What is Glutathione?
Glutathione (GSH) is often referred to as the
body's master antioxidant. Composed 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
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
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
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, it’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
disease—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 requirements—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 activity—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 antioxidants—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 levels—and
the GSH/GSSG redox ratio. GSH/GSSG balance is crucial to
homeostasis—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
Monograph provided by Alternative Medicine