Glutathione is an antioxidant present in almost every cell in the body, playing a role in the detoxification of drugs and xenobiotics.1 Furthermore, reduced glutathione (GSH) acts as a hydrogen donor in the detoxification of hydrogen peroxide.2
As a dietary supplement, GSH possesses various systemic effects such as improvement of liver abnormalities,3,4 improvement of diabetic complication,5 protection from viral infection,6 and antitumor activity.7,8 It is even used to treat autism.9
In vitro experiments have demonstrated that glutathione is related to melanogenesis.10–13 Its antimelanogenic properties result from a variety of mechanisms including stimulation of pheomelanin synthesis rather than darker eumelanin, its antioxidant effects,14 and interference with intracellular trafficking of melanogenic enzymes.15
Glutathione also possesses certain antiaging properties.16
Glutathione is generally a safe ingredient for use as a dietary supplement. An oral acute toxicity study of GSH in mice found that the lethal dose 50 (LD50) was more than 5 g/kg, indicating that glutathione is nontoxic. In many clinical trials, no serious adverse reactions have been observed.9,17–19 On the contrary, it can even reverse the toxic effects following excessive intake of other amino acids.20
In the human body, glutathione exists in two forms, reduced and oxidized (GSSG), which can be readily converted to each other. However, it is not clear whether the two forms are physiologically similar, especially when melanogenesis is concerned. Moreover, efficacy and long-term safety of either form have not been examined systematically.
Glutathione is regarded as food or health supplements in several countries including the Philippines, Malaysia, Taiwan, and Thailand, while it is considered a pharmaceutical agent in Korea, Japan, and People’s Republic of China. Our group previously reported that oral GSH administration (500 mg/d) resulted in lightening of skin color, when given for 4 weeks.21
The main objective of this study was to find out whether glutathione, in the reduced and oxidized forms, maintains its skin-lightening efficacy when given at a dose of 250 mg/d for 12 weeks, a dosage allowed by the Thai and Taiwanese Food and Drug Administrations.
Glutathione Physiology, Production, and Recycling
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 Figure 1, 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.
Concentration of Molecules in Cells
Glutathione exists in cells in 2 states: reduced (GSH) and oxidized (GSSG). As can be seen in Figure 2, oxidized glutathione is actually 2 reduced glutathiones bound together at the sulfur atoms.
Balance Between GSH and GSSG
The ratio of GSH to GSSG determines cell redox status of cells. Healthy cells at rest have a GSH/GSSG ratio >100 while the ratio drops to 1 to 10 in cells exposed to oxidant stress. Glutathione is also recognized as a thiol buffer maintaining sulfhydryl groups of many proteins in their reduced form. Glutathione is produced exclusively in the cytosol and actively pumped into mitochondria. GSH is made available in cells in 3 ways:
- De novo synthesis via a 2-step process catalyzed by the enzymes glutamate cysteine ligase (GCL) and glutathione synthetase (requires ATP).
- Regeneration of oxidized GSSG to reduced GSH by glutathione reductase (requires NADPH).
- Recycling of cysteine from conjugated glutathione via GGTP (requires NADPH).
Notice that all 3 require energy. The rate of synthesis, regeneration, and recycling is determined primarily by 3 factors 8:
- De novo glutathione synthesis is primarily controlled by the cellular level of the amino acid cysteine, the availability of which is the rate-limiting step.
- GCL activity is in part regulated by GSH feedback inhibition.
- If GSH is depleted due to oxidative stress, inflammation, or exposure to xenobiotics, de novo synthesis of GSH is upregulated primarily by increasing availability of cysteine through recycling of GSSG.
These 3 methods for producing glutathione can be seen in Figure 3.
Synthesis and Recycling of Glutathione 9
Critical Role of Glutathione in Detoxification, Inflammation, and So Much More
It is hard to overstate the importance of glutathione, key roles of which are summarized in Table 1. It plays a crucial role in shielding cellular macromolecules from endogenous and exogenous reactive oxygen and nitrogen species. While it directly quenches some free radicals, of perhaps greater importance is that it deals directly with the causes of oxidative stress such as mercury and POPs.
Table 1
The Critical Roles of Glutathione
- 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 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.11 Another way glutathione protects cells from oxidants is through recycling of vitamins C and E as shown in Figure 4.10
Glutathione Protection via Recycling 10
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.12 Glutathione depletion triggers apoptosis, although it is unclear whether it is mitochondrial or cytosol pools of GSH that are the determining factor.13
Perhaps the best indicator of the importance of glutathione is that its cellular and mitochondrial levels directly are highly associated with health and longevity.
Clinical Applications
As shown in Table 2, depletion of GSH has been implicated in many chronic degenerative diseases.
