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 Table of Contents  
EDITORIAL
Year : 2017  |  Volume : 4  |  Issue : 1  |  Page : 3-6

Glutathione for skin lightning: an update


1 SKINNOCENCE: The Skin Clinic & Research Centre, Sushant Lok-1, Gurgaon-122009, Haryana, India
2 Department of Dermatology & STD, MAMC-LN Hospital, New Delhi, India

Date of Web Publication19-Jun-2017

Correspondence Address:
Sidharth Sonthalia
SKINNOCENCE: The Skin Clinic & Research Centre, C-2246 (Ground Floor), ‘Suhridaya’, Sushant Lok-1, Block-C, Gurgaon-122009, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2349-5847.208348

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How to cite this article:
Sonthalia S, Sarkar R. Glutathione for skin lightning: an update. Pigment Int 2017;4:3-6

How to cite this URL:
Sonthalia S, Sarkar R. Glutathione for skin lightning: an update. Pigment Int [serial online] 2017 [cited 2017 Dec 12];4:3-6. Available from: http://www.pigmentinternational.com/text.asp?2017/4/1/3/208348




  Introduction Top


The obsession of people with skin of color to attain a lighter skin tone or fairer complexion has resulted in development of various topical and oral agents with depigmenting properties. Preparations containing chemicals, such as hydroquinone, tretinoin, mequinol, glycolic acid, kojic acid, arbutin, ascorbic acid, soy extracts, and newer cosmeceuticals, have been in vogue as popular depigmenting agents, single-agents as well as combination topicals.[1] However, apart from the local adverse effects of many of these agents, an important limitation is the localization of their effect to the application site alone. The quest for a systemic skin whitening logically ensued. Oral antioxidants such as vitamin C, vitamin E, tranexamic acid, l-cysteine peptide, and various botanical extracts have been tried but none is proven to provide an overall skin lightning effect.

The latest addition to this therapeutic armamentarium is that of glutathione (GSH) and its derivatives. GSH, a low-molecular-weight thiol-tripeptide is primal to the maintenance of intracellular redox balance. In addition to it being one of the richest antioxidants, it is being promoted as a skin lightening agent, following the discovery of its antimelanogenic properties. It inhibits tyrosinase, scavenges free radicals, and skews melanogenesis from the darker eumelanin to the lighter phaeomelanin.[2] The mechanisms postulated to be responsible for the skin lightning effect of GSH have been summarized in [Table 1]. Unfortunately, there is a clear contradiction between the extant evidence supporting its efficacy and safety, and the hype around its depigmentary properties, with pharmacosmoceuticals inundating dermatology therapeutics with GSH tablets, capsules, topical preparations, and parenteral preparations.[3]
Table 1: Mechanisms postulated to be responsible for the skin lightning effect of glutathione

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Hailed for generations as a “magical” skin whitening molecule in countries like the Republic of Phillipines, GSH has seen a rapid spurt in its popularity across the globe in a short duration of time. This has been the outcome of ardent manufacturer-supported media campaign about the almost preposterous effects of this molecule as a wonder drug for not only disorders of hyperpigmentation such as melasma, but also for general “skin whitening.” This editorial is meant to update healthcare professionals about the current status of efficacy, safety, and evidence of different formulations of GSH in skin tone lightning. For more detailed background information regarding the basic and applied physiology of GSH, readers may refer to a previously published exhaustive article on this aspect.[3]


