J. Cosmet. Sci.

, 63, 4354 ( January/February 2012)

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 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.

INTRODUCTION

The definition of fair skin is given as not dark and free from spots, specks, dirt or imperfection; unblemished; clean; pure. The booming cosmetics industry in recent decades can
be partly attributed to the elusive search for fair and flawless 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 therapies, to name a few (39).
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 commercially available for that purpose and the modes of action through which the lightening 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 conditions. However, consistent efforts are being made by industry to arrive at compatible,
minimally toxic, and highly efficacious ingredients that serve the purpose.
43

44

JOURNAL OF COSMETIC SCIENCE

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 stratum 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 first 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 (1315):
(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 -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. Chemical 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.

46

JOURNAL OF COSMETIC SCIENCE

(d) Interference with melanosome maturation and transfer
(e) Melanocyte loss, exfoliation

Successful treatments mostly combine two or more modes of action to achieve a synergistic effect.

CLASSIFICATION OF SKIN-LIGHTENING INGREDIENTS

Skin-lightening ingredients can also be classified 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) VitaminsA, 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 literature for skin-lightening ingredients. Tyrosinase is a copper-containing enzyme present in
melanocytes that catalyzes the production of melanin. The biosynthetic pathway of melanin synthesis was first 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 identification of tyrosinase inhibitors that are of synthetic origin. Such compounds are generally highly pure and potent. Synthetic compounds of various classes like hydroquinone
and derivatives, phenolic amines, coumarins, chalcone analogs, hydroxy stilbene derivatives, benzaldehyde analogs, biphenyls, and trihydroxy flavones have been studied for
their tyrosinase inhibitory properties (2133).
However, many of these compounds have been screened through in vitro assays and their
efficacy and adverse effects need to be established through clinical trials. Chemical compounds 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 enzyme tyrosinase, thus decreasing its activity by nearly 90% (34). It not only limits tyrosinase 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

Figure 3. Structures of some skin-lightening agents.

(MBEH) and monomethyl ether of hydoquinone (MMEH) also demonstrate tyrosinase

inhibitory properties (3739). Further, they also cause melanocyte loss through generation 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 ,D-glycopyranoside derivative of hydroquinone. Although it shows tyrosinase inhibition, it is not found to affect RNA synthesis as does hydroquinone. The -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.

48

JOURNAL OF COSMETIC SCIENCE

(ii) Botanical extracts. Extracts mostly contain a combination of two or more classes of compounds 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 inhibition 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 identified
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 exposure. Inflammation 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 depigmentation effects (66). The use of phytic acid, glutathione (Figure 4), and ubiquinone as popular skin-lightening agents is due to their strong antioxidant nature (6768). 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.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20

Extract

Type

Reference

Morus alba extract

Aloe barbadensis leaf extract
Crocus sativus extract
Uva ursi
Licorice extract
Camelia sinesis extract
Phylanthus embelica extract
Citrus limonum extract
Punica granatum extract
Vitis vinifera (grape) fruit extract
Anise extract
Cumin seed extract
Cinnamonum cassia extract
Artocarpus lakoocha heartwood extract
Purus comunis (pear) extract
Geranium extract
Ramulus mori extract
Ginseng extract
Malpighia punicifolia (Acerola) fruit extract
Mushroom (Agaricus blazei Muril) extract

2-Oxyresveratrol
Aloesin
Kaempferol
Arbutin
Glabridin
ECG
Vitamin C
Hisperidin
Ellagitannins
Procyanidins
Anisic acid
Cumic acid
Trans-cinnamaldehyde
2-Oxyresveratrol
Arbutin
Ellagic acid
2-Oxyresveratrol
p-Coumaric acid
Polyphenols
Tri-terpenoids

44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63

SKIN-LIGHTENING COSMETIC INGREDIENTS

49

Figure 4. Structures of (a) glutathione and (b) phytic acid.

