Objectives. To compare the efficacy and safety profiles of systemic glutathione as a skin-whitening agent in adults from several randomized controlled trials (RCTs). Methods. This study is an evidence-based case report with a literature search conducted on Clinical Key, Cochrane, Journal of the American Academy of Dermatology, Taylor and Francis Online, ScienceDirect, and PubMed databases. Three relevant RCTs were extracted and assessed for validity, importance, and applicability. Results. From 3 included trials, one of the studies opposed glutathione as a skin-whitening agent. However, the other two showed signifificant results only for some parts of the body or for certain age groups. As a skin-whitening agent, studies showed that glutathione yielded other cosmetic benefits as it may improve skin elasticity and reduce skin wrinkles. Furthermore, glutathione was well tolerated in oral preparations, but not in parenteral preparations. Conclusions. The highest evidence literature showed that glutathione is not beneficial enough as a skin-whitening agent as it was only effective in some parts of the body and did not elicit long-lasting effects. However, its safety profiles in oral preparations were well tolerated. More research regarding the time needed for skin color to return to its original state following drug withdrawal need to be conducted as it is yet to be discovered.

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1. Introduction 

The role of skin color in daily life is important, especially for women, as it may become one’s charm. Its socio-psychological significance may exceed its biological function, even to the extent of causing cosmetic problems, resulting in lower quality of life and one’s self-esteem. White-skinned individuals tan their skin, while dark-skinned individuals seek various ways to brighten their skin. Skin-whitening cosmetics are high in demand throughout Asia [1, 2].

Nowadays, skin-whitening agents, either in topical, oral, or intravenous preparations, are widely available in markets. Glutathione, one of the skin-whitening agents in cosmetic industries [1], is an antioxidant commonly found in the human body [2]. Reduced glutathione (GSH) yields several systemic effects, including improvements in liver abnormalities and diabetic complications, protection from viral infections, and antitumor activities [3]. Several in vitro experiments demonstrated that glutathione showed anti-melanogenic effects; thus, it is associated with melanin production [2]. It is known that glutathione may promote pheomelanin synthesis, inhibit intracellular melanogenic enzymes, and demonstrate antioxidative as well as antiaging effects [2, 3].

Even though glutathione is widely available, the efficacy and safety profiles of systemic glutathione have yet to be fully understood. Therefore, this systematic review aims to investigate the efficacy of systemic glutathione as a skin-whitening agent in adults.

2. Clinical Question 

Is systemic glutathione, as compared to placebo, effective as a skin-whitening agent?

3. Methods

3.1. Search Strategy. To answer the clinical question, a literature search on Clinical Key, Cochrane, Journal of the American Academy of Dermatology, Taylor and Francis Online, Pubmed, and ScienceDirect databases on June 3rd, 2018, was conducted. Details on the literature search are shown in Table 1.

3.2. Study Selection. Inclusion criteria were set to cohort studies, RCTs, meta-analyses, and systematic reviews. Conversely, exclusion criteria were also set: (1) incompatible language (articles not in English), (2) animal study, and (3) publications before 2008. From 16 studies, title, and abstract screening followed by deduplication of similar articles were done. In the end, 3 RCTs based on validity, importance, and applicability (VIA) were included. The literature search strategy is shown in Figure 1.

4. Critical Appraisal

Critical appraisal of the RCTs is shown in Table 2.

5. Results 

Based on the literature search, three RCTs (Arjinpathana and Asawanonda, Zubair et al., and Weschawalit et al.) were included. This is an evidence-based critical appraisal that will investigate the efficacy of glutathione as a skin-whitening agent (Table 3).

6. Discussion

Glutathione, a small, water-soluble thiol-tripeptide with low-molecular-weight, is made from three amino acids: glutamate, cysteine, and glycine [5]. Glutathione is commonly found in two forms: reduced glutathione (GSH) and oxidized glutathione (GSSH). Its biological function serves as a potent antioxidant in the human body [6].

