Fairness via formulations: A review of cosmetic skin-lightening ingredients

Abstract

Skin-lightening cosmetics are in big demand across Asia, and the quest for fairness has led to identification of many new ingredients. The mechanisms underlying pigmentation have been researched extensively and the knowledge is being updated regularly. This review serves to list the ingredients that are commercially available for that purpose and the modes of action through which the lightening is effected. Skin-lightening ingredients are also classified based on their sources; it is significant that far more botanicals have made the list than have synthesized compounds. Tyrosinase inhibition as a means of skin lightening is still the most reported method, followed by other methods such as Mitf inhibition, down regulation of MC1R activity, interference with melanosomal transfer, and melanocyte loss.

Full text

J. Cosmet. Sci., 63, 43–54 ( January/February 2012)
43
Fairness via formulations: A review of cosmetic
skin-lightening ingredients
R. KAMAKSHI, Cavinkare Research Centre,
Ekkatuthangal, Chennai 600 032, India.
Accepted for publication August 31, 2011.
Synopsis
Skin-lightening cosmetics are in big demand across Asia, and the quest for fairness has led to identifi cation
of many new ingredients. The mechanisms underlying pigmentation have been researched extensively and
the knowledge is being updated regularly. This review serves to list the ingredients that are commercially
available for that purpose and the modes of action through which the lightening is effected. Skin-lightening
ingredients are also classifi ed based on their sources; it is signifi cant that far more botanicals have made the
list than have synthesized compounds. Tyrosinase inhibition as a means of skin lightening is still the most
reported method, followed by other methods such as Mitf inhibition, down regulation of MC1R activity,
interference with melanosomal transfer, and melanocyte loss.
INTRODUCTION
The defi nition of fair skin is given as “not dark and free from spots, specks, dirt or imper-
fection; unblemished; clean; pure.” The booming cosmetics industry in recent decades can
be partly attributed to the elusive search for fair and fl awless skin (1,2). With the vast
information that is accessible in the 21st century, one has an option to choose methods
ranging from that of Cleopatra (soaking in donkey milk that is rich in AHA) to recent
advances in skin-lightening procedures such as dermabrasion, ultrasound, and laser ther-
apies, to name a few (3–9).
Skin-lightening agents are any ingredient or combination of ingredients that interfere
in any step of the melanogenesis pathway, melanin transfer, or desquamation that results in
lowering pigmentation on the surface of the skin (10). Skin-lightening cosmetics are in
big demand across the world, and this review serves to list the ingredients that are com-
mercially available for that purpose and the modes of action through which the lighten-
ing is effected. There are many reports of skin-lightening agents obtained from both
natural and synthetic sources. However, many ingredients in their original form may not
be compatible in cosmetic formulations for application to the skin due to various factors
such as cytotoxicity, insolubility, instability, and their sensitive nature to external condi-
tions. However, consistent efforts are being made by industry to arrive at compatible,
minimally toxic, and highly effi cacious ingredients that serve the purpose.

JOURNAL OF COSMETIC SCIENCE44
PIGMENTATION IN SKIN
The color of our skin is due to the polymeric, amorphous, non-proteinaceous pigment
called melanin. Melanin is produced in the skin through a biochemical process called
melanogenesis. Dermal melanin is produced by melanocytes, which are found in the stra-
tum basale of the epidermis. The pathway of melanogenesis as elucidated by Raper (18)
and Mason (19) is shown below (Figure 1).
The difference in skin color between fair people and dark people is due not to the number
(quantity) of melanocytes in their skin, but to the melanocytes’ level of activity (quantity
and relative amounts of eumelanin and pheomelanin). In skin that exhibits a dark color
the melanosomes are well distributed in the keratinocytes, which absorb radiation (11).
Pigmentation in skin is determined by various physiological processes occurring at
different stages (12):
(a) Development of melanocytes
(b) Density of melanocytes
(c) Expression of the enzymatic and structural constituents of melanosomes
(d) Synthesis of melanin
(e) Transport of melanosomes to dendrites
(f) Transfer of melanosomes to keratinocytes
(g) Distribution of melanin in the supra basal layers of the skin
Figure 1. Raper-Mason pathway of melanogenesis.

