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A regulatory review for products containing glutathione

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DOI: 10.4103/2045-080X.183029

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 Review Article

A regulatory review for products containing

glutathione
Nur Hidayah Abd Rahim1, Long Chiau Ming1,2, Yaser Mohammed Ali Al‑Worafi3,
Md. Moklesur Rahman Sarker4
1
Faculty of Pharmacy, Universiti Teknologi MARA, 2Vector‑borne Diseases Research Group (VERDI), Pharmaceutical and Life Sciences CoRe,
Universiti Teknologi MARA, 4Faculty of Pharmacy, Lincoln University College, No. 2, Jalan Stadium SS 7/15, Kelana Jaya, 47301 Petaling Jaya,
Selangor, Malaysia, 3Department of Pharmacy Practice, College of Pharmacy, Qassim University, Buraidah, Kingdom of Saudi Arabia

Address for correspondence:

Dr. Yaser Mohammed Ali Al‑Worafi,
Department of Pharmacy Practice,
College of Pharmacy, Qassim University,
Buraidah, Kingdom of Saudi Arabia.
E‑mail: yas.alworafi@qu.edu.sa
Dr. Long Chiau Ming,
Level 11, FF1 Building, Faculty of
Pharmacy, Universiti Teknologi MARA,
Puncak Alam, Selangor, Malaysia.
E‑mail: ming.long@bath.edu
Key words: Antioxidant, efficacy,
glutathione, health supplement, safety,
regulation of healthcare products
ABSTRACT
Glutathione is a potent antioxidant as well as has important role for DNA synthesis
and repair, protein synthesis, amino acid transport, and enzyme activation. Besides
this, Glutathione products are now mainly selling as whitening agent which are mainly
marketing through social media (Facebook) and different websites. Information is
not available whether glutathione product are following the regulatory guidelines of
National Pharmaceutical Control Bureau of Malaysia (NPCB) for selling, advertisement
and promotion. This review was carried out by extracting information about glutathione
from scientific database using PubMed, Cochrane Library and Embase. Analysis of the
available information, case example of glutathione products showed that a brand of
glutathione (Glutacaps HQ) did not show the product’s registration number from NPCB,
and also did not show the name, address, contact number of the advertiser, and even not
found the name of the manufacture. Without providing the above mentioned information,
the product is selling and promoting through social media (fb) which is not allowed
by the NPCB guidelines part 4.14. So far, only two clinical trials were conducted on
glutathione supplementation for 4 weeks duration. There was no serious or systematic
adverse effects reported in clinical trials. As the two clinic trials resulted contradictory
outcomes, further studies needed for conformation of the clinic benefits of glutathione.
Otherwise, random use of glutathione may be risk for the health of the people. Besides,
the marketer mainly promoting glutathione as the skin whitening beauty product instead
of using as health supplement, it may cause additional and serious risk to the users as
the manufacturer not providing sufficient information about the product, its registration
number, manufacturing company, etc.

INTRODUCTION response. GSH has multiple functions such as [1]