  Current Evidence on Oral and Topical Glutathione as a Skin Lightening Agent Top


As of now, there are only two published studies that evaluated the efficacy and safety of oral, and one each on the efficacy and safety of topical and intravenous (IV) GSH as a skin whitening agent. In a 4-week randomized, double-blind, two-arm, placebo-controlled study conducted in Thai population, Arjinpathana and Asawanonda, assessed the effect of orally administered GSH, 500 mg/day (in two divided doses) over the skin melanin index (at six different sites) of 60 otherwise healthy medical students. The results showed consistent reduction in the melanin indices at all six sites in GSH group subjects, with statistically significant reduction over placebo at just two sites.[4] The tolerance to GSH was excellent. To enhance the systemic absorption of GSH, in a recent open label study involving 30 healthy Filipino women (aged 22–42 years) with Fitzpatrick skin types IV or V, Handog et al. administered buccal lozenges of GSH (500 mg/day in two divided doses) for 4 weeks and reported significant reduction in melanin index at both sun-exposed and sun-protected sites in all the subjects and moderate skin lightening in 90% of the subjects on global evaluation.[5] The singular randomized, double-blind, placebo-controlled clinical trial by Watanabe et al., conducted in 30 healthy Filipino women aged 30 to 50 years, has provided some evidence favoring efficacy of topical glutathione disulfide (oxidized form of GSH) 2% lotion, applied twice daily for 10 weeks in temporary skin whitening. The results of the split-face protocol-based study revealed statistically significant reduction of skin melanin index with GSH compared to placebo, with no adverse drug effects.[6]

All three studies suffered from glaring limitations, especially short study duration and follow-up period, small sample size, choice of cohort being young and apparently healthy subjects, and lack of measurement of blood levels of GSH.[3] Further, there is no Indian data till date, regarding the use of GSH for skin lightening or treatment of hyperpigmentation.


  Insights From Recent Research on The Effect of GSH Versus Esterified GSH in Tyrosinase Inhibition Top


For GSH to exert antimelanogenic effect via tyrosinase inhibition and switching of melanogenesis from eumelanin to pheomelanin, the intracellular concentrations of GSH is crucial and transportation of GSH into melanosomes becomes essential. Although cysteine, the precursor of GSH, is known to be transported across melanosomes through a carrier-mediated lysosomal membrane transport system, previous research has established lack of any significant trans-melanosomal transportation of GSH through a membrane channel or diffusion.[7] A recent research by Chung et al. has revealed interesting facts. They evaluated the antimelanogenic effects and cytotoxicity of GSH and its three esterified derivatives − GSH monoethyl ester (GSH-MEE), GSH diethyl ester (GSH-DEE), and GSH monoisopropyl ester (GSH-MIPE) in vitro in three cell culture lines. Interestingly, GSH did not display a significant inhibitory effect on intracellular tyrosinase activity or melanin production, whereas GSH-MEE and GSH-MIPE did.[8] GSH-DEE and GSH-MIPE additionally demonstrated cytotoxic activity. The authors concluded that the lipophilicity of the esterified derivatives of GSH enhance their intracellular and intramelanosomal delivery with subsequent tyronisa inhibition and reduction of melanin synthesis.[8],[9] In view of in vitro efficacy and lack of cytotoxicity of GSH-MEE, the researchers suggested the development of GSH-MEE instead of GSH as an efficacious and safe molecule for the treatment of hyperpigmentation.[8]


  The Controversy Surrounding Intravenous Glutathione Top


GSH-based oral dietary supplements have been accorded the status of “Generally Recognized as Safe (GRAS)” consistent with Section 201(s) of the Federal Food, Drug, and Cosmetic Act of the United States Food and Drug Administration (US-FDA).[10] There is no restriction on its availability in this form in the United States, Philippines, and Japan. Oral GSH has also become available over-the-counter (OTC) in India.

Since oral GSH has a low bioavailability, manufacturers of IV injections of GSH “recommend” this route of administration to achieve desired therapeutic levels in the blood and skin rapidly and produce “instant” skin whitening results. Despite IV GSH having been used for years in the past (and still being practiced by many), there has been no clinical trial for a long time evaluating its efficacy. Despite the lack of any evidence, manufacturers of IV GSH have been “recommending” a dose of 600–1200 mg, to be injected weekly or twice a week, with no specified net duration of the therapy.[3] It is only recently, that Zubair et al. published the first placebo-controlled study of IV GSH (1200 mg given IV twice-a-week for 6 weeks in the treatment group versus normal saline in control group) for skin tone lightning in 25 patients.[11] Although the results from this singular trial did not favor IV GSH as an effective or lasting treatment for skin tone lightening, the sample size, study design, and high drop-out rate from the treatment group (9 out of 25) of this trial exhort a cautious reading and interpretation of the results.[11] The two major issues with the methodology of this study include the use of visual Taylor scale for pre- and post-treatment evaluation of change in skin hue and tone, and lack of mention of statistical tests applied. The Taylor scale is a very subjective and unreliable tool for observing subtle changes in skin pigmentation with a very high interinvestigator variability in its interpretation.[12] Results based on Taylor scale, rather than a reliable objective parameter like the melanin index using a mexameter can at best be speculative.

