Hindawi

Dermatology Research and Practice

Volume 2020, Article ID 8547960, 6 pages
https://doi.org/10.1155/2020/8547960

Review Article
Systemic Glutathione as a Skin-Whitening Agent in Adult

1 2
I. B. S. Sitohang and S. Ninditya
1
Division of Cosmetic Dermatology, Department of Dermatology and Venereology, Faculty of Medicine, Universitas Indonesia,
Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia
2
Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

Correspondence should be addressed to I. B. S. Sitohang; [email protected]

Received 18 December 2019; Accepted 1 April 2020; Published 24 April 2020

Academic Editor: E. Helen Kemp

Copyright © 2020 I. B. S. Sitohang and S. Ninditya. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.

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 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 significant results only to some parts of the body or to 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. Highest-
evidence literatures 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 researches 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.

1. Introduction infections, and antitumor activities [3]. Several in vitro

experiments demonstrated that glutathione showed anti-
The role of skin color in daily life is important, especially melanogenic effects; thus, it is associated with melanin
for women, as it may become one’s charm. Its socio- production [2]. It is known that glutathione may promote
psychological significance may exceed its biological pheomelanin synthesis, inhibit intracellular melanogenic
function, even to the extent of causing cosmetic problems, enzymes, and demonstrate antioxidative as well as antiaging
resulting in lower quality of life and one’s self-esteem. effects [2, 3].
White-skinned individuals tan their skin, while dark- Despite the facts that glutathione is widely available, the
skinned individuals seek various ways to brighten their efficacy and safety profiles of systemic glutathione have yet to
skin. Skin-whitening cosmetics are high in demand be fully understood. Therefore, this systematic review aims
throughout Asia [1, 2]. to investigate the efficacy of systemic glutathione as a skin-
Nowadays, skin-whitening agents, either in topical, oral, whitening agent in adults.
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 2. Clinical Question
human body [2]. Reduced glutathione (GSH) yields several
systemic effects, including improvements of liver abnor- Is systemic glutathione, as compared to placebo, effective as
malities and diabetic complications, protection from viral a skin-whitening agent?
2 Dermatology Research and Practice

3. Methods emphasizing the fact that glutathione use as a skin-whit-

ening agent is still rare and is yet to be researched ex-
3.1. Search Strategy. In order to answer the clinical question, tensively on human skin.
literature search on Clinical Key, Cochrane, Journal of the From three appraised RCTs, two out of three demon-
American Academy of Dermatology, Taylor and Francis strated the positive effects of glutathione as a skin-whitening
Online, Pubmed, and ScienceDirect databases on June 3rd, agent. However, Zubair et al. opposed this finding. Theo-
2018, was conducted. Details on literature search are shown retically, glutathione level in serum will be higher after
in Table 1. intravenous administration, thus resulting in higher adverse
effects. Furthermore, long-term use of glutathione as a skin-
3.2. Study Selection. Inclusion criteria were set to cohort whitening agent is not yet known [4].
studies, RCTs, meta-analyses, and systematic reviews. The effects of glutathione on Zubair et al.’s study was
Conversely, exclusion criteria were also set: (1) incompatible lower than in the other study. This finding was suspected to
language (articles not in English), (2) animal study, and (3) arise from different genetic backgrounds of study pop-
publications prior to 2008. From 16 studies, title and abstract ulation, degree of sun exposure, and/or different measure-
screening followed by deduplication of similar articles were ment scales [4]. Hong et al. demonstrated that some of the
done. At the end, 3 RCTs based on validity, importance, and GSH content was oxidized readily and removed from cir-
applicability (VIA) were included. The literature search culation with a half-time of 10 minutes following an in-
strategy is shown in Figure 1. travenous injection, and the remainder was split to three
amino acid components [10].
Arjinpathana and Asawanonda showed that glutathione
4. Critical Appraisal is effective in most sun-exposed areas of the body. This
Critical appraisal of the RCTs is shown in Table 2. finding corroborated the hypothesis that glutathione is ef-
fective only to new melanogenesis and not to existing
5. Results pigments. This is slightly different from Handog et al. who
demonstrated that melanin index decreased significantly in
Based on literature search, three RCTs (Arjinpathana and either sun-exposed or sun-protected areas of the body. GSH
Asawanonda, Zubair et al., and Weschawalit et al.) were acts as an antimelanogenic agent by converting eumelanin to
included. This evidence-based critical appraisal will inves- pheomelanin systemically, with or without sun exposure
tigate the efficacy of glutathione as a skin-whitening agent [11].
(Table 3). Weschawalit et al. reported that both glutathione forms,
GSH and GSSG, may improve skin elasticity in either sun-
6. Discussion exposed or sun-protected areas. GSH is superior to placebo
in reducing skin wrinkles, at least in some anatomical lo-
Glutathione, a small, water-soluble thiol-tripeptide with cations. GSSG and GSH showed significant effects on
low-molecular weight, is made from three amino acids: melanin index only in some skin areas and certain age
glutamate, cysteine, and glycine [5]. Glutathione is com- groups, especially in the sun-exposed area of the right
monly found in two forms: reduced glutathione (GSH) and forearm and the GSH group with age >40 years (p � 0.031)
oxidized glutathione (GSSH). Its biological function serves [3].
as a potent antioxidant in human body [6]. Campione et al. demonstrated that enzyme glutathi-
Melanin, a skin pigment, consists of blackish-brown one-s-transferase pi (GST-π), which is present in kera-
eumelanin and reddish-yellow pheomelanin. Higher tinocytes and melanocytes, has a protective role against
pheomelanin proportion will make skin brighter [7]. Hy- tumor progression, specifically sun exposure-associated
perpigmentation is caused by the exposure to ultraviolet melanoma cells. This report makes enzyme GST-π pos-
radiation, resulting in the formation of reactive oxygen and sible to be used as an adjuvant marker of a chronically
nitrogen species between cells [8, 9]. Oral antioxidants will sun-damaged melanoma pathway [12]. A systematic re-
reduce melanogenesis by suppressing those free radicals view performed by Dulokthornsakul et al. also stated there
[6]. was a trend that glutathione might lighten skin color at
Glutathione may affect skin pigmentation by inhib- sun-exposed areas. However, its skin-whitening effect was
iting tyrosinase activity during melanogenesis, either still inconclusive, with its inconsistent findings from
directly or indirectly. Direct inactivation is done by several studies [13].
binding to the active site of enzymes containing copper The limitations of oral clinical trials are evident since the
ion, while indirect inactivation eliminates free radicals ability of GSH as an intact molecule decreases as it passes
and peroxides in antioxidative manners. During mela- through the gastrointestinal tract. To pass the intestinal tract,
nogenesis, glutathione converts eumelanin to pheome- glutathione has to be broken down into three amino acid
lanin and modulates depigmentation of melanocytotoxic components prior to absorption. Several animal studies
agents [6]. showed that intact glutathione molecules may be absorbed
Literature search on search engines revealed scarce through the small intestine, thus increasing plasma gluta-
results regarding this topic. Furthermore, most of the ar- thione level. This would not be achieved if amino acid
ticles on this topic were published in the last 6 years, component is given in equivalent amount.
Dermatology Research and Practice 3

