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Review on Skin Whitening Agents

Authors:
  • Faculty of Pharmacy, Northern Border University

Abstract

Skin whitening is a term used for lightening the complexion of the skin through artificial means like creams, lotions, soaps and injections. Unfortunately the appeal of these skin bleaching products is based on the obsession of people across the world with skin color. Melanins are produced by specialized cells, termed melanocytes, which are located primarily in the skin, hair bulbs, and eyes. The melanins can be of two basic types: eumelanins, which are brown or black, and phaeomelanins, which are red or yellow, in mammals typ-ically there are mixtures of both types (Figure1). Increased produc-tion and accumulation of mela-nins characterize number of skin diseases, which include hyperpi-gentation such as melanoma, post-inflammatory melanoderma, solar lentigo, etc. Several modalities of treatment for these problems are available including chemical agents or physical therapies. The aim of this review article is to show that some of the skin whitening creams , often sold illegally without a prescription may contain dangerous ingredients that could put people health at risk.
Khartoum Pharmacy Journal Vol. 13 No. 1 June. 2010
5
ARTICLES
Review on Skin Whitening Agents
Abstract
Skin whitening is a term used
for lightening the complexion of
the skin through articial means
like creams, lotions, soaps and in-
jections. Unfortunately the appeal
of these skin bleaching products is
based on the obsession of people
across the world with skin color.
Melanins are produced by special-
ized cells, termed melanocytes,
which are located primarily in the
skin, hair bulbs, and eyes. The
melanins can be of two basic types:
eumelanins, which are brown or
black, and phaeomelanins, which
are red or yellow, in mammals typ-
ically there are mixtures of both
types (Figure1). Increased produc-
tion and accumulation of mela-
nins characterize number of skin
diseases, which include hyperpi-
gentation such as melanoma, post-
inammatory melanoderma, solar
lentigo, etc. Several modalities of
treatment for these problems are
available including
chemical agents or
physical therapies.
The aim of this
review article is to
show that some of
the skin whitening
creams , often sold
illegally without a
prescription may
contain danger-
ous ingredients that
could put people
health at risk.
Keywords: skin whitening;
melanin; mercury; hydroquinone;
corticosteroids.
Introduction
The term skin whitening (also
called skin bleaching) covers a
variety of cosmetic methods used
in an attempt to whiten the skin
(Wikipedia, 2007).
Visible pigmentation in mam-
mals results from the synthesis and
distribution of melanin in the skin,
hair bulbs, and eyes. The melanins
can be of two basic types: eumela-
nins, which are brown or black, and
phaeomelanins, which are red or
yellow, in mammals typically there
are mixtures of both types. Mela-
nins are produced by specialized
cells, termed melanocytes, which
are located primarily in the skin,
hair bulbs, and eyes. Melanocytes
synthesize melanin within discrete
organelles, termed melanosomes,
which can be produced in varying
sizes, numbers, and densities. The
melanosomes are then passed on,
in skin to keratinocytes and in hair
bulbs to the hair shaft, where the
nal distribution patterns of the
pigment are determined. This dis-
tribution plays an important role in
determining color; note for exam-
ple the variety of colors in the skin,
hair, and eyes of humans (Hearing
and Tsukamoto, 1991)
The most essential enzyme in
this melanin biosynthetic pathway
is tyrosinase and it is the only en-
zyme absolutely required for mela-
nin production. The main physi-
ological stimulus of melanogenesis
is the UV radiation of solar light,
which can act directly on melano-
cytes or indirectly through the re-
lease of keratinocyte-derived fac-
tors such as α-melanocyte stimu-
lating hormone (MSH). Increased
production and accumulation of
melanins characterize number of
skin diseases, which include hyper-
pigmentation such as melanoma,
post-inammatory melanoderma,
solar lentigo, etc. Several modali-
ties of treatment for these problems
are available including chemical
agents or physical therapies (Kang
et al., 2004; Pravez et al., 2007).