SKIN-LIGHTENING COSMETIC INGREDIENTS 45
The fi rst three stages are completely controlled genetically, while the next four stages
are targets for manipulation through skin-lightening agents. The most important
factor other than inheritance affecting skin pigmentation is ultraviolet (UV) radiation
(Figure 2). Exposure to UV triggers the following reactions that cause darkening of the
skin (13–15):
(a) Oxidation and polymerization of melanin
(b) Redistribution of melanosomes
(c) Activation of MITF (microphthalmia-associated transcription factor) leading to
increased melanin content
(d) Increase in expression of α-MSH (melanocyte-stimulating harmone) leading to
enhanced melanocyte responses
(e) Transfer of melanin from the lower to the upper epidermis to prevent damage from
radiation
A very effective method of reducing UV-induced pigmentation would be to incorporate
sunscreens in the vehicle used for skin lightening. Physical sunscreens like zinc oxide and
titanium oxide are available to suit delivery vehicles like creams, lotions, gels, etc. Chem-
ical sunscreens may be chosen from a variety of synthetic compounds such as ethyl hexyl
methoxy cinnamate, butyl methoxydibenzoylmethane, phenyl benzimidazole sulfonic
acid, and other substituted salicylates.
SKIN LIGHTENING
Skin-lightening agents are those that cause depigmenting activity on human skin, and
they have been widely used in dermatology and cosmetics. A huge number of actives
(both from biological sources and synthetic chemical compounds) have been reported in
the literature (16,17). Their mechanism of action is generally through:
(a) Tyrosinase inhibition
(b) Mitf inhibition
(c) Down regulation of MC1R activity
Figure 2. Schematic representation of the effect of UV rays on skin leading to pigmentation.

JOURNAL OF COSMETIC SCIENCE46
(d) Interference with melanosome maturation and transfer
(e) Melanocyte loss, exfoliation
Successful treatments mostly combine two or more modes of action to achieve a synergis-
tic effect.
CLASSIFICATION OF SKIN-LIGHTENING INGREDIENTS
Skin-lightening ingredients can also be classifi ed by their source, such as the classes to
which they belong. The important classes are:
(i) Chemical tyrosinase inhibitors (hydroquinone and similar type of compounds)
(ii) Botanicals (essentially from plants and algae)
(iii) Anti-oxidants
(iv) Vitamins—A, B, C, E
(v) Peptides
(vi) Alpha and beta hydroxyl acids and derivatives
TYROSINASE INHIBITION
The inhibition of tyrosinase is the most widely reported screening method in the litera-
ture for skin-lightening ingredients. Tyrosinase is a copper-containing enzyme present in
melanocytes that catalyzes the production of melanin. The biosynthetic pathway of mela-
nin synthesis was fi rst elucidated by Raper (18). Tyrosinase inhibition may be achieved by
inhibitors from chemical or biological sources.
(i) Chemical tyrosinase inhibitors (Figure 3). There has been tremendous activity in the iden-
tifi cation of tyrosinase inhibitors that are of synthetic origin. Such compounds are gener-
ally highly pure and potent. Synthetic compounds of various classes like hydroquinone
and derivatives, phenolic amines, coumarins, chalcone analogs, hydroxy stilbene deriva-
tives, benzaldehyde analogs, biphenyls, and trihydroxy fl avones have been studied for
their tyrosinase inhibitory properties (21–33).
However, many of these compounds have been screened through in vitro assays and their
effi cacy and adverse effects need to be established through clinical trials. Chemical com-
pounds with depigmenting activity have been used in cosmetics for a long time. Some of
the best known tyrosinase inhibitors are hydroquinone, kojic acid, and similar types of
compounds.
(a) HYDROQUINONE AND DERIVATIVES. Hydroquinone is considered to be the gold standard for
depigmenting agents. Hydroquinone interacts with copper at the active site of the en-
zyme tyrosinase, thus decreasing its activity by nearly 90% (34). It not only limits ty-
rosinase but also oxidizes membrane lipids and proteins through generation of reactive
oxygen species (35). The radicals generated inhibit cellular metabolism by affecting
DNA and RNA synthesis (36). It is generally administered at concentrations ranging from
1.5% to 5% concentration. The use of hydroquinone in cosmetics has diminished because
of adverse side effects due to its cytotoxic nature. Monobenzyl ether of hydroquinone