Most of the natural extracts contain flavanoids 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 leading 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 Kligmans
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 identified 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, investigators have shown that niacinamide inhibits the transfer of melanosomes from melanocytes to keratinocytes (73). The results of clinical studies using topically applied
niacinamide 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

50

JOURNAL OF COSMETIC SCIENCE

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 exposure. It has been demonstrated that vitamin E provides protection against UV-induced
inflammation and hyperpigmentation (78). Vitamin E has also been studied in combination therapies with other vitamins as well as in other classes of skin-lightening compounds (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 interaction with the protease-activated receptor 2 (PAR-2) of keratinocytes. PAR-2 activation
in involved in cell growth, differentiation, and inflammatory processes and was shown to
affect melanin and melanosome ingestion by human keratinocytes (81). The proteaseactivated receptor-2 upregulates keratinocyte phagocytosis. The peptide-based antagonist 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 identified 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 preparations. These act as superficial 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 microdermabrasion techniques. In addition, they act as moisturizers and promote the synthesis of
elastin fibers, 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 commonly 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. Efficacy studies for skin-lightening
formulations are carried out through clinical trails. Some of the techniques used involve 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 cosmetics industry. With advances in technology in measurement techniques, it is becoming
easier to identify the efficacy of formulations in different skin types.

CONCLUSION

Research in the area of skin-lightening agents in an expanding field, with new ingredients 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 identified. It has been noted that ingredients that interfere with the pathways affecting melanin synthesis and transfer show promise as depigmenting agents.
Persistent research into skin lightening has also led to new mechanisms being discovered in recent years.
The aspiration for light skin is on an upward curve and can be satisfied only when the
cosmetic in the bottle fulfils the promise of fair skin. A careful and complete investigation of the ingredient on the basis of its efficacy 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.

REFERENCES
(1) E. N. Glenn, Yearning for lightness, Gender & Society, 22(3), 281302 (2008).
(2) P. H. Eric, H. J. Li, R. W. Min, J. Belk, S. Kimura, and S. Bahl, Skin lightening and beauty in four
Asian cultures, Adv. Consumer Res., 135, 444449 (2008).
(3) A. Gupta, M. Gover, K. Nouri, and S. Taylor, The treatment of melasma: A review of clinical trials,
J. Am. Acad. Dermatol., 55, 10481065 (2006).
(4) E. Berardesca, M. Ardig, M. Berardesca, and N. Cameli, Melasma: Current and future treatments,
Expert Rev. Dermatol., 3(2), 187193 (2008).
(5) A. E. Reszko, D. Berson, and M. P. Lupo, Cosmeceuticals: Practical applications, Dermatologic Clinics,
27, 401416 (2009).
(6) T. Kono, W. F. Groff, H. Sakurai, M. Takeuchi, T. Yamaki, K. Soejima, and M. Nozaki, Comparison
study of intense pulsed light versus a long-pulse pulsed dye laser in the treatment of facial skin rejuvenation, Ann. Plastic Surg., 59, 479483 (2007).
(7) T. Hakozaki, T. Hirotsugu, M. Kukizo, Y. Sato, and S. Arase, Ultrasound enhanced skin-lightening
effect of vitamin C and niacinamide, Skin Res. Technol., 12, 105113 (2006).
(8) B. Green, R. Yu, and E. Van Scott, Clinical and cosmeceutical uses of hydroxyacids, Clinics Dermatol.,
27, 495501 (2009).
(9) E. Clark and L. Scerri, Superficial and medium-depth chemical peels, Clinics Dermatol., 26, 209218
(2008).
(10) L. Petit and G. E. Pierard, Skin lightening products revisited, Int. J. Cosmet. Sci, 25, 169181 (2003).

52

JOURNAL OF COSMETIC SCIENCE

(11) T. Todokora, N. Kobayashi, B. Z. Zmudzka, S. Ito, K. Wakamtsu, Y. Yamaguchi, K. S. Korossy,