Stretch marks
Ahmed Hassan H. Arbab (M.Pharm) & Mahmoud Mudawi Eltahir (PhD)
Faculty of Pharmacy, Omdurman Islamic University
6
ARTICLES
The classication of
depigmenting activity
and skin whitening
agents:
Depigmentation can be
achieved by (i) regulating the
transcription and activity of tyro-
sinase, (ii) regulating the uptake
and distribution of melanosomes
in recipient keratinocytes and (iii)
interference with melanosomes
maturation and transfer ( Solano et
al., 2006). However, as a result of
the key role played by tyrosinase
in the melanin biosynthesis, most
whitening agents acts specially
to reduce the function of enzyme
by mean of several mechanisms
(Donsing and Viyoch, 2008).
Therefore, tyrosinase inhibitors
have become increasingly impor-
tant in the cosmetic and medicinal
products used in the prevention of
hyperpigmentaion and skin whit-
ening (Khan, 2007).
Skin whiteners in
commercial use
1- Mercury containing
compounds:
In the early days, toxic com-
pounds, such as mercury containing
compounds have been used for skin
whitening purposes because mercu-
ry inactivates the enzyme that leads
It may also function by interfering
with the formation or degradation
of melanosomes and by inhibiting
the synthesis of DNA and RNA
within melanocytes.
Hydroquinone is a most widely
used depigmenting agent at pres-
ent, but is considered to be highly
cytotoxic to melanocytes and po-
tentiality mutagenic to mammalian
cells (Thiele et al., 1997; Dons-
ing and Viyoch, 2008). It can be
irritating and causes redness and
burning, also it has been shown
to cause exogenous ochronosis.
Ochronosis may result in loss of
elasticity of the skin and impaired
wound healing which has resulted
in a ban on its over-the-counter use
in USA and many other countries.
It was only ever allowed for small
areas of skin and for treating things
like age spots or sun spots (Gabri-
el, 2008).
3- Corticosteroids:
Topical corticosteroids whiten
the skin by initial blanching due
to vasoconstriction, slowing down
skin cell turnover so reducing the
number and activity of melano-
cytes and reducing production of
melanocyte stimulating hormone
(Oakley, 2010), but their absorp-
tion through the skin can cause ad-
renal suppression and even Cush-
ing’s syndrome depending on the
area of the body being treated and
the duration of treatment. Local
to the production
of melanin. Long
term application of
mercurial products
to the skin makes
the skin and nails
darker, because the
mercury is depos-
ited in the epidermis and hair fol-
licles (Oakley, 2010).
Mercury poisoning results in
acute and chronic toxicity includ-
ing neurological and kidney dam-
age, as well as acrodynia, which is
characterised by pink discoloration
of the hands and feet, irritabil-
ity, photophobia and polyneuritis
(Oakley, 2010). These toxic com-
pounds have been banned in the
majority parts of the world, and are
no longer used in cosmetic prod-
ucts for this purpose. It should be
mentioned that there are still some
illegal uses of mercury containing
products in developing countries.
2- Hydroquinone:
Its bleaching properties were
discovered when it was observed
that colored tanners wearing rub-
ber gloves acquired discolored
areas on hands and forehands.
The studies on the cause of this ef-
fect pointed out to hydroquinone,
an agent used in rubber synthesis
(Parvez, 2007). Hydroquinone is
a hydroxyphenolic compound that
inhibits the synthesis of melanin
by inhibiting tyrosinase enzyme.
Tyrosinase
Tyrosine Dopa Dopaquinone
Pheo-melanin
Eu-melanin
Figure1 : Production of melanin
Khartoum Pharmacy Journal Vol. 13 No. 1 June. 2010
7
ARTICLES
side-effects of topical corticoster-
oids include spread and worsening
of untreated infection; irreversible
thinning of the skin, contact der-
matitis, perioral dermatitis, acne,
or worsening of acne or acne rosa-
cea and hypertrichosis also report-
ed (British Medical Association
and Royal Pharmaceutical Society,
2007).
4- Ascorbic acid (Vitamin C):
Ascorbic acid and its deriva-
tives are used as an antioxidant
because its capacity to reduce
back o-dopaquinone to dopa, thus
avoiding melanin formation, also
it have a protective effect against
skin damage induced by UV- ir-
radiation (Policarpio and Lue,
2009). However, ascorbic acid has
other adverse affects as it can in-
duce a large increase of free radi-
cals with traces of metal ions. To
improve its stability, skin absorp-
tion and hypopigmenting effect,
some ascorbate esters, such as the
magnesium ascorbyl-2-phosphate
(MAP), has been synthesized.
