Although often thought of as an amino acid, the antioxidant glutathione (GSH) is actually a tripeptide1,2 primarily synthesized in the liver and composed of the amino acids cysteine, glutamic acid and glycine.3,4 Arguably, GSH is the most important tripeptide in the body, playing critical roles in the synthesis and repair of DNA and protein, as well as the synthesis of prostaglandins. It is likewise involved in the transport of amino acids, the metabolism of toxins and carcinogens, the function of the immune system function, the prevention of oxidative cell damage, and the activation of enzymes activation.5-7 While there are many reasons to supplement with GSH, two particularly compelling reasons are the benefits it offers for liver health and beautiful skin—the focus of this article. First, though, let’s review data on GSH depletion and absorption.
There are a number of oxidative stressors that can deplete GSH, including ultraviolet and other radiation, viral infections, environmental toxins, household chemicals, heavy metals, surgery, inflammation, burns, septic shock, and dietary deficiencies of GSH precursors and enzyme cofactors.8 In addition, research suggests that GSH levels decline with age.9-10
As a dietary supplement, glutathione has had a rocky beginning due to perceived bioavailability problems. The reason for this is that, in the 1990s, some researchers pointed out that despite being present in fruits, vegetables, and meats, the levels of glutathione in the body do not seem to correlate to dietary intake; this suggested that oral GSH might be inactivated by peptidases in the gut.11 Also, two older studies12,13 showed that there was no increase in blood GHS levels when 1,000-3,000 mg were given to subjects. Consequently, other strategies were used to increase GSH levels, such as supplementation with NAC.14
In 2014, however, GSE’s perceived bioavailability issues changed. A new study15 was published in the Journal of Agricultural and Food Chemistry, which helped put a new light on the old research. The new study demonstrated that intact GSH (as OPITAC, a yeast-derived glutathione by Kohjin/Mitsubishi) can be rapidly transported across intestinal epithelial cells. Then, the GSH was rapidly converted into oxidized glutathione (GSSG) and accumulated in red blood cells and liver but was little present in plasma. So, to reiterate, the GSH was definitely absorbed (in fact very quickly) but didn’t show up in blood plasma since was converted to GSSG and then stored in red blood cells and the liver. The take home message from this research is that supplementation with GSH is an effective way to increase GSH levels in the body.
This mechanism was verified in another study16 describing how (as OPITAC, a yeast-derived glutathione by Kohjin/Mitsubishi) is directly absorbed in its electrochemically reduced form in the intestine, is then transported in the blood in bound forms, and is finally deposited into the liver in reduced form.
Perhaps even more meaningful is a six-month randomized, double-blinded, placebo-controlled trial17 of oral GSH (250 or 1,000 mg/day, as OPITAC glutathione, Kohjin/Mitsubishi) on GSH levels in blood, erythrocytes, plasma, lymphocytes and exfoliated buccal mucosal cells conducted in 54 adults. Results showed that GSH levels in blood increased after one, three and six months versus baseline at both doses. At six months, mean GSH levels increased 30–35 percent in erythrocytes, plasma and lymphocytes and 260 percent in buccal cells in the 1,000 mg group (P < 0.05), and at 17 and 29 percent in blood and erythrocytes, respectively, in the low-dose group (P < 0.05). The take home message from this research is that supplementation with GSH is an effective way to increase and maintain GSH levels in the body.
