ARTICLES
2010 5
Review on Skin Whitening Agents
Ahmed Hassan H. Arbab (M.Pharm) & Mahmoud Mudawi Eltahir (PhD)
Faculty of Pharmacy, Omdurman Islamic University
Abstract
Skin whitening is a term used
for lightening the complexion of
the skin through artificial 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-
inflammatory melanoderma, solar
lentigo, etc. Several modalities of
treatment for these problems are
Khartoum Pharmacy Journal Vol. 13 No. 1 June.
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
final 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-inflammatory 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
 6 ARTICLES
The classification 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
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
Figure1 : Production of melanin
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
Pheo-melanin
Eu-melanin
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 significant 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
Khartoum Pharmacy Journal Vol. 13 No. 1 June. 2010
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 inflammatory 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-
7
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 inflammatory
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-
 8 ARTICLES
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
inflammatory hyperpigmentation.
Thus is not considered a first-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).
Folliculitis
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

Table: Comparison between skin whitening agents

Mechanisms of
Agent Advantage Disadvantage Recommendations
action
Mercury Inactivate - Acute and chronic Should not be used
tyrosinase enzyme toxicity, neurological and
kidney damage, acrodynia,
irritability, photophobia ,

Hydroquinone -Inhibits tyrosinase Stable in combinations Cytotoxic, mutagenic Only allowed for small
- Cytotoxic to Ochronosis, contact areas of skin under
melanocytes dermatitis,skin irrtation, medical supervision
redness & burning
Corticosteroids -Vasoconstriction Useful for inflammatory Spread and worsening Not recommended for
- reducing the conditions of the skin of untreated infections, skin whitening
number and activity like eczema, contact contact dermatitis, acne
of melanocytes dermatitis, and scabies rosacea, hypertrichosis,
-reducing adrenal suppression
production of MSH

Ascorbic acid - Reduce back Have a protective Highly unstable, low MAP is more effective
(vitamin C) o-dopaquinone to effect against skin penetration, weak and safe derivative
dopa damage induced by UV- activity
-Antioxidsnt irradiation

Tretinoin -Inhibits tyrosinase useful for treating Quite irritating and may Should not be used
- interferes with inflammatory lesions in cause contact irritant without prescription
melanin transfer mild to moderate acne dermatitis
Azelaic acid Weak inhibitor Usefulfor lentigines, Therapeutic response is Should be used under
of tyrosinase, rosacea, and post rather slow medical supervision
cytotoxic effect on inflammatory
melanocytes hyperpigmentation.

Laser Emit a high- Discomfort, redness, Not considered a first-

intensity energy mild swelling, and line treatment
source that destroy postinflammatory
melanin in the skin hyperpigmentation.
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
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Gabriel, J., Hydroquinone:
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Khartoum Pharmacy Journal Vol. 13 No. 1 June. 2010
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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
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9
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.
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Bae, H., Naturally Occurring Tyrosinase
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108: 753-757.
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