S. A. Miller, J. Z. Beer, and V. J. Hearing, UV-induced DNA damage and melanin content in human
skin differing in racial/ethnic origin, FASEB J., 17, 11771179 (2003).
(12) Y. Yamaguchi, M. Brenner, and V. J. Hearing, The regulation of skin pigmentation, J. Biol. Chem.,
282(38), 2755727561 (2007).
(13) M. S. Eller and B. A. Gilchrest, Tanning as part of the eukaryotic SOS response, Pigment Cell. Res., 13,
9497 (2000).
(14) B. A. Gilchrest, H. Y. Park, M. S. Eller, and M. Yaar, Mechanisms of ultraviolet induced pigmentation,
Photochem. Photobiol., 63, 110 (1996).
(15) S. G. Coelho, Y. Zhou, H. F. Bushar, S. A. Miller, B. Z. Zmudzka, V. J. Hearing, and J. Z. Beer, Longlasting pigmentation of human skin, a new look at an overlooked response to UV, Pigment Cell Melanoma
Res., 22, 238241 (2009).
(16) F. Soalno, S. Briganti, M. Picardo, and G. Ghanem, Hypopigmenting agents: An updated review on
biological, chemical and clinical aspects, Pigment Cell. Res., 19, 550571 (2006).
(17) P. S. Kang, H. S. M. Chung, C. Cho, M. C. Hong, M. K. Shin, and H. Bae, Survey and mechanism of
skin depigmenting and lightening agents, Phytother. Res., 20, 921934 (2006).
(18) H. S. Raper, The anaerobic oxidases, Physiol. Rev., 8, 245282 (1928).
(19) H. S. Mason, The chemistry of melanin. III. Mechanism of the oxidation of trihydroxy phenylalanine by
tyrosinase, J. Biol. Chem., 172, 8399 (1948).
(20) T. B. Fitzpatrick, E. Calkins, and W. H. Summerson, Mammalian tyrosinasePreparation and properties,
J. Biol. Chem., 178, 185189 (1949).
(21) A. Palumbo, M. dIschia, and G. Misuraca, Mechanism of inhibition of melanogenesis by hydroquinone, Biochim. Biophys. Acta, 1073, 8590 (1991).
(22) O. H. Mills. Jr. and A. M. Kligman, Further experience with a topical cream for depigmenting human
skin, J. Soc. Cosmet. Chem, 29, 147154 (1978).
(23) J. Yukitake, H. Otake, S. Inoue, K. Wakamatsu, C. Olivares, F. Solano, K. Hasegawa, and S. Ito, Synthesis and selective in vitro anti-melanoma effect of enantiomeric (alpha)-methyl- and (alpha)-ethyl
-4-S-cysteaminyl phenol, Melanoma Res., 13, 603609 (2003).
(24) T. Yamamura, J. Onishi, and T. Nishiyama, Anti-melanogenic activity of hydrocoumarins in cultured human
melanocytes by stimulating intra cellular glutathione synthesis, Arch. Dermatol. Res., 294, 349354 (2002).