The liver is the largest reservoir GSH, which makes sense since the liver is a major site of GSE maunfacture in the body.18 Special cells in the liver synthesize GSH for purposes of detoxification, and the GSH is also transported to other parts of the body.19
The liver is a primary organ of detoxification in our bodies. Its cells have sophisticated mechanisms to break down toxic substances, including both internal and external compounds. During the process, the toxin is attached or conjugated to a water-soluble substance. This attachment makes the toxic molecule more water-soluble, less harmful, and easier to get rid of via the urine or bile. Glutathione conjugation produces water-soluble mercaptates which are excreted via the kidneys and effectively detoxifies acetaminophen and nicotine. The elimination of fat-soluble compounds, especially heavy metals like mercury and lead, is dependent upon adequate levels of glutathione.20 Likewise, GSH is used as a cofactor by multiple peroxidase enzymes, to detoxify peroxides generated from oxygen radical attack on biological molecules, and by transhydrogenase enzymes to reduce oxidized centers on DNA, proteins and other biomolecules.21
The practical applications of this were seen in a study22 with 10 workers exposed to lead. Five received GSH at 200 mg/day for 30 days, and five subjects were designated as the control, to measure the ALA dehydratase activity (which is inhibited by lead). The ALA dehydratase activity showed a significant increase in the GSH treatment group compared to the control group (p < 0.05), indicating that GSH was useful for treating patients with lead-poisoning.
Alcohol consumption is known to induce hepatic steatosis (fatty liver disease)23 and cause biomembrane disorder24 because of hepatic lipid peroxidation. Hepatic steatosis may trigger various lifestyle-related diseases, as well as hepatic cirrhosis because it decreases hepatic physiological function. However, animal research has demonstrated that GSH protects the liver against alcohol intoxication.25
A human crossover comparative study26 was conducted to examine the impact of GSH supplementation on the effects of alcohol intake. Twenty healthy men and women were divided into three groups including placebo, GSH 100 mg (as OPITAC glutathione, Kohjin/Mitsubishi), and curcumin 30 mg. Evaluated laboratory parameters were 1) breath alcohol concentration (mg/L) measured using an alcohol checker 20, 60, 120 and 180 minutes after alcohol consumption, and 2) subjective feeling questionnaire. All subjects received whiskey, double diluted with an amount equal to the subject’s weight × 1.25 mL, and the subject was instructed to drink the entire sample within 10 minutes. Results were that the breath alcohol concentration in the GSH group significantly decreased 20 (p<0.01), 60 (p<0.01), 120 (p<0.05), and 180 (p<0.08) minutes after alcohol consumption compared to the placebo and curcumin groups.
In addition, the GSH group scored better in the “sleepiness,” “headache” and “upset stomach” items on the subjective feeling questionnaire. Furthermore, aspartate aminotransferase (AST) concentrations were significantly lower than that of the placebo group after two months. This is important since an elevated AST in an alcoholic or heavy alcohol consumer indicates alcohol-induced organ damage.27 In conclusion, the oral intake of GSH demonstrated the effectiveness of the oral intake of GSH on alcohol consumption-related stress, as well as its long-term improvement of hepatic function.
Nonalcoholic fatty liver disease
Nonalcoholic fatty liver disease (NAFLD) refers to the accumulation of fat in the liver of people who drink little or no alcohol. Unfortunately, NAFLD is common—with easily one-third of all American adults being affected,28 often without obvious signs and symptoms, and sometimes no complications. In more serious cases, however, the fat that accumulates in NAFLD can cause liver inflammation and scarring.29 In addition, NAFLD is usually associated with insulin resistance, central obesity, reduced glucose tolerance, type-2 diabetes and high triglyceride levels.
Given the crucial roles of GSH in phase 2 liver detoxification, an open label, single arm, multicenter, pilot trial30 was conducted to examine the therapeutic effects of GSH supplementation (300 mg/day, as OPITAC glutathione, Kohjin/Mitsubishi) in 29 patients with NAFLD. Clinical parameters were evaluated before and after GSH supplementation. Liver fat and fibrosis were also quantified. The primary outcome of the study was the change in alanine aminotransferase (ALT) levels. Results were that ALT levels significantly decreased. Triglycerides, non-esterified fatty acids, and ferritin levels also decreased. This pilot study demonstrates the potential therapeutic effects of oral administration of glutathione in practical dose for patients with NAFLD. Large-scale clinical trials are needed to verify its efficacy.