SKIN-LIGHTENING COSMETIC INGREDIENTS 47
(MBEH) and monomethyl ether of hydoquinone (MMEH) also demonstrate tyrosinase
inhibitory properties (37–39). Further, they also cause melanocyte loss through genera-
tion of free radicals. However, the use of these compounds for depigmentation is limited
by their adverse effects, similar to those of hydroquinone.
(b) ARBUTIN. Arbutin is a naturally occurring β,D-glycopyranoside derivative of hydro-
quinone. Although it shows tyrosinase inhibition, it is not found to affect RNA synthe-
sis as does hydroquinone. The α-derivative shows a stronger inhibitory effect on tyrosinase
and melanosome maturation (40,41). It is also present in many of the botanical extracts.
Arbutin is highly pH-sensitive and can hydrolyze to hydroquinone at both acidic and
alkaline pH. Hence, care should be taken during use in commercial skin-lightening
products.
(c) KOJIC ACID. Kojic acid is a powerful tyrosinase inhibitor. It functions by the chelation of
copper at the active site of the enzyme tyrosinase (42). Further, it acts as an antioxidant
and a free radical scavenger. Although powerful, the use of kojic acid is under scrutiny by
dermatologists because of its adverse side effects such as allergic dermatitis (43). It
is found to be unstable in formulations and may also cause discoloration. Some stable
derivatives, such as kojic acid dipalmitate, are being used to enhance effectiveness by
enhanced skin penetration. Thus there exists a demand for safe and effective alternative
botanicals as preferred skin-lightening ingredients.
Figure 3. Structures of some skin-lightening agents.

JOURNAL OF COSMETIC SCIENCE48
(ii) Botanical extracts. Extracts mostly contain a combination of two or more classes of com-
pounds that work synergistically to achieve skin lightening. Botanicals connote nature and
are hence more acceptable to people. Further, a large number of yet undiscovered plants are
available to provide for exotic products and claims for cosmetics. However, it should also be
observed that natural extracts may be highly unstable and may not be compatible within
formulations. A large number of ingredients (Table I) have been studied for tyrosinase inhi-
bition and have been processed to make them viable for use in cosmetic products. These are
available commercially through suppliers for use as skin-lightening agents.
(iii) Antioxidants as skin-lightening agents. Antioxidants serve to reduce oxidation of tyrosine
to DOPA quinone and therefore are shown to have skin-lightening activity (64).
In addition, they act in the melanogenesis pathway, reducing the synthesis of melanin.
Exposure to UV radiation results in the generation of free radicals. It has been identifi ed
that ROS (reactive oxygen species) are able to oxidize tyrosinase and DOPA to melanin,
and this is one of the major causes for tanning (65). Although antioxidants are present in
tissues, they may not be able to reduce the radicals, depending on the extent of UV expo-
sure. Infl ammation is a source of free radicals. Hence the quenching of free radicals would
also help in reducing the synthesis of melanin, thereby contributing to skin depigmenta-
tion effects (66). The use of phytic acid, glutathione (Figure 4), and ubiquinone as popu-
lar skin-lightening agents is due to their strong antioxidant nature (67–68). Melanin
synthesis in melanocytes is accompanied by the generation of hydrogen peroxide that
can lead to the formation of ROS that further increase the proliferation of melanocytes.
Table I
Botanicals That are Mostly Used in Skin-Lightening Cosmetics
S. No. Extract Type Reference
1Morus alba extract 2-Oxyresveratrol 44
2Aloe barbadensis leaf extract Aloesin 45
3Crocus sativus extract Kaempferol 46
4Uva ursi Arbutin 47
5 Licorice extract Glabridin 48
6Camelia sinesis extract ECG 49
7Phylanthus embelica extract Vitamin C 50
8Citrus limonum extract Hisperidin 51
9Punica granatum extract Ellagitannins 52
10 Vitis vinifera (grape) fruit extract Procyanidins 53
11 Anise extract Anisic acid 54
12 Cumin seed extract Cumic acid 55
13 Cinnamonum cassia extract Trans-cinnamaldehyde 56
14 Artocarpus lakoocha heartwood extract 2-Oxyresveratrol 57
15 Purus comunis (pear) extract Arbutin 58
16 Geranium extract Ellagic acid 59
17 Ramulus mori extract 2-Oxyresveratrol 60
18 Ginseng extract p-Coumaric acid 61
19 Malpighia punicifolia (Acerola) fruit extract Polyphenols 62
20 Mushroom (Agaricus blazei Muril) extract Tri-terpenoids 63