Safety of IV GSH, extrapolated from studies evaluating its use for male infertility and liver disorders, seems to be convincing.[13],[14] However, sundry adverse effects of IV GSH have been documented from Philippines, resulting in the release of a position paper by the Food and Drug Administration, Department of Health, Republic of the Philippines with a warning for the public on the subject of the safety of the off-label use of GSH solution for injection. The adverse effects mentioned include Adverse cutaneous eruptions, including potentially fatal Stevens–Johnson syndrome and toxic epidermal necrolysis, thyroid dysfunction, renal dysfunction, severe abdominal pain and lethal complications such as air embolism, or potentially fatal sepsis due to incorrect/unsterile method of IV administration of GSH.[15] Adverse effects to IV GSH were reported in all patients in the treatment group in the trial by Zubair et al., with 32% patients having sustained deranged liver function.[11] Proponents of IV GSH contest that these adverse effects are attributable to other additives present in the GSH injection vials and the risk is dependent on the purity of GSH; however, this claim needs validation.

Apart from lack of any evidence of IV GSH for skin lightening, the extremely high cost of injection vials constitute another compelling deterrent to its use. Although, relatively cheaper versions are available, they run the risk of being counterfeit, with risk of life-threatening events.


  The Apparent Incongruence of The Adverse Effects of IV GSH Based On Indication Top


There is lack of clarity regarding the apparent differential “safety” of IV GSH, when administered for a medically approved reason versus administration for skin lightning. In contrast to the relative lack of safety of IV GSH (as per the Philippines’ FDA, and the trial by Zubair et al.), the analysis of two systematic reviews of IV GSH for preventing chemo-induced toxicity and one review of its use as for Parkinson’s disease (overall 10 trials included) reported minimal-to nil-adverse effects, and no long-term complications.[16] However, the number of treatments given and total treatment duration were different in these studies compared to the popular (but not validated) protocol of using IV GSH for skin lightning. Thus, this conundrum needs further exploration.


  Statutory Status of Glutathione for Skin Lightening In India Top


Akin to the labeling of oral GSH as GRAS by the US-FDA, in India, oral GSH and its combinations with ingredients like alpha-lipoic acid, ascorbic acid, and others have been covered under the Prevention of Food Adulteration Act as “food supplement,” and apparently excluded from the purview of the Drugs and Cosmetic Acts 1940, regulated by Drug Controller General of India (DCGI).[17] Thus, these supplements can be obtained OTC by consumers.

Lyka Labs, one of the major manufacturers of parenteral GSH, received permission from DCGI according to their letter dated September 14, 2011 to manufacture GSH for injection for the following indications: (1) alcoholic fatty liver, (2) alcoholic liver fibrosis, (3) alcoholic liver cirrhosis, and (4) alcoholic hepatitis.[18] However, currently, the DCGI-approved indications for IV GSH are limited to the above four hepatic disorders only. At present, there is no DCGI-approved indication for the use of IV GSH for any skin condition, hyperpigmentation or general skin lightening.


