Glutathione

Glutathione (γ-glutamyl-cysteinylglycine) with the molecular formula: C10H17N3O6S, is a small, low molecular weight, water-soluble thiol tripeptide consisting of three amino acids (glutamate, cysteine and glycine). Glutathione is a ubiquitous compound with a biologically active sulfhydryl group, which is contributed by the cysteine moiety and functions as the active part of the molecule. This sulfhydryl group enables interaction with a variety of biochemical systems, hence the abbreviation "GSH" for its active form. Glutathione is one of the most active antioxidant systems in human physiology (Sonthalia S et al. 2016).

The postulated effects of glutathione on pigmentation were an accidental discovery when skin whitening was observed as a side effect of high doses of glutathione. It is mainly due to the inhibition of tyrosinase. Glutathione can inhibit tyrosinase activity in three different ways.

1. Tyrosinase is inhibited directly by chelation at the copper site by the thiol group.
2. Glutathione interferes with the cellular transfer of tyrosinase to the premelanosomes - a prerequisite for melanin synthesis.
3. Tyrosinase is inhibited indirectly via its antioxidant effect. Glutathione shifts melanogenesis from eumelanin to pheomelanin synthesis through reactions between thiol groups and dopaquinone, which lead to the formation of sulfhydryl-dopa conjugates.

Glutathione has strong antioxidant properties. The radical-scavenging effect of glutathione blocks the induction of tyrosinase activity caused by peroxides. This effect mainly counteracts the reactive oxygen radicals that are released during UV irradiation. Due to these biochemical properties, the potential of glutathione in the treatment of melasma and hyperpigmentation seems plausible (Villarama CD et al. 2005).

Oral glutathione: The literature on the efficacy of orally administered glutathione is patchy. In a randomized, double-blind, two-arm, placebo-controlled study (n=60) conducted in the Thai population, the effect of orally administered glutathione (500 mg/day) on the melanin index of the skin was investigated in sixty healthy individuals. The study showed positive effects in terms of skin whitening. Another field report with lozenges containing glutathione reported an improvement in the melanin index of the skin (Handog EB et al. 2016).

Intravenous glutathione: Due to the low bioavailability of oral glutathione, intravenous injection has been promoted to achieve the desired therapeutic concentrations in the blood and skin and to achieve "instant" skin whitening. Although intravenous glutathione injections have been used for years, there is no usable clinical study on this. The manufacturers of intravenous glutathione injections recommend a dose of 600-1200 mg once or twice a week for skin whitening. There is no information on the duration of use (Sonthalia S et al. 2016).

Oral glutathione (pharmacokinetics and metabolism of orally administered glutathione): Oral glutathione is extracted from Torula yeast (Candida utilis). It is marketed as a food or dietary supplement, either alone or in combination with vitamin C, alpha-lipoic acid and other antioxidants. The fate of orally administered glutathione has been studied in animal models and human subjects. The main site of absorption is the upper jejunum. Circulating glutathione is primarily excreted via the kidney. Older studies suggest that glutathione is absorbed intact from the intestine. After systemic absorption, glutathione is broken down into amino acids and re-synthesized intracellularly. Administration of cysteine-rich glutathione precursors, particularly N-acetylcysteine, has been shown to increase intracellular glutathione levels (Whillier S et al. 2009).

The bioavailability of orally ingested glutathione in humans is controversial. An increase in plasma glutathione levels was reported in four out of five subjects after a single oral dose of 15 mg/kg body weight. In this study, plasma glutathione levels increased to 300% of baseline levels after one hour, followed by a decrease to approximately 200% of baseline levels within the next three hours. A randomized, double-blind, placebo-controlled study of oral glutathione supplementation (500 mg twice daily for four weeks) in 40 healthy adult volunteers showed no significant change in serum glutathione levels. Another randomized, double-blind, placebo-controlled study was conducted in 54 adults who received oral glutathione at a dose of either 250 mg or 1000 mg per day for six months. The results showed a steady increase in glutathione levels compared to baseline. Levels were higher in the high-dose group (30-35% increase versus 17% increase in the low-dose group). The increased levels returned to baseline after a one-month weaning period (Richie JP Jr et al. 2015).