Daily application of a cream con-
taining 10% of this ascorbic acid
derivative has been found to pro-
duce a signicant whitening effect
in patients with melasma. Ascorbic
acid has been demonstrated as an
effective depigmenting strategy in
a randomized, double-blind, place-
bo-controlled trial (Solano et al.,
2006).
5- Tretinoin:
Tretinoin is the main topical
retinoid that has been used in skin
whitening products. The mecha-
nisms for reducing pigmentation
include inhibition of tyrosinase
induction, interference with pig-
ment transfer, and acceleration
of epidermal turnover. They also
have the ability to disperse pig-
ment granules within keratino-
cytes. Retinoids may act as pen-
etration enhancers when used
with other whitening agents like
hydroquinone and mequinol. The
most common adverse effects in-
clude burning, stinging, erythema,
dryness, and scaling. Although
the adverse effects are reversible,
retinoid dermatitis may itself lead
to hyperpigmentation, especially
in dark-skinned individuals (Poli-
carpio and Lue, 2009). It is a pre-
scription medication because of
potential risk in pregnancy. It can
be quite irritating and may cause
contact irritant dermatitis (Oakley,
2010). Tretinoin is useful for treat-
ing inammatory lesions in mild
to moderate acne (British Medical
Association and Royal Pharma-
ceutical Society, 2007).
6- Azelaic acid:
Azelaic acid is a naturally oc-
curring straight chain, saturated di-
carboxylic acid which is produced
by yeast, Pityrosporum ovale. Aze-
laic acid is a rather weak competi-
tive inhibitor of tyrosinase. In addi-
tion, it has an antiproliferative and
cytotoxic effect on melanocytes
(Pravez et al., 2007). Although
azelaic acid was initially pre-
scribed for the treatment of acne,
it has been successfully used in the
treatment of lentigines, rosacea,
melasma and post inammatory
hyperpigmentation (Policarpio and
Lue, 2009). Azelaic acid is not
able to induce depigmentation on
normally pigmented skin, suggest-
ing its selective antiproliferative
and cytotoxic action on abnormal
melanocytes. It has been reported
to be effective in hypermelanosis
caused by physical and chemical
agents, as well as other skin dis-
orders characterized by abnormal
proliferation of melanocytes. The
only problem of treatment with
azelaic acid is that its therapeutic
response is rather slow (Solano et
al., 2006)
7- Laser treatments:
Both ablative and nonablative
lasers can have a profound effect on
melasma. Lasers function by emit-
ting a monochromic, high-intensity
energy source that is absorbed by
melanin in the skin,. The absorp-
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ARTICLES
Table: Comparison between skin whitening agents
Agent
Mechanisms of
action
Advantage Disadvantage Recommendations
Mercury Inactivate
tyrosinase enzyme
-
Acute and chronic
toxicity, neurological and
kidney damage, acrodynia,
irritability, photophobia ,
Should not be used
Hydroquinone -Inhibits tyrosinase
- Cytotoxic to
melanocytes
Stable in combinations Cytotoxic, mutagenic
Ochronosis, contact
dermatitis,skin irrtation,
redness & burning
Only allowed for small
areas of skin under
medical supervision
Corticosteroids
-Vasoconstriction
- reducing the
number and activity
of melanocytes
-reducing
production of MSH
Useful for inammatory
conditions of the skin
like eczema, contact
dermatitis, and scabies
Spread and worsening
of untreated infections,
contact dermatitis, acne
rosacea, hypertrichosis,
adrenal suppression
Not recommended for
skin whitening
Ascorbic acid
(vitamin C)
- Reduce back
o-dopaquinone to
dopa
-Antioxidsnt
Have a protective
effect against skin
damage induced by UV-
irradiation
Highly unstable, low
penetration, weak
activity
MAP is more effective
and safe derivative
Tretinoin -Inhibits tyrosinase
- interferes with
melanin transfer
useful for treating
inammatory lesions in
mild to moderate acne
Quite irritating and may
cause contact irritant
dermatitis
Should not be used
without prescription
Azelaic acid Weak inhibitor
of tyrosinase,
cytotoxic effect on
melanocytes
Usefulfor lentigines,
rosacea, and post
inammatory
hyperpigmentation.