participating directly in the neutralization of free
Glutathione (GSH) is the richest endogenous radicals and reactive oxygen compounds, as well as
antioxidant produced by the cell in the body and
functioned as the critical oxidative stress and immune This is an open access article distributed under the terms of the Creative
Commons Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows
others to remix, tweak, and build upon the work non‑commercially, as long as the
Access this article online author is credited and the new creations are licensed under the identical terms.
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For reprints contact: reprints@medknow.com
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 Rahim, et al.: A regulatory review for products containing glutathione
maintaining exogenous antioxidants such as Vitamins
C and E in their active forms,[2] used in metabolic and
biochemical reactions such as DNA synthesis and
repair, protein synthesis, prostaglandin synthesis,
amino acid transport, and enzyme activation for the
purpose in the immune system, the nervous system, the
gastrointestinal system, and the lungs, and also[3] vital
function in iron metabolism, for example, the yeast cells
depleted of or containing toxic levels of GSH show an
intense iron starvation‑like‑response and impairment
of the activity of extramitochondrial ISC enzymes.
Oral GSH is currently become widely used due to its
antiradical activities; however, less pharmacological
trial was found in electronic databases. In
systemic circulation, GSH is degraded rapidly by
gamma‑glutamyl transpeptidase yielding glutamate,
cysteine, and glycine. In certain condition, cysteine
can be oxidized immediately to cystine (Cys2). It
known that extracellular methionine was as strong an
antioxidant as cysteine against intracellular reactive
oxygen species  (ROS). Pharmacokinetic study of
injection GSH done by Hong et al. showed that GSH
has a very short half‑life, which is <10 min, it is difficult
to maintain it at a therapeutic concentration, glutamate
and cysteine reached their peak concentrations at
10 min, and methionine at 20 min. However, Cys2
increased gradually, peaked at 30 min, and then slowly
decreased. The 10‑  and 20‑min concentrations of
glutamate, cysteine, and methionine were significantly
higher than their baseline values, but no significant
change was observed in Cys2. Using metabolite
kinetics while assuming that cysteine is a metabolite
of GSH and that area under the curve (Cys)single i.v. is
4108.4 µM/min  after administering GSH at 50 mg/kg
of body weight, the expected cysteine concentration is
over 20 µM when this dose is given every 205.4 min.
In the same way, when it comes to methionine, the
concentration is over 50 µM when the same dose is
given every 427.4 min.[1]
CASE EXAMPLE OF PRODUCT
CONTAINING GLUTATHIONE
Glutacaps Plus®  is widely marketed through social
media. Searching through Google search engine under
search term “Glutacaps” founded 311,000 results,
whereas using term “Glutacaps Malaysia” founded
206,000 results. Glutacaps Plus® was registered under
National Pharmaceutical Control Bureau (NPCB) for
products other than cosmetics with MAL 15065008NC
and using Facebook page (FB) of Glutacaps HQ, the
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way it is marketed in Malaysia toward Medicine
Advertisement Board (MAB) is been assessed.
Effective on September 1, 2015, guideline on
advertising of medicines and medicinal products
to general publics is intended to complement the
provisions of the medicines (advertisement and sale)
act 1956 and the MAB Regulation 1976. This guideline
to be implemented for products registered with drug
control authority and to put responsibility of the
advertiser to ensure that advertising medicines and
medicinal products does not in any way put patient
and consumer safety at risk.
In general, the Glutacaps Plus® advertisement provides
information that is reliable, accurate, informative,
balanced, up to date, and good taste. Since Glutacaps
Plus ® is a medicinal product containing GSH,
hyaluronic acid, and Vitamin C, their advertisement
in FB seemed using correct and verifiable information,
thus it is not induced to unjustifiable medical use or to
give rise to undue risk. However, under the part 4.14
of this guideline, Glutacaps HQ up to this date did
not show Kementerian Kesihatan Lembaga Iklan Ubat
number, and not even stated the name, address, and
contact number of advertiser on every advertisement
post. Other than that under part of 5.3, advertisement
may include testimonials, but the individual who give
the testimony must be genuinely exist and responsible
as well as accountable to the advertisement and
its testimonial must refer to indications approved.
Glutacaps Plus® FB showed many testimonials being
used but they not state for every advertisement “The
effect of the product may vary among individuals”
and not supported with consent letter containing
information such a name of testimony, IC number,
signature, and his/her contact number.
In terms of therapeutic claims, Glutacaps Plus®
FB only promoting the use of their products for
moisturizing the skin, control acnes, and brings fairer
and glowing skin. There is no therapeutic claim of
treatment or prevention of disease which prohibited
under part 4.4 and above and not diagnosing disease
being made from their advertisement in social media.
Further assessment on this product, they are should
Search criteria used
Keywords used Glutathione, skin whitening
Years searched All
Total number of articles reviewed 12
Relevant abstracts reviewed 12
Relevant full‑text articles reviewed 3
Archives of Pharmacy Practice  Vol. 7  Supplement 1  2016
 Rahim, et al.: A regulatory review for products containing glutathione
include for each advertisement approved registration
number by NPCB anyway in the advertisement in a
clear manner and a statement: “This is a supplement
product advertisement.”
METHODOLOGY
An electronic search of PubMed, Cochrane Library,
and EMBASE to reviews of effects for studies and
trials using the following research criteria were carried
out [Table 1].
Literatures were systemically reviewed, and three
most relevant studies are reported in the evidence
tables attached.
SAFETY AND EFFICACY OF PRODUCT
It was reported that there were three mechanisms GSH
inhibit melanogenesis in in vitro. One mechanism is the
inhibition of tyrosinase activity; this is a well‑known
function of thiol compounds in general including
GSH and cysteine. Tyrosinase is rate‑limiting enzyme
controlling the production of melanin and catalyze the
conversion of L‑tyrosine supplied from the blood to
3,4‑dihydroxyphenylalanine, then to dopaquinone.
Kojic acid, arbutin, and hydroquinone are commonly
used to whiten skin and having inhibitory effects on
