What is Glutathione?
Glutathione (GSH) is often referred to as the body's master antioxidant. Composted of three amino acids - cysteine, glycine, and glutamate - glutathione can be found in virtually every cell of the human body. The highest concentration of glutathione is in the liver, making it critical in the body's detoxification process.
Glutathione is also an essential component to the body's natural defense system. Viruses, bacteria, heavy metal toxicity, radiation, certain medications, and even the normal process of aging can all cause free-radical damage to healthy cells and deplete glutathione. Glutathione depletion has been correlated with lower immune function and increased vulnerability to infection due to the liver's reduced ability to detoxify.
As the generation of free radicals exceeds the body's ability to neutralize and eliminate them, oxidative stress occurs. A primary function of glutathione is to alleviate this oxidative stress.
Reduced glutathione (GSH) is a linear tripeptide of L-glutamine, L-cysteine, and glycine. Technically N-L-gamma-glutamyl-cysteinyl glycine or L-glutathione, the molecule has a sulfhydryl (SH) group on the cysteinyl portion, which accounts for its strong electron-donating character.
As electrons are lost, the molecule becomes oxidized, and two such molecules become linked (dimerized) by a disulfide bridge to form glutathione disulfide or oxidized glutathione (GSSG). This linkage is reversible upon re-reduction.
GSH is under tight homeostatic control both intracellularly and extracellularly. A dynamic balance is maintained between GSH synthesis, itâ€™s recycling from GSSG/oxidized glutathione, and its utilization.
GSH synthesis involves two closely linked, enzymatically-controlled reactions that utilize ATP. First, cysteine and glutamate are combined by gamma-glutamyl cysteinyl synthetase. Second, GSH synthetase combines gamma-glutamylcysteine with glycine to generate GSH. As GSH levels rise, they self-limit further GSH synthesis; otherwise, cysteine availability is usually rate-limiting. Fasting, protein-energy malnutrition, or other dietary amino acid deficiencies limit GSH synthesis.
GSH recycling is catalyzed by glutathione disulfide reductase, which uses reducing equivalents from NADPH to reconvert GSSG to 2GSH. The reducing power of ascorbate helps conserve systemic GSH.
GSH is used as a cofactor by (1) multiple peroxidase enzymes, to detoxify peroxides generated from oxygen radical attack on biological molecules; (2) transhydrogenases, to reduce oxidized centers on DNA, proteins, and other biomolecules; and (3) glutathione S-transferases (GST) to conjugate GSH with endogenous substances (e.g., estrogens), exogenous electrophiles (e.g., arene oxides, unsaturated carbonyls, organic halides), and diverse xenobiotics. Low GST activity may increase risk for diseaseâ€”but paradoxically, some GSH conjugates can also be toxic.
Direct attack by free radicals and other oxidative agents can also deplete GSH. The homeostatic glutathione redox cycle attempts to keep GSH repleted as it is being consumed. Amounts available from foods are limited (less that 150 mg/day), and oxidative depletion can outpace synthesis.
The liver is the largest GSH reservoir. The parenchymal cells synthesize GSH for P450 conjugation and numerous other metabolic requirementsâ€”then export GSH as a systemic source of SH-reducing power. GSH is carried in the bile to the intestinal luminal compartment. Epithelial tissues of the kidney tubules, intestinal lining and lung have substantial P450 activityâ€”and modest capacity to export GSH.
GSH equivalents circulate in the blood predominantly as cystine, the oxidized and more stable form of cysteine. Cells import cystine from the blood, reconvert it to cysteine (likely using ascorbate as cofactor), and from it synthesize GSH. Conversely, inside the cell, GSH helps re-reduce oxidized forms of other antioxidantsâ€”such as ascorbate and alpha-tocopherol.
Mechanism of Action
GSH is an extremely important cell protectant. It directly quenches reactive hydroxyl free radicals, other oxygen-centered free radicals, and radical centers on DNA and other biomolecules. GSH is a primary protectant of skin, lens, cornea, and retina against radiation damage and other biochemical foundations of P450 detoxification in the liver, kidneys, lungs, intestinal, epithelia and other organs.
GSH is the essential cofactor for many enzymes that require thiol-reducing equivalents, and helps keep redox-sensitive active sites on enzyme in the necessary reduced state. Higher-order thiol cell systems, the metallothioneins, thioredoxins and other redox regulator proteins are ultimately regulated by GSH levelsâ€”and the GSH/GSSG redox ratio. GSH/GSSG balance is crucial to homeostasisâ€”stabilizing the cellular biomolecular spectrum, and facilitating cellular performance and survival.
GSH and its metabolites also interface with energetics and neurotransmitter syntheses through several prominent metabolic pathways. GSH availability down-regulates the pro-inflammatory potential of leukotrienes and other eicosanoids. Recently discovered S-nitroso metabolites, generated in vivo from GSH and NO (nitric oxide), further diversify GSH's impact on metabolism.