SKIN-LIGHTENING COSMETIC INGREDIENTS 49
Most of the natural extracts contain fl avanoids that provide antioxidant effects and are
thus used as skin-lightening agents (69).
(iv) Vitamins as skin-lightening agents. Vitamins have been known to improve skin tone and
texture, and they have found remarkable acceptance among consumers. Most of the lead-
ing brands of skin-lightening agents that are available commercially utilize vitamins or
their derivatives as ingredients.
VITAMIN A. Vitamin A has been used for some decades for the removal of spots in Kligman’s
treatment (70). It is used along with hydroquinone and topical steroids for the treatment
of melasma. Tretinoin acts as a skin-lightening agent by inducing exfoliation. Further, it
accelerates the loss of epidermal melanin by increasing the turnover rate and by promoting
the proliferation of keratinocytes (71,72). However, users of tretinoin suffer from side
effects such as burning and increased photosensitization. Retinyl palmitate, a derivative
of retinoic acid, is used in skin-lightening cosmetic preparations.
VITAMIN B. Among the classes of vitamins that comprise vitamin B, two have been identi-
fi ed to have skin-lightening activity:
(a) Vitamin B3 (niacinamide): This is one of the most used hypopigmenting agents.
It is a well known antioxidant and interferes in melanasome transfer leading to skin
lightening. Using co-cultures of human melanocytes and keratinocytes, investiga-
tors have shown that niacinamide inhibits the transfer of melanosomes from mela-
nocytes to keratinocytes (73). The results of clinical studies using topically applied
niacin amide have demonstrated a reversible reduction in hyperpigmented lesions and
increased skin lightness compared with the vehicle alone after four weeks of use (74).
(b) Vitamin B5 (panthenoic acid): A derivative of vitamin B5, calcium pantetheine
sulfonate has been observed to interfere with the glycosylation of tyrosinase,
thereby leading to depigmenting effects (75).
VITAMIN C. Vitamin C is required for the production of collagen and is a photoprotectant as
it deactivates UV-induced free radicals and decreases erythema. Further, Vitamin C also
acts as a tyrosinase inhibitor, thereby lightening the skin (76). Although most effective,
ascorbic acid is a highly unstable compound. Stable derivatives of ascorbic acid in the
Figure 4. Structures of (a) glutathione and (b) phytic acid.