(25) S. Khatib, O. Nerya, R. Musa, M. Shmuel, S. Tamir, and J. Vaya, Chalcones as potent inhibitors:
The importance of a 2,4- substituted resorcinol moiety, Bioorg. Med. Chem., 13, 433441 (2005).
(26) O. Nerya, R. Musa, S. Khatib, S. Tamir, and J. Vaya, Chalcones as potent tyrosinase inhibitors: The
effect of hydroxyl positions and numbers, Phytochemistry, 65, 13891395 (2004).
(27) Y. M. Kim, J. Yun, C. K. Lee, H. Lee, K. R. Min, and Y. Kim, Oxyresveratrol and hydroxy stillbene
compounds, J. Biol. Chem, 277, 1634016344 (2002).
(28) K. I. Nihei, Y. Yamagiwa, T. Kamikawab, and I. Kubo, 2-Hydroxy-4-isopropylbenzaldehyde, a potent
partial tyrosinase inhibitor, Bioorg. Med. Lett, 14, 681683 (2004).
(29) I. Kubo and I. Kinst-Hori, 2-Hydroxy-4-methoxy benzaldehyde: A potent tyrosinase inhibitor from
African medicinal plants, Planta Med., 65, 1922 (1999).
(30) Y. J. Kim, J. K. No, J. H. Lee., and H. Y. Chung, 4,4-Dihydroxybiphenyl as a new potent tyrosinase
inhibitor, Biol. Pharm. Bull., 28, 323327 (2005).
(31) K. Nakamura, M. Yoshida, H. Uchiwa, Y. Kawa, and M. Mizoguchi, Down regulation of melanin synthesis by a diphenyl derivative and its mechanism, Pigment Cell. Res., 16, 494500 (2003).
(32) T. S. Chang, H. Y. Ding, and H. C. Lin, Identifying 6,7,4-trihydroxyisoflavone as a potent tyrosinase
inhibitor, Biosci. Biotech. Biochem., 69, 19992001 (2005).
(33) D. Kim, J. Park, J. Kim, C. Han, J. Yoon, N. Kim, J. Seo, and C. Lee, Flavanoids as mushroom tyrosinase inhibitors: A fluorescent quenching study, J. Agric. Food. Chem, 54, 935941 (2006).
(34) V. M. Verallo-Rowell, V. Verallo, K. Graupe, L. Lopez-Villafuerte, and M. Garcia-Lopez, Double-blind
comparison of azelaic acid and hydroquinone in the treatment of melasma., Acta Derm. Venereol. Suppl.
(Stockh.), 143, 5861 (1989).
(35) S. Briganti, E. Camera, and M. Picardo, Chemical and instrumental approaches to treat hyperpigmentation, Pigment Cell. Res., 16, 101110 (2003).
(36) A. Palumbo, M. dIschia, and G. Misuraca, Mechanism of inhibition of melanogenesis by hydroquinone, Biochim. Biophys. Acta, 1073, 8590 (1991).
(37) M. D. Njoo, W. Westerhof, J. D. Bos, and P. M. Bossuyt, The development of guidelines for vitiligo,
Arch. Dermatol., 135, 15141521 (1999).