Therapeutic response is
rather slow
Should be used under
medical supervision
Laser Emit a high-
intensity energy
source that destroy
melanin in the skin
Discomfort, redness,
mild swelling, and
postinammatory
hyperpigmentation.
Not considered a rst-
line treatment
tion of energy destroys the melanin.
However, the results are not always
consistent, and problems have been
reported. Adverse effects from la-
ser treatment include discomfort,
redness, mild swelling, and post
inammatory hyperpigmentation.
Thus is not considered a rst-line
treatment because of the adverse
effects of hyperpigmentation (Poli-
carpio and Lue, 2009). Laser treat-
ments are more likely to result in
problems for those with darker skin
tones (Wikipedia, 2007).
8- Fruits:
Many fruits have skin whiten-
ing effect when they are eaten or
scrubbed on skin. The leading fruit
is papaya, wherein its enzyme pa-
pain can whiten the skin. Other no-
table fruits are lemon, lime, calam-
ondin, and orange; all of these have
Vitamin C which is said to have a
skin whitening effect (Wikipedia,
2007).
The danger of using
skin whitening agents
without prescription
Skin whitening creams - often
sold illegally without a prescrip-
tion - may contain dangerous in-
gredients that could put your health
at risk. Dermatologists say they are
Folliculitis
Khartoum Pharmacy Journal Vol. 13 No. 1 June. 2010
9
ARTICLES
seeing more and more women of
Hispanic and African descent suf-
fering from complications related
to the use of skin whitening creams
(Parker et al., 2010).
Side effects of skin whitening
applications
Dermatitis with severe •
drying, cracking of the skin
and itching
Melasma and •
hyperpigmentation of the
skin
Mercury poisoning•
Fetal toxicity in pregnant •
women
Cushing’s syndrome•
Liver failure•
Skin cancer•
The hypopigmentation (lack
of skin pigment) leaves the skin
prone to UV damage by sunlight.
This can predispose to skin can-
cers like a melanoma. (Health i
Talk, 2010).
Treatment of skin damaged
by skin whiteners
The hyperpigmentation caused
by skin whitening agents is not
‘curable’ and will persist for a
lifetime. Using a sunscreen on a
daily basis will assist in reducing
the damage caused by sun expo-
sure. Emollients are useful for dry
and cracking skin and in cases of
severe itching; a mild hydrocorti-
sone cream may be used for a short
period. Always consult a derma-
tologist for medical attention when
treating skin damaged by long
References
British Medical Association (BMA)
and Royal Pharmaceutical Society (RPS)
54, British National Formulary (BNF)
54, BMJ Publishing Group Ltd and RPS,
September (2007).
Donsing,P., and Viyoch,J., Thai
Breadfruitûs Heartwood Extract: A New
Approach to Skin Whitening., SWU Sci. J.
2008; 24 (1): 9-23.
Gabriel, J., Hydroquinone:
Cancer-Causing Skin Bleach, http://
thegreenbeautyguide.com, (2008).
Hearing,V.J., and Tsukamoto, K.,
Enzymatic control of pigmentation in
mammals. The FASEB Journal. 1991; 5:
2902-2909.
Health i Talk, http://www.healthitalk.
com/what-is-skin-whitening-skin-
lightening-bleaching-cream (Accessed:
12/05/2010).
Kang, H.S., Kim, H. R., Byun , D.S., Son,
B.W., Nam , T. J. and Chio, J.S., Tyrosinase
Inhibitors Isolated from the Edible Brown
AlgaEcklonia stolonifera. Arch Pharm
Res. 2004; 27(12): 1226-1232.
Khan, H. T. M. Molecular design of
tyrosinase inhibitors: A critical review of
promising novel inhibitors from synthetic
origins. Pure Appl. Chem. 2007; 79 (12):
2277–2295.
Oakley, A., Bleaching creams, New
Zealand Dermatological Society
Incorporated. http://www.dermnetnz.org/
treatments/bleach.html Last updated 24
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Parker Waichman Alonso LLP, Beware
of Skin Lightening Creams. http://www.
yourlawyer.com/articles/read/17500, Jan
18, 2010.