Table 1: Literature search strategy.

Database Key words Results Included
Clinical Key Oral glutathione as skin whitening 3 1
Cochrane Glutathione 2 0
Journal of the American Academy of
Glutathione in Article title AND skin in Article title 2 1
Dermatology
Taylor and Francis Online Glutathione as skin whitening 1 1
(((glutathione [Title]) OR glutathion [Title]) AND skin whitening
PubMed 3 1
[Title])
TITLE-ABSTR-KEY (glutathione) and TITLE-ABSTR-KEY (skin
ScienceDirect 5 1
whitening)

AND “Skin whitening” OR “skin

“Glutathione”
bleaching”

Taylor and
Clinical J. Am . Science
Cochrane Francis Pubmed
key Ac Derm. direct
Online

3 2 2 1 3 5

Title and abstract screening

1 0 1 1 1 1

Deduplication
Exclusion criteria
Non-English articles, 5
animal study, cohort study,
studies published prior to
2008 Full-text articles included in this study
Inclusion criteria
RCT, meta-analysis,
systematic review 3

Figure 1: Literature search strategy.

On the contrary, a study of 30 Filipino women with whitening effects only in some areas. For cosmetic purposes,
Fitzpatrick skin type IV or V used glutathione in oral patients will have to bear their own costs as health insurances
mucosal preparations (lozenges). Handog et al. demon- do not cover cosmetic expenses. Currently, systemic glu-
strated that melanin index decreased significantly either in tathione is yet to be legally distributed in Indonesia as its
sun-exposed or sun-protected areas. Nevertheless, subjective efficacy and safety profiles are still unknown.
assessments only showed mild to moderate skin-whitening Glutathione is not recommended for long-term use,
effects [11]. especially if the patient shows noncompliance to main-
These findings are applicable to Indonesian populace. All tenance therapies, including protection from UV rays and
appraised studies were conducted on individuals with sunscreen use. Despite the fact that the appraised meta-
similar characteristics (i.e., healthy women). This is espe- analysis is valid and evident, in addition with the fact that
cially true since women tend to long for brighter skin color appraised studies were conducted in Asia (Thailand and
than men. In addition, this will exclude any different hor- Philippines), clinical trials regarding the use of systemic
monal effects that may act as confounders. From risk-benefit glutathione in Indonesian populace need to be
analysis, oral glutathione consumption shows skin- conducted.
 4

Table 2: Summary of critical appraisal of included RCTs.