SKIN-LIGHTENING COSMETIC INGREDIENTS

53

(38) P. A. Riley, Mechanism of pigment cell toxicity produced by hydroxyanisole, J. Pathol., 101, 163169
(1970).
(39) S. Naish-Byfield, C. J. Cooksey, A. M. Later, C. I. Johnson, and P. A. Riley, In vitro assessment of the
structure activity relationship of tyrosinase dependent cytotoxicity of a series of substituted phenols,
Melanoma Res., 1, 273287 (1991).
(40) K. Maeda and M. Fukuda, Arbutin: Mechanism of its depigmenting action in human melanocyte
culture, J. Pharmacol. Exp. Ther., 276, 765769 (1996).
(41) A. K. Chakraborthy, Y. Funassaka, M. Komoto, and M. Ichihashi, Effect of arbutin on melanogenetic
proteins in human melanocytes, Pigment Cell Res., 11, 206212 (1998).
(42) J. Cabanes, S. Chazzarra, and F. Garcia-Carmona, Kojic acid, a cosmetic skin whitening agent, is a slowbinding inhibitor of catecholase activity of tyrosinase, J. Pharm. Pharmacol., 46, 982985 (1994).
(43) M. Nakagawa and K. Kawai, Contact allergy to kojic acid in skin care products, Contact Dermatitis,
32, 913 (1995).
(44) S. H. Lee, S. Y. Choi, H. Kin, J. S. Hwang, B. G. Lee, and J. J. Gao, Mulberoside F isolated from the
leaves of Morus alba inhibits melanin biosythesis, Biol. Pharm. Bull., 25, 10451048 (2002).
(45) K. Jones, J. Hughes, M. Hong, Q. Jia, and S. Orndorff, Modulation of melanogenesis by aloesin:
A competitive inhibitor of tyrosinase, Pigment Cell Res., 15, 335340 (2002).
(46) I. Kubo and K. Hori, Flavanols from saffron flower: Tyrosinase inhibitory activity and inhibition mechanism, J. Agric. Food Chem., 47, 41214125 (1999).
(47) I. Parejo, F. Viladomat, J. Bastida, and C. Codina, Variation of the arbutin content in different wild
populations of Arctostaphylos uva-ursi in Catalonia, Spain Journal of Herbs, Spices & Medicinal Plants,
9, 329333 (2002).
(48) B. Fu, H. Li, X. Wang, F. S. Lee, and S. Cui, Isolation and identification of flavonoids in licorice and a
study of their inhibitory effects on tyrosinase, J. Agric. Food Chem., 53, 74087414 (2005).
(49) J. K. No, D. Y. Soung, and Y. J. Kim, Inhibition of tyrosinase by green tea components, Life Sci.,
65, 241245 (1999).
(50) A. Adhikari, H. P. Devkota, A. Takano, K. Masuda, T. Nakane, P. Basnet, N. Skalsko, and N. Basnet,
Screening of Nepalese crude drugs traditionally used to treat hyperpigmentation: In vitro tyrosinase
inhibition, Int. J. Cosmet. Sci., 30, 353360 (2008).
(51) C. Zhang, L. Tao, X. Tao, and X. Su, Tyrosinase inhibitory effects and inhibition mechanism of nobiletin and hesperidin from citrus peel crude extracts, J. Enz. Inhib. Medicinal Chem., 22, 8390 (2007).
(52) M. Yoshimura, Y. Watanabe, K. Kasai, J. Yamakoshi, and T. Koga, Inhibitory effect of an ellagic acid
rich pomegranate extract on tyrosinase activity and ultraviolet induced pigmentation, Biosci. Biotechmol.
Biochem., 69, 23682373 (2005).
(53) T. Shoji, S. Masumoto, N. Moriichi, M. Kobori, T. Kanda, H. Shinmoto, et al. Procyanidin trimers to
pentamers fractionated from apple inhibit melangenesis in B16 mouse melanoma cells, J. Agric. Food.
Chem., 53, 61056111 (2005).
(54) H. S. Lee, Tyrosinase inhibitors of Pulsatilla cernua root derived materials, J. Agric. Food Chem,
50, 14001403 (2002).
(55) I. Kubo and I. Kint-Hori, Tyrosinase inhibitors from cumin, J. Agric Food Chem., 46, 53385341
(1988).
(56) S. E. Lee, M. O. Kim, S. G. Lee, Y. J. Ahn, and H. S. Lee, Inhibitory effects of Cinnamonum cassia bark
derived materials on mushroom tyrosinase, Food Sci. Biotechnol., 9, 330333 (2000).
(57) P. Tengamnuay, K. Pengrungruangwong, I. Pheansri, and K. Likhitwitayawuid, Artocarpus lakoocha
heartwood extract as a novel cosmetic ingredient: Evaluation of the in vitro anti-tyrosinase and in vivo
skin whitening activities, Int. J. Cosmet. Sci., 28, 269276 (2006).
(58) A. B. Durkee, F. B. Johnston, P. A. Thivierge, and P. A. Poaps, Arbutin and a related glucoside in
immature pear fruit, J. Food Sci., 33, 461463 (1968).
(59) H. Shimogaki, Y. Tanaka, H. Yamai, and M. Masuda, In vitro and in vivo evaluation of ellagic acid on
melanogenesis inhibition, Int. J. Cosmet. Sci., 22, 291303 (2000).
(60) K. T. Lee, K. S. Lee, J. H. Jeong, B. K. Jo, M. Y. Heo, and H. P. Kim, Inhibitory effects of Ramulus mori
extracts on melanogenesis, J. Cosmet. Sci., 54, 133142 (2003).
(61) J. Y. Lim, K. Ishiguro, and I. Kubo, Tyrosinase inhibitory effects of p-coumaric acid from ginseng
leaves, Phytother. Res., 13, 371375 (1999).
(62) T. Hanamura, E. Uchida, and H. Aoki, Skin lightening effect of a polyphenol extract from
Acreola (Malphigia emarginata DC) fruit on UV-induced pigmentation, Biosci. Biotechnol. Biochem.,
72, 32113218 (2008).