Policarpio, B., Lui, H., Skin Lightening
and Depigmenting Agent. e medicine,
http://emedicine.medscape.com/
article/1068091-overview. Last updated:
term use of skin bleaches. (Health
i Talk, 2010).
Recommendations
The use of skin whitening •
agents must be controlled.
In Sudan, the skin whitening •
agents sold in unlicensed
places and might be affected
by the high temperature;
therefore the regulatory
authority must increase the
efforts to protect the people
from the side effects of these
agents.
Different methods must •
be used to increase the
awareness of the people
about the use and danger of
the whitening agents.
Research should be •
conducted to study the
effect of temperature on
the stability and use of the
whitening agents.
26.10. 2009 (Accessed: 12/05/2010).
Pravez, S., Kang, M., Chung, H. S. and
Bae, H., Naturally Occurring Tyrosinase
Inhibitors: Mechanism and Applications
in Skin Health, Cosmetics and Agriculture
Industries. Phytother. Res. 2007; 21:
805–816.
Solano,F., Bringati,S., Picardo,M., and
Ghanem,G., Hypopigmenting agents: an
updated review on biological, chemical
and clinical aspects. Pigment Cell Res.
2007; 19: 550–571.
Thiele,J.J M. G. Traber, T. G. Polefka,
C. E. Cross and L. P.Packer, Ozone
exposure depletes vitamin E and induces
lipid peroxidation in murine stratum
cormeum. J. Invest. Dermatol. 1997;
108: 753-757.
Wikipedia, the free encyclopedia,
Skin whitening. http://en.wikipedia.org/
wiki/Skin_whitening , November 2007
(Accessed: 12/05/2010).
... 4 To inhibit the formation of melanin, the tyrosinase enzyme becomes one of the targets of whitening drugs. 5 Melanin production is induced after exposure to UV radiation and plays a major role in protecting skin cells from UV radiation. However, melanin pigmentation in the epidermis can cause skin changes such as darkening of skin color and pigmentation spots. ...
... Excessive use of steroids can cause side effects of skin thinning, hypertrichosis, and hormonal disorders, while mercury is toxic, as well as kidney and nerve damage. 5 Due to the increasing circulation of various beauty products to watch out for, especially those that use chemicals that ultimately endanger the consumer, the medical world of the present era has studied again the plants that have antioxidant and antiaging effects scientifically. Some examples of plants that have been proven to be antioxidants and antiaging here are roselle flowers (Hisbiscus sabdarifa), 6 jasmine flowers (Jasminum sambac), 7 ripe sesoot (Garcinia picrorrhiza Miq.). ...
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An overview of agents causing hypopigmentation in human skin is presented. The review is organized to put forward groups of biological and chemical agents. Their mechanisms of action cover (i) tyrosinase inhibition, maturation and enhancement of its degradation; (ii) Mitf inhibition; (iii) downregulation of MC1R activity; (iv) interference with melanosome maturation and transfer; (v) melanocyte loss, desquamation and chemical peeling. Tyrosinase inhibition is the most common approach to achieve skin hypopigmentation as this enzyme catalyses the rate-limiting step of pigmentation. Despite the large number of tyrosinase inhibitors in vitro, only a few are able to induce effects in clinical trials. The gap between in-vitro and in-vivo studies suggests that innovative strategies are needed for validating their efficacy and safety. Successful treatments need the combination of two or more agents acting on different mechanisms to achieve a synergistic effect. In addition to tyrosinase inhibition, other parameters related to cytotoxicity, solubility, cutaneous absorption, penetration and stability of the agents should be considered. The screening test system is also very important as keratinocytes play an active role in modulating melanogenesis within melanocytes. Mammalian skin or at least keratinocytes/melanocytes co-cultures should be preferred rather than pure melanocyte cultures or soluble tyrosinase.
Thai Breadfruitûs Heartwood Extract: A New Approach to Skin Whitening
  • P Donsing
  • J Viyoch
Donsing,P., and Viyoch,J., Thai Breadfruitûs Heartwood Extract: A New Approach to Skin Whitening., SWU Sci. J. 2008; 24 (1): 9-23