  Conclusion Top


At present, there is clear lack of convincing evidence in favor of GSH as a therapy for hyperpigmentation. The trials available till date that evaluated the role of oral topical and parenteral GSH (oral and topical) as a skin lightening agent suffered from many limitations. Safety of topical and oral GSH seems to be good. Currently, IV GSH has minimal and poor quality evidence to support or discourage its use for pigmentation. Adverse effect profile of IV GSH is another serious concern. Generation of more evidence in the form of randomized, double-blind, placebo-controlled trials with larger sample size, long-term follow-up, and well defined primary and secondary outcomes, targeted to evaluate the efficacy and safety of skin whitening effects of topical, oral as well as parenteral GSH is warranted.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Sarkar R, Chugh S, Garg VK. Newer and upcoming therapies for melasma. Indian J Dermatol Venereol Leprol 2012;78:417-28.  Back to cited text no. 1
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2.
Villarama CD, Maibach HI. Glutathione as a depigmenting agent: an overview. Int J Cosmet Sci 2005;27:147-53.  Back to cited text no. 2
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3.
Sonthalia S, Daulatabad D, Sarkar R. Glutathione as a skin whitening agent: facts, myths, evidence and controversies. Indian J Dermatol Venereol Leprol 2016;82:262-72.  Back to cited text no. 3
[PUBMED]  [Full text]  
4.
Arjinpathana N, Asawanonda P. Glutathione as an oral whitening agent: a randomized, double-blind, placebo-controlled study. J Dermatolog Treat 2012;23:97-102.  Back to cited text no. 4
[PUBMED]    
5.
Handog EB, Datuin MS, Singzon IA. 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 2016;55:153-7.  Back to cited text no. 5
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6.
Watanabe F, Hashizume E, Chan GP, Kamimura A. Skin-whitening and skin-condition-improving effects of topical oxidized glutathione: a double-blind and placebo-controlled clinical trial in healthy women. Clin Cosmet Investig Dermatol 2014;7:267-74.  Back to cited text no. 6
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7.
Potterf SB, Virador V, Wakamatsu K, Furumura M, Santis C, Ito S et al. Cysteine transport in melanosomes from murine melanocytes. Pigment Cell Res 1999;12:4-12.  Back to cited text no. 7
    
8.
Chung BY, Choi SR, Moon IJ, Park CW, Kim YH, Chang SE. The glutathione derivative, GSH monoethyl ester, may effectively whiten skin but GSH does not. Int J Mol Sci 2016;17:629.  Back to cited text no. 8
    
9.
Wellner VP, Anderson ME, Puri RN, Jensen GL, Meister A. Radioprotection by glutathione ester: transport of glutathione ester into human lymphoid cells and fibroblasts. Proc Natl Acad Sci USA 1984;81:4732-5.  Back to cited text no. 9
[PUBMED]    
10.
GRAS notice for Glutathione; 2009. URL http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-foods-gen/documents/document/ucm269318.pdf. [Accessed on February 26, 2017].  Back to cited text no. 10
    
11.
Zubair S, Hafeez S, Mujtaba G. Efficacy of intravenous glutathione vs. placebo for skin tone lightening. J Pak Ass Dermatol 2016;26:177-81.  Back to cited text no. 11
    
12.
Taylor SC, Arsonnaud S, Czernielewski J, Hyperpigmentation Scale Study Group. The Taylor Hyperpigmentation Scale: a new visual assessment tool for the evaluation of skin color and pigmentation. Cutis 2005;76:270-4.  Back to cited text no. 12
    
13.
Lenzi A, Lombardo F, Gandini L, Culasso F, Dondero F. Glutathione therapy for male infertility. Arch Androl 1992;29:65-8.  Back to cited text no. 13
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14.
Cook GC, Sherlock S. Results of a controlled clinical trial of glutathione in cases of hepatic cirrhosis. Gut 1965;6:472-6.  Back to cited text no. 14
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15.
Lazo SH. Safety on the off-label use of glutathione solution for injection (IV). Food and Drug Administration, Department of Health, Republic of the Phillipines; 2011. URL http://www.doh.gov.ph/sites/default/files/Advisories_cosmetic_DOH-FDA%20Advisory%20No.%202011-004.pdf. [Accessed on February 26, 2017].  Back to cited text no. 15
    
16.
Davids LM, Van Wyk JC, Khumalo NP. Intravenous glutathione for skin lightening: Inadequate safety data. S Afr Med J 2016;106:782-6.  Back to cited text no. 16
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17.
http://www.cdsco.nic.in/writereaddata/Notice%20DTAB.pdf. [Accessed on February 26, 2017].  Back to cited text no. 17
    
18.



 
 
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