tyrosinase. The second mechanism of skin whitening
effect of GSH is activation of the pheomelanin
pathway. Synthesis of pheomelanin starts with the
conjugation of L‑dopaquinone formed from L‑tyrosine
and cysteine. This reaction yields the pheomelanin
precursor cysteinyldopa. When the cysteinyldopa
synthesis is induced, it leads to increase production
of pheomelanin, which is yellow–red. The third
mechanism was the skin whitening effect of GSH
is attributed to its antioxidant activity. GSH has
the ability to scavenge ROS generated in epidermal
cells following ultraviolet exposure and thus
prevent ROS‑induced melanogenesis. Other skin
whitening agents that have antioxidant activity and
melanogenesis inhibitory effects include L‑ascorbic
acid and its derivatives.[2]
Importantly, it is known that the melanogenetic
pathway is shifted from eumelanin toward
pheomelanin formation when GSH or cysteine is added
to melanocytes or melanoma cell lines. Oral dosing of
GSH is not well absorbed from the gastrointestinal
tract, and thus, intravenous (IV) administration has
been used in many countries, especially in Southeast
Asia. In Thailand, IV GSH had been banned by the
Archives of Pharmacy Practice  Vol. 7  Supplement 1  2016
authority for such modality due to severe adverse
reactions including anaphylaxis shock.[3]
To the author’s knowledge, there were only two
clinical trials done on oral GSH supplementation. The
first double‑blind, randomized, placebo‑controlled,
4  weeks duration of a clinical trial of oral GSH
supplementation was performed in 2011 by Allen and
Bradley with main objective was to determine the effect
of oral GSH on biomarkers of systemic oxidative stress
in human volunteers. The impact of this study was
more on analysis related to mechanistic efficacy than
effectiveness.[4] The second study was randomized,
double–blind, two–arm, placebo‑controlled, 4 weeks
duration of clinical trial by Arjinpathana and
Asawanonda in 2012 with the main objectives to
determine whether orally administered oral GSH
affects the skin melanin index compared to placebo.
Assessment of efficacy for oral GSH results from
Allen and Bradley using 39 participants showed there
were no differences in oxidative stress biomarkers
between treatment groups at baseline. Because
GSH status is dynamic, the outcome measures
were extended beyond GSH status alone to include
8‑hydroxy‑2’‑deoxyguanosine (8‑OHdG) and
F2‑isoprostanes (F2‑isoP), in case a change in oxidation
status was exemplified by the evidence of reduced
oxidation products rather than a change in GSH or
GSH: Oxidized GSH (GSH:GSSG) ratio. Changes in
creatinine standardized F2‑isoP (ng/mg creatinine)
and 8‑OHdG  (lg/g creatinine) were not significant
between groups at week 4. Total reduced, oxidized,
and ratio measures of GSH status were also
unchanged. However, study from Arjinpathana and
Asawanonda using analysis of covariance showed
there was statistically significant in greater reduction
of melanin indices in the GSH group compared to the
controls on all sun‑exposed areas.
Assessment of safety, in both studies, there were no
serious or systematic adverse effects were reported.
There were no isolated or combined alterations in
clinical laboratory measures including hematology,
hepatic, and renal function tests during GSH
supplementation. Side effects were generally mild
included flatulence, loose stools, flushing, and weight
gain.
POTENTIAL RISK TO GENERAL PUBLIC
Since there are two contradictory results of studies,
which the first short‑term, oral intake of GSH does
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 Rahim, et al.: A regulatory review for products containing glutathione
not improve GSH status, nor reduce markers of
oxidative stress in healthy adults, and thus routine
supplementation may not offer health benefits in the
absence of disease or oxidative challenge. Another
study stated that oral GSH significantly reduced
melanin indices and showed lighter skin after the trial.
These gap differences lead to further research with
longer duration, additional outcome measure such
as measuring reduced GSH status, demonstrating
levels of oxidative stress in the study candidates before
the inclusion and/or the study to be performed in
populations with increased oxidative burden such as
in type 2 diabetes patients.
RECOMMENDATIONS AND
CONCLUSIONS
The desire for white and fair skin is a global
phenomenon, and it is being highly capitalized by
both the cosmetic and dermatologic industries. It is
an essential role of the healthcare providers to make
the public aware that skin lightening agents may
progressively revert back the facultative color to the
constitutive level and normally this color change will
not go beyond the constitutive level. If such a change
is claimed, it should be considered to be dangerous as
such alterations can become nonreversible resulting in
vitiligo and may also predispose to other complications
such as skin cancer as the normal biochemical processes
are altered. Till date, systemic skin whitening agents
do not have much scientific evidence regarding their
use and strict laws should be enforced to ban the use
of these agents until well‑conducted randomized
controlled trials are available ensuring the safety and
efficacy of these agents.[5]
Acknowledgment
This work was supported by Academic and Research
Assimilation grants: 600‑RMI/DANA5/3/ARAS
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(64/2015). The authors would like to express their
gratitude to Ministry of Higher Education and
Universiti Teknologi MARA  (UiTM), Malaysia for
financial support for this research. The funders had
no role in the study design, data collection, and
analysis, decision to publish or preparation of the
manuscript.
Financial support and sponsorship
This work was supported by Academic and Research
Assimilation grants: 600‑RMI/DANA5/3/ARAS
(64/2015). The authors would like to express their
gratitude to Ministry of Higher Education and
Universiti Teknologi MARA  (UiTM), Malaysia for
financial support for this research.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. Hong SY, Gil HW, Yang JO, Lee EY, Kim HK, Kim SH, et al.
Pharmacokinetics of glutathione and its metabolites in
normal subjects. J Korean Med Sci 2005;20:721‑6.
2. 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.
3. Arjinpathana N, Asawanonda P. Glutathione as an
oral whitening agent: A randomized, double‑blind,
placebo ‑controlled study. J Dermatolog Treat
2012;23:97‑102.
4. Allen J, Bradley RD. Effects of oral glutathione
supplementation on systemic oxidative stress biomarkers
in human volunteers. J Altern Complement Med
2011;17:827‑33.
5. Malathi M, Thappa DM. Systemic skin whitening/
lightening agents: What is the evidence? Indian J
Dermatol Venereol Leprol 2013;79:842‑6.
Archives of Pharmacy Practice  Vol. 7  Supplement 1  2016