Melanin, a skin pigment, consists of blackish-brown eumelanin and reddish-yellow pheomelanin. Higher pheomelanin proportion will make skin brighter [7]. Hyperpigmentation is caused by exposure to ultraviolet radiation, resulting in the formation of reactive oxygen and nitrogen species between cells [8, 9]. Oral antioxidants will reduce melanogenesis by suppressing those free radicals [6].

Glutathione may affect skin pigmentation by inhibiting tyrosinase activity during melanogenesis, either directly or indirectly. Direct inactivation is done by binding to the active site of enzymes containing copper ions, while indirect inactivation eliminates free radicals and peroxides in an antioxidative manner. During melanogenesis, glutathione converts eumelanin to pheomelanin and modulates the depigmentation of melanocytotoxic agents [6].

Literature searches on search engines revealed scarce results regarding this topic. Furthermore, most of the articles on this topic were published in the last 6 years, emphasizing the fact that glutathione use as a skin-whitening agent is still rare and is yet to be researched extensively on human skin

From three appraised RCTs, two out of three demonstrated the positive effects of glutathione as a skin-whitening agent. However, Zubair et al. opposed this finding. Theoretically, glutathione levels in serum will be higher after intravenous administration, thus resulting in higher adverse effects. Furthermore, the long-term use of glutathione as a skin-whitening agent is not yet known [4].

The effects of glutathione in Zubair et al.’s study were lower than in the other study. This finding was suspected to arise from different genetic backgrounds of the study population, degree of sun exposure, and/or different measurement scales [4]. Hong et al. demonstrated that some of the GSH content was oxidized readily and removed from circulation with a half-time of 10 minutes following intravenous injection, and the remainder was split into three amino acid components [10].

Arjinpathana and Asawanonda showed that glutathione is effective in most sun-exposed areas of the body. This finding corroborated the hypothesis that glutathione is effective only for new melanogenesis and not for existing pigments. This is slightly different from Handog et al. who demonstrated that the melanin index decreased significantly in either sun-exposed or sun-protected areas of the body. GSH acts as an anti-melanogenic agent by converting eumelanin to pheomelanin systemically, with or without sun exposure [11].

Weschawalit et al. reported that both glutathione forms, GSH and GSSG, may improve skin elasticity in either sun-exposed or sun-protected areas. GSH is superior to placebo in reducing skin wrinkles, at least in some anatomical locations. GSSG and GSH showed significant effects on melanin index only in some skin areas and certain age groups, especially in the sun-exposed area of the right forearm and the GSH group with age >40 years (p =0.031) [3].

Campione et al. demonstrated that the enzyme glutathione-s-transferase pi (GST-π), which is present in keratinocytes and melanocytes, has a protective role against tumor progression, specifically sun-exposure-associated melanoma cells. This report makes the enzyme GST-π possible to be used as an adjuvant marker of a chronically sun-damaged melanoma pathway [12]. A systematic review performed by Dulokthornsakul et al. also stated there was a trend that glutathione might lighten skin color in sun-exposed areas. However, its skin-whitening effect was still inconclusive, with inconsistent findings from several studies [13].

The limitations of oral clinical trials are evident since the ability of GSH as an intact molecule decreases as it passes through the gastrointestinal tract. To pass the intestinal tract, glutathione has to be broken down into three amino acid components before absorption. Several animal studies showed that intact glutathione molecules may be absorbed through the small intestine, thus increasing plasma glutathione levels. This would not be achieved if the amino acid composition is given in an equivalent amount.

On the contrary, a study of 30 Filipino women with Fitzpatrick skin type IV or V used glutathione in oral mucosal preparations (lozenges). Handog et al. demonstrated that the melanin index decreased significantly either in sun-exposed or sun-protected areas. Nevertheless, subjective assessments only showed mild to moderate skin-whitening effects [11].

These findings apply to the Indonesian populace. All appraised studies were conducted on individuals with similar characteristics (i.e., healthy women). This is especially true since women tend to long for brighter skin color than men. In addition, this will exclude any different hormonal effects that may act as confounders. From risk-benefit analysis, oral glutathione consumption shows skinwhitening effects only in some areas. For cosmetic purposes, patients will have to bear their costs as health insurance does not cover cosmetic expenses. Currently, systemic glutathione is yet to be legally distributed in Indonesia as its effiffifficacy and safety profiles are still unknown.