Natural food sources of glutathione: Fresh fruits, vegetables and nuts are natural sources of glutathione. Tomatoes, avocados, oranges, walnuts and asparagus are among the most common foods that help increase glutathione levels in the body. Whey protein is another rich source of glutathione and has been used to increase systemic glutathione levels in cystic fibrosis (Sonthalia S et al. 2016).

Pharmaceutical formulations: Glutathione is primarily available as oral formulations (tablets, solutions, sublingual tablets, syrup and sprays) and parenteral formulations (intravenous and intramuscular). It has also been administered intranasally and intrabronchially. The three main routes of administration for skin whitening are topical (creams, facial washes), oral (capsules and sublingual/buccal tablets) and intravenous injection.

Topical glutathione: Glutathione is commercially available in the form of facial washes and creams. A randomized, double-blind, placebo-controlled clinical trial conducted in 30 healthy Filipino women aged 30 to 50 years provided some evidence for the efficacy of a topical 2% GSSG lotion for temporary skin whitening. Patients were randomized to apply glutathione as 2% GSSG lotion and a placebo lotion in a split-face protocol twice daily for ten weeks. GSSG was preferred over GSH because GSH is unstable in aqueous solutions. GSSG eventually produces GSH after absorption through the skin. The changes in melanin index, stratum corneum moisture content, skin smoothness, skin elasticity and wrinkle formation were objectively evaluated. The reduction of the melanin index by glutathione was significant (Sonthalia S et al. 2016).

Glutathione deficiency and supplementation in medical conditions.

Melasma and hyperpigmentation: Melanin in human skin is a polymer of various indole compounds synthesized from L-tyrosine by the Raper-Mason pathway of melanogenesis, where tyrosinase is the rate-limiting enzyme. Exposure to ultraviolet radiation leads to the formation of reactive oxygen and nitrogen species in the cells. Oral antioxidants partially reduce melanogenesis by suppressing these free radicals. One of the earliest evidences of the link between thiols and skin came from the effect of a human skin extract containing an active sulfhydryl-containing compound that inhibited melanin formation. Halprin and Ohkawar provided physical and biochemical evidence that this "sulfhydryl compound" is glutathione.

Several studies point to a (non-significant!) connection between a glutathione deficiency and various diseases: these include: Emphysema, asthma, allergic diseases, drug toxicity, metabolic disorders, malignancies and SARS-CoV-2. Most studies have been conducted on autism and cystic fibrosis (Sonthalia S et al. 2016). Confirmatory studies remain to be seen.

Since glutathione is a component of human cell metabolism, the adverse effects observed with oral intake of glutathione are likely to be minor, similar to those observed with high-dose vitamin supplements. Describe:

Lightening of hair color: A logically expected effect, since hair color depends on the amount and type of melanin that can be altered by glutathione supplementation.

patchy hypopigmentation: this occurs particularly in sun-exposed areas and has been observed after 10-12 doses of intravenous injections (Sonthalia S et al. 2016).

Exacerbation of Helicobacter pylori-associated gastric ulcers

Potentially increased susceptibility to melanoma: Theoretically, long-term administration of systemic glutathione leads to conversion of eumelanin to pheomelanin and could increase susceptibility to melanoma development in the long term.

1. Handog EB et al. (2016) An open-label, single-arm trial of the safety and efficacy of a novel preparation of glutathione as a skin-lightening agent in Filipino women. Int J Dermatol 55:153-157.

2. Richie JP Jr et al. (2015) Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Eur J Nutr 54:251-263.
3. Sonthalia S et al. (2016) Glutathione as a skin whitening agent: Facts, myths, evidence and controversies. Indian J Dermatol Venereol Leprol 822: 62-72.
4. Villarama CD et al. (2005) Glutathione as a depigmenting agent: An overview. Int J Cosmet Sci 27:147-153.