Markedly increased melanin formation, due to activation of melanocytes in the skin, is known to cause blemishes such as freckles, pigmentation and UV-induced skin spots (aka age spots or liver spots), especially after tanning. On the areas of skin that have had years of frequent and prolonged sun exposure, age spots appear when melanin becomes “clumped” or is produced in high concentrations.31 Glutathione is known to be one of materials to prevent deterioration or to improve such pigmentation-related skin conditions.
Skin Pigmentation, Wrinkles and Pores
A study32 was conducted in which eight women in their 30s or early 40s each supplemented with GSH 100 mg/day (as OPITAC glutathione, Kohjin/Mitsubishi). The test period was two months, and their skin condition at the beginning of the test and after two months was compared using the Robo Skin Analyzer. Five parameters were analyzed: skin brightness, amount of skin pigmentation, total area of skin pigmentation, number of pores and number of wrinkles (under the eyes). When subjects’ skin brightness was measured on the second day of the study, the level of brightness for all subjects had improved. In addition, it was shown that the amount of skin pigmentation and the total area of skin pigmentation decreased over the two months. Blemishes and pigmentation appeared to improve. In addition to the whitening effect, the number of wrinkles under the eyes and pores also decreased.
UV-induced Skin Spots
To determine whether supplementing with 500 mg of glutathione daily for four weeks affects the skin melanin index compared with placebo, a randomized, double-blind, two-arm, placebo-controlled study33 was conducted with 60 otherwise healthy medical students. Melanin indices were measured at six different sites on the body. Results were that, at four weeks, melanin indices decreased consistently at all six sites in subjects who received glutathione. The reductions were statistically significantly greater than those receiving placebo at two sites, namely the right side of the face and the sun-exposed left forearm (p = 0.021 and 0.036, respectively). This was similarly reflected in the changes in the number of UV spots. Both glutathione and placebo were very well tolerated. In conclusion, oral glutathione administration results in a lightening of skin color in the subjects tested.
The use of a lozenge containing GSH 500 mg was investigated in an open-label, single-arm trial34 in order to evaluate the buccal mucosa as a route for GSH administration in relation to skin lightening. Substances that are absorbed through the buccal route go directly into the systemic circulation, effectively bypassing the gastrointestinal tract. Thirty Filipino females with Fitzpatrick skin types IV or V received a glutathione-containing lozenge daily for eight weeks. Results were significant decrease in melanin indices from baseline to endpoint that became evident in as little as two weeks. There were no serious adverse events, and laboratory examination findings remained normal. The researchers concluded that the lozenge containing glutathione was safe and effective in lightening the skin of Filipino women.
Topical GSH for Skin
A double blind randomized clinical trial35 was conducted in Yogyakarta, Indonesia, in 74 healthy Indonesian women, with average age 33.3 ± 5.9 years, to assess the topical benefits of GSH. Each subject received supervised applications of facial wash twice a day, day cream with sunscreen and night cream. The subjects were divided into three groups based on the active ingredients of the tested products, which included GSH (as OPITAC glutathione, Kohjin/Mitsubishi) 0.1 percent, GSH 0.5 percent, and without GSH. The effects of the tested products in lightening skin color and pigmentation were measured colorimetry with Chromameter Minolta for L*. Compared to a baseline, there were significant increases of L* (lightness) or ΔL*detected as early as week 2 in which group of GSH 0.1 percent were significantly higher compared to group of GSH 0.5 percent and group without GSH. Hyperpigmented lesions also improved, where GSH 0.5 percent group showed its superiority compared to other groups in week 8. In conclusion, the skin care products containing GSH 0.1 percent and 0.5 percent were effective in facial skin lightening.
GSH performs a variety of important function in the human body. Despite previous misconceptions to the contrary, it is now understood that supplemental GSH is bioavailable and will increase GSH levels in the body. Research has demonstrated the effectiveness of GSH (as OPITAC glutathione, Kohjin/Mitsubishi) for liver health and beautiful skin (in both oral and topical applications). VR
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Gene Bruno, MS, MHS, Professor Emiritus of Nutraceutical Science, is a nutritionist, herbalist, writer and educator. For more than 40 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. He can be reached at email@example.com.