A lighter skin tone has been considered a superior trait in most races, especially in women of Asian or African descent who have Fitzpatrick skin types IV–VI. The higher prevalence of pigmentary disorders in these skin types adds to the woes of the patients. In relatively conservative societies such as India, many people are obsessed with the desire for a fair complexion for themselves as well as their spouse. Such traditions motivate the patient to desire fair complexion and sometimes seek it even against their will.
Realizing this growing need for fair skin, many pharmaceutical companies are developing different molecules for skin lightening. A lot is already known about topical depigmenting agents such as hydroquinone, glycolic acid, arbutin, kojic acid, vitamin C, vitamin E and niacinamide, all of which are readily available over-the-counter. The advent of newer depigmenting molecules such as pycnogenol, orchid and marine algae extracts, cinnamic acid, soy, aloesin and Boswellia has offered more topical options. Apart from the local adverse effects of these agents, the important limitation is the localization of their effect to the site of application alone. The quest for systemic skin lightening logically ensued. Agents that have been promoted for this purpose include glutathione, tranexamic acid, l-cysteine peptide, vitamin C, different plant extracts and their combinations.
This review focuses on glutathione as a skin-lightening agent. Aggressive media campaigns about its exaggerated effects as a “skin lightening” agent and over-the-counter availability of this drug have resulted in consumption of improper doses and schedules. These consumers, as well as dermatologists who prescribe oral glutathione for general skin lightening or as an adjuvant for disorders of hyperpigmentation, are often oblivious about its efficacy, dosing and adverse effects. Dermatologists frequently encounter patients who are inclined to self-medicate with glutathione, enticed by the manufacturers' claims. We are expected to intelligently answer queries regarding the efficacy and safety of this drug.
Oral and intravenous glutathione have been available in some countries such as the Philippines for many years. This drug has recently made inroads in other countries including India. Most of the patients who desperately seek fair complexion or a new treatment modality for their refractory facial melanosis are typically internet and social media savvy. They are rich enough to afford expensive treatment. Pharmaceutical companies that manufacture intravenous glutathione have a marketing agenda and pursue dermatologists to administer this drug to such patients. Not surprisingly, the trend of recommending and administering intravenous glutathione has increased within months of it becoming available, despite the potential adverse effects and lack of evidence.
It is important that dermatologists know about glutathione: its efficacy, the mechanism of hypopigmentary effects, pharmacokinetics, evidence-level and safety profile. In this review, we attempt to crystallize these concepts and analyze the current evidence supporting the efficacy of glutathione as an inhibitor of melanization.
Glutathione (γ-glutamyl-cysteinylglycine) is a small, low-molecular weight, water-soluble thiol-tripeptide formed by three amino acids (glutamate, cysteine and glycine). It is a ubiquitous compound with a biologically active sulfhydryl group contributed by the cysteine moiety that acts as the active part of the molecule. This sulfhydryl group allows for 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.
Glutathione exists in two interconvertible forms, reduced glutathione (GSH) and oxidized glutathione (GSSG). GSH is the predominant intracellular form, which acts as a strong antioxidant and defends against toxic compounds and xenobiotics. In this process, GSH is constantly oxidized to GSSG by the enzyme glutathione peroxidase. To maintain the intracellular redox balance, GSH is replenished through the reduction of GSSG by glutathione reductase enzyme.
Glutathione plays a key role in multiple biological functions. The most important ones have been enumerated.
Extensive research in various specialties has shown that many human diseases are associated with low glutathione levels. These conditions and causes include emphysema, asthma, allergic disorders, drug toxicity, metabolic disorders, cancer, chemotherapy and human immunodeficiency virus-acquired immune deficiency syndrome, among others. Research on the role of glutathione supplementation in these diseases is limited. Most of the studies have been done for autism and cystic fibrosis.
Melanin in human skin is a polymer of various indole compounds synthesized from L-tyrosine by the Raper–Mason pathway of melanogenesis with tyrosinase being the rate limiting enzyme. The ratio of the two different types of melanin found in skin, black-brown colored eumelanin and yellow-red pheomelanin, determines the skin colour. An increased proportion of pheomelanin is associated with lighter skin colour.
