Glutathione, reduced - GSH - Monograph

Alternative Medicine Review, Dec, 2001

Introduction

Reduced glutathione, most commonly called glutathione or GSH, is a relatively small molecule ubiquitous in living systems. (1-3) Occurring naturally in all human cells, GSH is a water-phase orthomolecule. Its intracellular depletion ultimately results in cell death and its clinical relevance has been researched for decades. (4)

GSH is the smallest intracellular thiol (-SH) molecule. Its high electron-donating capacity (high negative redox potential) combined with high intracellular concentration (millimolar levels) generate great reducing power. (2) This characteristic underlies its potent antioxidant action and enzyme cofactor properties, and supports a complex thiol-exchange system, which hierarchically regulates cell activity.

GSH levels in human tissues normally range from 0.1 to 10 millimolar (mM), most concentrated in the liver (up to 10 mM) and in the spleen, kidney, lens, erythrocytes, and leukocytes. (5) Plasma concentration is in the micromolar range (approx. 4.5 [micro]M).(6) Oxidative stressors that can deplete GSH include ultraviolet and other radiation; (7) viral infections; (2,8) environmental toxins, household chemicals, and heavy metals; (2) surgery, inflammation, burns, septic shock; (9,10) and dietary deficiencies of GSH precursors and enzyme cofactors. (11)

Biochemistry and Metabolism

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. (2) A dynamic balance is maintained between GSH synthesis, its recycling from GSSG/oxidized glutathione, and its utilization.

GSH synthesis involves two closely linked, enzymatically controlled reactions that utilize ATP. (12-14) 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, (11) pro self-limit further GSH synthesis; otherwise, cysteine availability is usually rate-limiting. Fasting, (11) protein-energy malnutrition, or other dietary amino acid deficiencies (15) 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. (16)

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) and to exogenous electrophiles (e.g., arene oxides, unsaturated carbonyls, organic halides), and diverse xenobiotics. GST underactivity may increase risk for disease (17) but paradoxically, some GSH conjugates can also be toxic. (18,19)

Direct attack by free radical and other oxidative agents can also deplete GSH. The homeostatic glutathione redox cycle attempts to keep GSH repleted as it is being consumed. (21) Amounts available from foods are limited (less than 150 mg/day), (5) 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. (12) GSH is carded 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. (13)

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), (16) and from it synthesize GSH. Conversely, inside the cell GSH helps re-reduce oxidized forms of other antioxidants such as ascorbate and alpha-tocopherol. (16)

Mechanisms 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. (2) GSH is a primary protectant of skin, lens, cornea, and retina against radiation damage, and the biochemical foundation of P450 detoxication in the liver, kidneys, lungs, intestinal epithelia, and other organs.

GSH is the essential cofactor for many enzymes which require thiol-reducing equivalents, and helps keep redox-sensitive active sites on enzymes in the necessary reduced state. (20) 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. (2,20)