54

JOURNAL OF COSMETIC SCIENCE

(63) C. C. Chien, M. L. Tsai, C. C. Chen, S. J. Chang, and C. H. Tseng, Effects on tyrosinase activity by the
extracts of Ganoderma lucidum and related mushrooms, Mycopathologia, 166, 2 (2008).
(64) A. D. Katsambas and A. J. Stratigos, Depigmenting and bleaching agents: Coping with hyperpigmentation, Clinics Dermatol., 19, 483488 (2001).
(65) D. Roshchupkin, M. Y. Pistov, and A. Y. Patapenlo, Inhibition of UV induced erythema by antioxidants, Arch. Dermatol. Res., 266, 9194 (1979).
(66) N. Muizzuddin, A. R. Shakoori, and K. D. Marenus, Effect of antioxidants and free radical scavengers
on protection of human skin against UVB, UVA and IR irradiation, Skin Res. Technol., 5, 260265
(1999).
(67) A. Pompella, A. Visvikis, A. Paolicchi, V. De Tata, and A. F. Casini, The changing face of glutathione,
a cellular protagonist, Biochem. Pharmacol., 66, 14991503 (2003).
(68) Z. D. Draelos, Novel topical therapies in cosmetic dermatology, Curr. Prob. Dermatol. (Elsevier,
New York, 2000).
(69) T. Aburjai and F. M. Natsheh, Plants used in cosmetics, Phytother. Res., 17, 9871000 (2003).
(70) A. M. Kligman and I. Willis, A new formula for depigmenting human skin, Arch. Dermatol., 111,
40 (1975).
(71) K. Yoshimura, A. Momosawa, E. Aiba, K. Sato, D. Matsumoto, Y. Mitoma, K. Harii, T. Aoyama,
and T. Iga, Clinical trial of bleaching treatment with 10% all trans-retinol gel, Dermatol. Surg.,
29, 21552160 (2003).
(72) A. M. Kligman, The growing importance of topical retinoids in clinical dermatology: A retrospective
and prospective analysis, J. Am. Acad. Dermatol., 39, S2S7 (1998).
(73) T. Hokazaki, L. Minwalla, and J. Zhuang, The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosomal transfer, Br. J. Dermatol., 147, 2031 (2002).
(74) W. Gehring, Nicotinic acid/niacinamide and the skin, J. Cosmet. Dermatol., 8893 (2004).
(75) J. Franchi, M. C. Coutadeur, C. Marteau, M. Mersel, and A. Kupferberg, Depigmenting effects of
calcium D-pantetheine-S-sulfonate on human melanocytes, Pigment Cell Res., 13, 165171 (2000).
(76) J. R. Ros, J. N. Rodriguez-Lopes, and F. Garcia-Canovas, Effects of L-ascorbic acid on the monophenolase activity of tyrosinase, Biochem. J., 295, 309312 (1993).
(77) K. Kameyama, C. Sakai, and S. Kondoh, Inhibitory effects of magnesium 1-ascorbyl-2-phosphate
(VC-PMG) on melanogenesis in vitro and in vivo, J. Am. Acad. Dermatol., 34, 2933 (1996).
(78) K. E. Burke, J. Clive, G. F. Combs Jr., J. Commisso, C. L. Keen, and R. N. Nakamura, The effects of
topical and oral vitamin E on pigmentation and skin cancer induced by ultraviolet irradiation in skh:
2 hairless mice, J. Nutr. Cancer, 28873897 (2001).
(79) K. E. Burke, Interaction of vitamins C and E as better cosmeceuticals, Dermatolog. Ther., 20, 314321
(2007).
(80) G. R. Kantharaj, Skin lightening agents: New chemical and plant extractsOngoing search for the
Holy Grail, Ind. J. Dermatol. Venerol. Leperol., 76, 36 (2010).
(81) E. R. Sharlow, C. S. Paine, L. Babiarz, M. Eisinger, S. Shapiro, and M. Seiberg, J. Cell Sci., 113, 30933101
(2000).
(82) B. M. Hantash, US Patent application 2009/099093 A1.
(83) H. Yamada, N. Fuwa, and M. Nomura, US Patent 6,165,982.
(84) M. Sieberg, Keratinocytemelanocyte interactions during melanosome transfer, Pigment Cell Res.,
14, 236242 (2001).
(85) J. E. Fulton and S. Porumb, Chemical peels: Their place within the range of resurfacing techniques,
Am. J. Clin. Dermatol., 5, 179187 (2004).