Glutathione is not recommended for long-term use, especially if the patient shows noncompliance to maintenance therapies, including protection from UV rays and sunscreen use. Even though the appraised meta-analysis is valid and evident, in addition to the fact that appraised studies were conducted in Asia (Thailand and the Philippines), clinical trials regarding the use of systemic glutathione in the Indonesian populace need to be conducted

7. Conclusion and Recommendations 

Based on evidence-based critical appraisal of three trials, the role of systemic glutathione is not effective enough as a skin-whitening agent as it was only effective in some areas. Furthermore, skin color will return to its original state following the withdrawal of glutathione consumption; hence, long-term effects are unsustainable. However, more researches need to be conducted to investigate how much time is needed for skin color to return to its original state following drug withdrawal.

Conflicts of Interest

The authors declare no conflicts of interest in this study.

References

[1] N. Arjinpathana and P. Asawanonda, “Glutathione as an oral whitening agent: a randomized, double-blind, placebo-controlled study,” Journal of Dermatological Treatment, vol. 23, no. 10, pp. 1–6, 2010. 

[2] R. Kamakshi, “Fairness via formulations: a review of cosmetic skin-lightening ingredients,” Journal of Cosmetic Science, vol. 63, no. 1, pp. 43–54, 2011.

[3] S. Weschawalit, S. Thon this, P. Phutrakool, and P. Asawanonda, “Glutathione and its antiaging and anti-melanogenic effects,” Clinical, Cosmetic and Investigational Dermatology, vol. 10, no. 10, pp. 147–153, 2017. 

[4] S. Zubair, S. Hafeez, and G. Mujtaba, “Efficacy of intravenous glutathione vs. placebo for skin tone lightening,” -e-Journal of Pakistan Association of Dermatologists, vol. 26, no. 23, pp. 177–181, 2016.

[5] D. A. Dickinson and H. J. Forman, “Glutathione in defense and signaling: lessons from a small thiol,” Annals of the New York Academy of Sciences, vol. 973, no. 1, pp. 488–504, 2002. 

[6] S. Sonthalia, D. Daulatabad, and R. Sarkar, “Glutathione as a skin whitening agent: facts, myths, evidence and controversies,” Indian Journal of Dermatology, Venereology, and Leprology, vol. 82, no. 3, pp. 262–272, 2016.

[7] J. J. Nordlund and R. Boissy, “The biology of melanocytes,” in -e Biology of the Skin, R. K. Freinkel and D. T. Woodley, Eds., pp. p113–30, CRC Press, New York, NY, USA, 2001.

[8] F. Watanabe, E. Hashizume, G. P. Chan, and A. Kamimura, “Skin-whitening and skin-condition-improving effects of topical oxidized glutathione: a double-blind and placebo-controlled clinical trial in healthy women,” Clinical, Cosmetic and Investigational Dermatology, vol. 267, pp. 267–274, 2014. 

[9] H. Masaki, “Role of antioxidants in the skin: anti-aging effects,” Journal of Dermatological Science, vol. 58, no. 2, pp. 95–90, 2010. 

[10] S.-Y. Hong, H.-W. Gil, J.-O. Yang et al., “Pharmacokinetics of glutathione and its metabolites in normal subjects,” Journal of Korean Medical Science, vol. 20, no. 5, pp. 721–726, 2005.

[11] E. B. Handog, M. S. L. Datuin, and I. A. Singzon, “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,” International Journal of Dermatology, vol. 55, no. 2, pp. 153–157, 2016.

[12] E. Campione, E. Medda, E. Paterno, et al., “Chronically sun-damaged melanomas express low levels of nuclear glutathione-S-transferase-π: an epidemiological and clinicopathological study in Italy,” Acta Dermato Venerelogical, vol. 95, no. 1, pp. 40–44, 2015. 

[13] W. Dilokthornsakul, T. Dhippayom, and P. Dilokthornsakul, “The clinical effect of glutathione on skin color and other related skin conditions: a systematic review,” Journal of Cosmetic Dermatology, vol. 18, no. 3, pp. 1–10, 2019.

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