cancer due to radiation.
      • Sinusitis
    • Vitamin E:
      • Vitamin E (α-tocopherol) is a potent antioxidant which can limit the development of inflammation following oxidative stress. In those with the G allele are thought to have a reduced anti-oxidative capacity supplementation with vitamin E had a large beneficial effect. A positive effect was also observed in those carrying the A allele although to a lesser extent.
      • Men supplementing with 75 IU of alpha-tocopherol can have increased inflammatory cytokines depending on the genotype. Specifically, for the GSTP1 polymorphism, rs1695, those with AA and AG had an increase in interleukin-6.
      • Interleukin-6 It is a cytokine that is involved in inflammation. It induces an inflammatory response and is implicated in several autoimmune diseases including diabetes, arteriosclerosis, and rheumatoid arthritis.
      • AA: increased interleukin-6 (inflammation) with supplementing alpha-tocopherol
      • AG: increased interleukin-6 (inflammation) with supplementing alpha-tocopherol
      • GG: decreased interleukin-6 (inflammation) with supplementing alpha-tocopherol
    • Breast Cancer:
      • GG carriers can have a reduced risk of breast cancer in postmenopausal women vs. AA. GG were found to have a higher risk of breast cancer in a 2008 Chinese study.
      • Those with the lowest intake of cruciferous vegetables with GG were found to have the highest risk of breast cancer.The difference between the two studies may be ethnicity or pre- vs. post-menopausal women.
    • Suggestions:
      • Minimize exposure to cigarette smoke, charred food, industrial solvents, toxic metals, herbicides, fungicides, lipid peroxidases and heavy metals such as mercury, cadmium and lead.
      • Consume an antioxidant rich diet rich in cruciferous and high sulfur vegetables including onions, leeks, garlic, broccoli, cabbage, Brussels sprouts, cauliflower, kale, radish sprouts is suggested.
      • If you feel sluggish, consider supplementation of glutathione or cruciferous vegetable extract. Natural production of glutathione drops by roughly 10% per decade
    • Supplements:
      • L-Methionine, Glutathione, glutamine, glycine, magnesium, pyridoxal-5-phosphate (B6), NAC, and SAMe.

Rs1138272 A114V:

    • Supplementation for this SNP is L-Methionine, Glutathione, glutamine, glycine, magnesium, pyridoxal-5-phosphate (B6), NAC, and SAMe.
    • When this gene is combined with GSTM1 and GSTT1 there is an additional risk of cell damage from a diet low in antioxidants.
    • Minimize exposure to cigarette smoke, charred food, industrial solvents, smog, toxic metals, herbicides, fungicides, and insect sprays.
    • An antioxidant rich diet including onions, leeks, garlic, broccoli, cabbage, Brussels sprouts, cauliflower, kale, radish sprouts is suggested.

Cbs And Glutathione:

    • CBS (cystathionine beta synthase) is a gene that converts homocysteine in to cystathionine. The CBS pathway is the gateway into a number of essential biochemical processes. The biochemical pathways that follow and are linked to CBS are Transsulfuration and Glutathione Synthesis.
    • It is essential to address that Glutathione (GSH) is among the most important endogenously-produced antioxidants in every cell of the body. Glutathione activity in cells is critical for normal detoxification and defense mechanisms in every cell.
    • In the CBS pathway, the sulfur amino acids are removed, if they are in excess. However, under certain circumstances, it appears that abnormalities can ensue, causing an excessive pooling of sulfur groups. As a result of normal cystathionine reactions, ammonia is generated, glutathione gets made, hydrogen sulfides are converted into sulfites and then into sulfates.
    • Hyperhomocysteinemia and the genetic condition, homocystinuria. Elevated levels of homocysteine are implicated in both cancer and cardiovascular disease. In these regards, one mechanism that may exist for lowering elevated levels of homocysteine in some individuals is taking supplemental NAC (n-acetyl cysteine). NAC is the precursor of glutathione.
    • Certain individuals are predisposed towards up-regulated CBS pathway activity.
    • Elevations in CBS pathway activity may be more likely to occur in individuals who are ++, or +/- in the following genetic mutations:
      • CBS C699T
      • CBS A360A
      • CBS N212N
    • Even without a CBS mutation, there may still be elevated CBS/transsulfuration activity. This may be true of individuals with BHMT down-regulations, specifically in individuals who are ++ or +/- the following mutations:
      • BHMT 1
      • BHMT 2
      • BHMT 4
      • BHMT 8

GPX:

    • Glutathione peroxidase 1 gene encodes a protein responsible for the detoxification of peroxides.
    • GPX1 is expressed in almost all tissue of the body as it plays a major role in protecting cells from oxidative stress.
    • There are 8 known isoforms of glutathione peroxidase (GPx 1-8).
    • This family of enzymes primarily protects from harmful levels of hydrogen peroxide within the cell.
    • Glutathione peroxidase may change oxidize glutathione back to reduced glutathione.
    • Is one of the few proteins in humans which contain the non-standard amino acid selenocysteine, which replaces the standard cysteine This replacement is a major contributor to the potent antioxidant activity of GPX1.
    • Catalyzes the reduction of organic hydroperoxides and hydrogen peroxide (H2O2) by glutathione, and thereby protect cells against oxidative damage. H2O2 is also essential for growth-factor mediated signal transduction, mitochondrial function, and maintenance of thiol redox-balance.