Table 2
Diseases Associated with GSH Depletion 14
- Neurodegenerative disorders (Alzheimer’s, Parkinson’s, and Huntington’s diseases, amyotrophic lateral sclerosis, Friedreich’s ataxia)
- Pulmonary disease (COPD, asthma, and acute respiratory distress syndrome)
- Immune diseases (HIV, autoimmune disease)
- Cardiovascular diseases (hypertension, myocardial infarction, cholesterol oxidation)
- Chronic age-related diseases (cataracts, macular degeneration, hearing impairment, and glaucoma)
- Liver disease
- Cystic fibrosis
- Aging process itself
GSH depletion has been strongly associated with the diseases and loss of function with aging. A representative study of community-dwelling elderly found that higher glutathione levels were associated with higher levels of physical health, fewer illnesses, and higher levels of self-rated health.15 As might be expected, then, GSH status has been found to parallel telomerase activity, an important indicator of lifespan.16 This depletion of GSH also shows up as progressive loss of mitochondrial function due to accumulation of damage to mtDNA.17 The ability of animal species to protect their mtDNA is directly proportional to longevity.18
GGT as Measure of Glutathione Need
GGT (gamma-glutamyl transferase) is upregulated in proportion to the need for glutathione such as for the detoxification of POPs.19 It provides the rate-limiting cysteine through a catabolic “salvage pathway.” Increases in GGT correlate with many diseases: metabolic syndrome, both fatal and nonfatal coronary heart disease (CHD) events, atherosclerosis, fatty liver, diabetes, cancer, hypertension, and carotid intima-media thickness.20–22 Of particular note, these are elevations of GGT within the supposedly “normal” range.
For example, men with a GGT of 40 to 50 have a 20-fold increased risk of diabetes.23 Research also shows a GGT 30 to 40—well within the normal range—is associated with a doubling of the risk of all-cause mortality.24 (For a more comprehensive discussion of the remarkable correlations between GGT and disease risks, please see my editorial in IMCJ 8.3).2
Ways to Increase Intracellular Glutathione
Considering how important glutathione is to health, many researchers have looked for ways to increase intracellular and intramitochondrial levels. The good news is that there are several effective strategies. The first, of course, is to decrease the need for glutathione, which means decreasing toxic load.
The most obvious is limiting alcohol consumption (see my editorial in IMCJ 11.6).6,25 Less obvious is decreasing exposure to POPs, the primary source of which are conventionally grown foods. (See my editorial in IMCJ 12.2.)7
Another strategy is to provide other antioxidants to decrease oxidative stress. A good example is α-lipoic acid, supplementation of which increases mitochondrial glutathione levels even though ALA is not used in the synthesis or recycling of glutathione.26
The obvious strategy is to directly administer glutathione. This can be done orally, topically, intravenously, intranasally, or in nebulized form. Glutathione administered intravenously, inhaled, and ingested intranasally increases systemic levels.27 IV glutathione has a short half-life but has shown at least short-term efficacy in several diseases.
Oral administration is controversial; while most research shows that oral glutathione does not increase RBC glutathione, there are a few studies that show efficacy.28
My opinion is that unmodified oral glutathione is unlikely to consistently elevate cellular levels. Oral and transdermal liposomal glutathione show promise, but research is early.29
Finally, we can provide specific nutrients to promote glutathione production. As noted above, cysteine availability is the rate-limiting step in the de novo production of glutathione. While oral cysteine does not make it through the digestive track, supplemental cysteine in the form of whey or N-acetylcysteine (NAC) is effective at raising levels. While there is substantial variation, 1000 mg/d of NAC will substantially increase glutathione in virtually all patients.30
For the rare patient who reacts to NAC, SAMe can be used.31 Do not use methionine as it will increase homocysteine. Interestingly, supplementing with NAC (600 mg/d for 4 wk) decreases GGT 25%, suggesting that increasing de novo synthesis decreases the need for GGT recycling.32
For those looking for a nonsupplemental solution, 500 mL of alcohol-free beer per day raises RBC glutathione 29%!33
There are many other examples of foods that increase glutathione. For example, 83 g/d of almonds increases glutathione in smokers by 16% and decreases their DNA damage by 29%.34
Finally, there is meditation – practitioners have 20% higher levels of glutathione.35
Clinical Application
Direct administration and promotion of production of glutathione have been used effectively in a wide range of diseases: Parkinson’s, peripheral obstructive arterial disease, cystic fibrosis, emphysema, COPD, preterm infants autism, contrast-induced nephropathy, chronic otitis media, lead exposure, nail biting(!), nonalcoholic fatty liver disease, exercise-induced fatigue – the list is long and surprisingly diverse.36–46
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