Exposure to ultraviolet radiation is the most important factor that causes undesirable hyperpigmentation. The crucial cellular event is enhanced tyrosinase activity. Exposure to ultraviolet radiation results in generation of excessive amounts of reactive oxygen and nitrogen species within the cells. Oral antioxidants partially reduce melanogenesis by suppressing these free radicals.
One of the earliest pieces of evidence of the association between thiols and skin came from the effect of an extract of human skin that contained an active sulfhydryl-containing compound. It prevented melanin formation by tyrosinase inhibition. Hyperpigmentation was observed when this compound got oxidized and inactivated by factors such as heat, radiation and inflammation with consequent loss of the inhibitory effect on tyrosinase. Halprin and Ohkawaraprovided physical and biochemical evidence that this “sulfhydryl compound” was glutathione!
The role of glutathione as a skin-lightening agent was an accidental discovery when skin lightening was noticed as a side effect of large doses of glutathione. Various mechanisms for the hypopigmentary effect of glutathione have been proposed, with inhibition of tyrosinase being the most important. Glutathione can reduce tyrosinase activity in three different ways. Tyrosinase is directly inhibited through chelation of the copper site by the thiol group. Secondly, glutathione interferes with the cellular transfer of tyrosinase to premelanosomes, a prerequisite for melanin synthesis. Thirdly, tyrosinase inhibition is effected indirectly via its antioxidant effect. Glutathione shifts melanogenesis from eumelanin to phaeomelanin synthesis by reactions between thiol groups and dopaquinone leading to the formation of sulfhydryl-dopa conjugates.
Glutathione has potent antioxidant properties. The free radical scavenging effect of glutathione blocks the induction of tyrosinase activity caused by peroxides. Glutathione has been shown to scavenge ultraviolet radiation induced reactive oxygen species generated in epidermal cells. A recent study on melasma patients noted significantly higher levels of glutathione-peroxidase enzyme in patients compared to controls, confirming the role of oxidative stress in melasma. Based on these observations, the potential of glutathione in management of melasma and hyperpigmentation seems plausible.
Fresh fruits, vegetables, and nuts are natural sources of glutathione. Tomatoes, avocados, oranges, walnuts and asparagus are some of the most common edibles that help to increase levels of glutathione in the body. Whey protein is another rich source of glutathione and has been used to enhance systemic glutathione levels in cystic fibrosis.
Glutathione is primarily available as oral formulations (pills, solutions, sublingual tablets, syrups and sprays) and parenteral formulations (intravenous and intramuscular). It has been administered by intranasal and intrabronchial routes as well. The three major routes of administration used for skin lightening are topical (creams, face washes), oral (capsules and sublingual/buccal tablets) and intravenous injections.
Glutathione is commercially available as face washes and creams. A randomized, double-blind, placebo-controlled clinical trial conducted in 30 healthy Filipino women aged 30–50 years has provided some evidence favouring the efficacy of topical 2% GSSG lotion in temporary skin lightening. Patients were randomized to apply glutathione as 2% GSSG lotion and a placeholder lotion in a split-face protocol, twice daily for ten weeks. GSSG was preferred over GSH, as GSH is unstable in aqueous solutions. GSSG eventually generates GSH after cutaneous absorption. The changes in the melanin index, moisture content of the stratum corneum, skin smoothness, skin elasticity and wrinkle formation were objectively assessed. The reduction of the melanin index with glutathione was statistically significant when compared to placebo. Glutathione treated areas had significant improvement in other parameters as well. No adverse drug effects were reported. Glutathione has also become available in the form of soaps, face washes and creams. Recently, a glutathione based chemical peel has been launched. Although evidence of efficacy is lacking, the manufacturers claim improvement of melasma, hyperpigmentation and skin ageing.
Despite the lack of published literature on the efficacy and methodology of using glutathione solution as mesotherapy, it is widely practiced by dermatologists for the treatment of melasma and other facial melanoses. It is used as monotherapy, or in combination with ascorbic acid, vitamin E, tranexamic acid, etc. Although the results are claimed to be very good, use of glutathione as mesotherapy remains controversial.