Influencers:

    • Cofactors: Selenium, in the form of a selenoprotein i Cu, Fe, Hg, Zn h High H2O2, high ROS, spirulina, vitamin C, and, indirectly, via increased glutathione production: alpha-lipoic acid and sulforaphane.

rs1050450 or C559T GPX1 Pro199Leu:

    • With a mutation in this SNP, one has the potential for glutathione deficiency.
    • The T allele may interfere with the incorporation of the non-standard amino acid selenocysteine into the GPX1 enzyme, which provides its potent antioxidant activity. Therefore, GPX1 function may be increased, but its actual effective activity may be reduced.
    • GPX1 is a selenoprotein, meaning it incorporates selenium into its protein structure.
    • The T allele reduces an individual’s ability to utilise selenium. Selenium intake may need to be assessed to afford protection to hydrogen peroxide-sensitive tissues, particularly lung and breast tissues.
    • This variant downregulates the enzyme's activity in RBC by between 9% (AG/AA) to 13% (AA in males).
    • In AA Japanese men an increased risk for metabolic syndrome was found.
    • AG, CT: 9-13% of the population have reduced enzyme activity compared to homozygous C genotype. Increased risk of damage caused by oxidative stress in many diseases
    • TT: Increased risk of damage caused by oxidative stress in many diseases.
    • Associated Symptoms And Conditions:
      • Brain tumors
      • Breast cancer and possibly a poorer response to anticancer therapies.
      • Cancer (breast and lung)
      • Cardiovascular risk
      • Drug-induced liver damage
      • Hemolytic Anemia Due To Glutathione Peroxidase Deficiency and Keshan Disease
      • Osteoporosis
      • Peripheral neuropathy in diabetes
      • Selenium deficiency induced osteoporosis
    • Supplements:
      • Glutathione:
        • Is used by GPX1 as a cofactor. Those with the T allele with impaired antioxidant capacity supplementation with glutathione may improve outcome by allowing GPX1 to function correctly.
      • Ascorbic acid:
        • Vitamin C is one of the most potent antioxidants, which can protect against oxidative stress induced by free radicals. Those with the T allele may benefit from vitamin C supplementation to maintain antioxidant defense.
      • Vitamin E (α-tocopherol):
        • Those with the T allele can benefit by taking Vitamin E as an antioxidant, especially for lipid-derived free radicals.
      • Vitamin A (Retinol):
        • A strong antioxidant that targets lipid-derived free radicals can benefit T carriers.
      • Turmeric Root Extract-Curcumin:
        • Curcumin which is commonly extracted from turmeric roots demonstrates a beneficial antioxidant effect by increasing SOD2 expression. T carriers can benefit from increased antioxidant activity.
    • Contraindications:
    • Selenium:
      • T carriers can have increased DNA damage with higher selenium intake.
    • Selenium Sources:
    • The selenium content in food depends on the concentration of selenium in the soil where the crops were grown.
      • Brazil nuts
      • Eggs
      • Fish (tuna, halibut, sardines, flounder, salmon)
      • Grains (wheat germ, barley, brown rice, oats)
      • Meat (beef, liver, lamb, pork)
      • Mushrooms (button, shiitake)
      • Onions
      • Poultry (chicken, turkey)
      • Shellfish (oysters, mussels, shrimp, clams, scallops)
      • Sunflower seeds
    • Selenium Metabolism:
      • The presence of genetic polymorphisms in selenoprotein genes may:
      • Influence the gene expression of specific selenoproteins
      • Influence the pattern of global gene expression after Brazil nut supplementation. Brazil nut supplementation significantly increased GPX1 mRNA expression only in subjects with CC genotype at rs1050450. SELENOP mRNA expression was significantly higher in A-carriers at rs7579 either before or after supplementation
    • Diet:
    • Consume a diet rich in fruits and vegetables. Include cruciferous vegetables such as:
      • Arugula
      • Broccoli
      • Brussels
      • Cauliflower
      • Kale
      • Sprouts
    • Testing:
    • Test lipid peroxidation

Rs1800668:

    • Decreased activity of glutathione peroxidase.
    • Lead exposure, polymorphisms in genes related to oxidative stress, and risk of adult brain tumors.