JOURNAL OF COSMETIC SCIENCE50
form of sodium ascorbyl phosphate (SAP), magnesium ascorbyl phosphate (MAP), and
ascorbyl palmitate are widely used in cosmetic products (77).
VITAMIN E. Vitamin E is the most important lipid-soluble antioxidant in the body. It is
abundant in the sebum and acts to absorb the oxidative stress of sunlight and skin expo-
sure. It has been demonstrated that vitamin E provides protection against UV-induced
infl ammation and hyperpigmentation (78). Vitamin E has also been studied in combina-
tion therapies with other vitamins as well as in other classes of skin-lightening com-
pounds (79,80).
Vitamins B, C, and E are used individually or in combination in many skin-lightening
treatment therapies.
(v) Peptides in skin lightening. Peptides are reported to reduce pigmentation through inter-
action with the protease-activated receptor 2 (PAR-2) of keratinocytes. PAR-2 activation
in involved in cell growth, differentiation, and infl ammatory processes and was shown to
affect melanin and melanosome ingestion by human keratinocytes (81). The protease-
activated receptor-2 upregulates keratinocyte phagocytosis. The peptide-based antago-
nist for PAR-2 can be used to regulate melanin ingestion by keratinocytes, thus effecting
skin-lightening.
Short peptides have also been reported in reducing the enzymatic activity of tyrosinase
(82). The use of sericin, a high-molecular-weight soluble glycoprotein from silk, as
a tyrosinase inhibitor has also been documented (83). Peptide residues that act as MSH
inhibitors have been known to lighten the skin. Soy trypsin inhibitors have been identi-
fi ed as interfering in melanosomal transfer, thereby reducing skin pigmentation (84).
(vi) Alpha and beta hydroxyl acids and derivatives. Alpha and beta hydroxyl acids have been
the most important class of compounds that are most widely used in cosmetic prepara-
tions. These act as superfi cial chemical peels that target the stratum corneum to improve
skin color and tone. They are comparatively pure and inexpensive, and they may be used
in higher amounts without many side effects (85). They are generally used in conjunction
with other skin-lightening agents to improve performance. Also referred to as fruit acids,
they improve skin texture by promoting desquamation or the shedding of the outer layers
of the stratum corneum. Alpha hydroxyl acids (AHA) have also been noted to increase
the enzymatic activity leading to epidermolysis. They are also employed in microderm-
abrasion techniques. In addition, they act as moisturizers and promote the synthesis of
elastin fi bers, leading to improved skin tone. However, care should be taken to neutralize
the skin after AHA treatment, as it might cause burning and erythema. The most com-
monly used AHAs are glycolic, lactic, citric, malic, pyurvic, and salicylic acids and their
derivatives.
THE EFFICACY OF SKIN-LIGHTENING FORMULATIONS
Formulations for skin lightening have been majorly based on o/w emulsions that have a
higher aesthetic appeal. The fact that many of the ingredients get better dispersions is
also an added feature for the choice of such emulsions. Recently gel-based formulations
are being considered for suitability in certain skin types. Effi cacy studies for skin-lightening
formulations are carried out through clinical trails. Some of the techniques used in-
volve the use of the mexameter, chromameter, spectrophotometer, and VISIA, along with

SKIN-LIGHTENING COSMETIC INGREDIENTS 51
dermatologist assessment. Also, other skin parameters such as moisturization, texture,
barrier integrity, pH, etc, are being evaluated to give picture of skin health after the use
of skin-lightening agents. This leads to screening the potentially harmful side effects of
hydroquinone-like substances in addition to the high-value claim proposition for the cos-
metics industry. With advances in technology in measurement techniques, it is becoming
easier to identify the effi cacy of formulations in different skin types.
CONCLUSION
Research in the area of skin-lightening agents in an expanding fi eld, with new ingre-
dients being added to the repertoire with every new discovery. Although tyrosinase
inhibition is still the most sought after mechanism skin lightening, newer pathways
are being identifi ed. It has been noted that ingredients that interfere with the path-
ways affecting melanin synthesis and transfer show promise as depigmenting agents.
Persistent research into skin lightening has also led to new mechanisms being discov-
ered in recent years.
The aspiration for light skin is on an upward curve and can be satisfi ed only when the
cosmetic in the bottle fulfi ls the promise of fair skin. A careful and complete investiga-
tion of the ingredient on the basis of its effi cacy and tolerance to individuals through
clinical trails is essential to ascertain that the product delivers the promise.
ACKNOWLEDGMENTS
We thank Dr. Yash Kamath for reviewing the manuscript. Thanks are also due to
Dr. Usha Ranganathan and Dr. Lakshmi Madhavi for their help in the preparation of the
manuscript.
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