Validity Relevance
Author Study Subject Intention to Equal Similar baseline Outcome Level of
Randomization Blinding Domain Determinant
design size treat treatment characteristics measurements evidence
Arjinpathana and
RCT 60 + + + + + + + + 2
Asawanonda (2010) [1]
Zubair et al. (2016) [4] RCT 32 — — — + + + + + 2
Weschawalit et al. (2017) [3] RCT 60 + + + + + + + + 2
Dermatology Research and Practice
Dermatology Research and Practice 5

Table 3: Outcome of included trials.

Author Objectives Results Summary
Baseline vs posttreatment. (1)
Melanin index in 6 areas decreased
significantly in glutathione groups.
On the contrary, in placebo arm,
melanin index increased in facial
area and decreased in the other
areas. (2) No significant difference
between baseline and post-
treatment on VISIA analysis. There
were significant increases for right
and left UV spot in placebo arm
Comparison between baseline and
(p � 0.006 and p � 0.012,
posttreatment on melanin index
respectively).
Arjinpathana and measured by Mexameter (face, sun-
Comparison between glutathione Glutathione was significant in most
Asawanonda [1] exposed forearm, sun-protected arm)
and placebo. of the sun-exposed areas.
(2012) ™
and VISIA CR system (UV spots,
evenness, and pores) for each group as
Melanin index in glutathione arm
decreased significantly compared to
well as between groups.
the control in all sun-exposed areas,
especially right side of the face
(p � 0.021) and left forearm
(p � 0.036).
UV spot in glutathione arm
increased slightly. However,
increased skin smoothness and
decreased pore size were also
observed in this group. Compared
to placebo, these findings were not
significant.
Six out of 16 (37.5%) subjects
experienced significant
improvements in glutathione group
and 3 (18.75%) subjects in placebo
group.
Changes in skin color were observed Nonetheless, within 6 months after
after 12 injections of glutathione as the last glutathione injection,
This study demonstrated poor
Zubair et al. [4] measured by Taylor hyperpigmentation gradual skin color improvements
outcomes of glutathione in terms of
(2016) scale in 2 sun-protected body areas: (1) disappeared, leaving only 1 (6.2%)
efficacy as well as cost-effectiveness.
medial arm under the axilla, and (2) out of 16 subjects with skin color
lateral upper thigh. improvements.
Both groups (glutathione and
placebo) did not demonstrate
significant difference in skin color
(p � 0.985 and p � 0.998,
respectively).
On all subjects, melanin index and
GSSG and GSH showed significant
UV spot on all areas including the
Changes in melanin index as measured effects toward melanin index only
face and arm of GSSG and GSH
by Mexameter in six body parts (sun- in some areas of the skin and
groups tend to be lower than
exposed and sun-protected). certain age groups, especially
placebo group (p > 0.05).
Other measured parameters including subjects with age >40 years on sun-
No significant difference was
quantitative evaluation of UV spots, exposed area of right forearm
observed between GSSG and GSH
Weschawalit et al. pores, and evenness measured by (p � 0.031).
groups.
[3] (2017) ™
VISIA CR system, TEWL
(transepidermal water loss) by
Subgroup analysis of subjects aged
GSH was effective to reduce facial
wrinkles at least in some anatomical
>40 years who received GSH (N � 7)
®
Tewameter TM300, water content by
showed lower melanin index than
locations, as compared to placebo.
®
Corneometer CM825, skin elasticity
placebo arm (N � 10, p � 0.031).
Both glutathione preparations
®
by Cutometer MPA580 , and skin
Melanin index on sun-exposed area
increased skin elasticity either in
wrinkles by Visioscan .
® of the left forearm in GSH group
sun-exposed or sun-protected
areas.
was lower than placebo (p � 0.057).
6 Dermatology Research and Practice

7. Conclusion and Recommendations clinicopathological study in Italy,” Acta Dermato Venere-

ologica, vol. 95, no. 1, pp. 40–44, 2015.
Based on evidence-based critical appraisal of three trials, the [13] W. Dilokthornsakul, T. Dhippayom, and P. Dilokthornsakul,
role of systemic glutathione is not effective enough as a skin- “The clinical effect of glutathione on skin color and other
whitening agent as it was only effective in some areas. related skin conditions: a systematic review,” Journal of
Furthermore, skin color will return to its original state Cosmetic Dermatology, vol. 18, no. 3, pp. 1–10, 2019.
following withdrawal of glutathione consumption; hence,
long-term effects are unsustainable. However, more re-
searches need to be conducted in order 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.

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