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Survey and mechanism of skin depigmenting andlightening agents

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SKIN DEPIGMENTATION AND LIGHTENING 921

Copyright © 2006 John Wiley & Sons, Ltd. Phytother. Res. 20, 921–934 (2006)DOI: 10.1002/ptr

Copyright © 2006 John Wiley & Sons, Ltd.

PHYTOTHERAPY RESEARCHPhytother. Res. 20, 921–934 (2006)Published online 14 July 2006 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/ptr.1954

REVIEW ARTICLE

Survey and Mechanism of Skin Depigmentingand Lightening Agents

Shoukat Parvez1†, Moonkyu Kang1, Hwan-Suck Chung1, Chongwoon Cho1,Moo-Chang Hong2, Min-Kyu Shin2 and Hyunsu Bae1,2,*1Purimed R&D Institute, Kyung-Hee University #1 Hoegi-Dong, Dongdaemun-Ku, Seoul 130-701, Korea2Department of Physiology, College of Oriental Medicine, Kyung-Hee University, #1 Hoegi-Dong, Dongdaemun-Ku,Seoul 130-701, Korea

The type and amount of melanin synthesized by the melanocyte, and its distribution pattern in the surrounding

keratinocytes, determines the actual color of the skin. Melanin forms through a series of oxidative reactions

involving the amino acid tyrosine in the presence of the enzyme tyrosinase.

Tyrosinase catalyses three different reactions in the biosynthetic pathway of melanin in melanocytes: the

hydroxylation of tyrosine toL

-DOPA and the oxidation ofL

-DOPA to dopaquinone; furthermore, in humans,dopaquinone is converted by a series of complex reactions to melanin.

Among the skin-lightening and depigmenting agents, magnesium-L-ascorbyl-2-phosphate (MAP), hydro-

xyanisole, N -acetyl-4-S-cysteaminylphenol, arbutin (hydroquinone-beta-D-glucopyranoside) and hydroquinone

(HQ) are the most widely prescribed worldwide. However, with reports of potential mutagenicity and epi-

demics of ochronosis, there has been an increasing impetus to find alternative herbal and pharmaceutical

depigmenting agents. A review of the literature reveals that numerous other depigmenting or skin-lightening

agents are either in use or in investigational stages. Some of these, such as kojic, glycolic and azelaic acids, are

well known to most dermatologists. Others have been discovered and reported in the literature more recently.

Several depigmentation and lightening agents are discussed, including their historical background,

biochemical characteristics, type of inhibition and activators from various sources. In addition, the clinical

importance of mushroom tyrosinase as a recent prospect is discussed in this paper. Copyright © 2006 John

Wiley & Sons, Ltd.

Keywords: arbutin; azelaic acid; melanin; kojic acid; hydroquinone; hyperpigmentation; tyrosine; L-DOPA; tyrosinase.

Received 26 February 2006

Revised 27 March 2006

Accepted 12 May 2006

† Permanent address: NIBGE, P.O. Box 577, Faisalabad, Pakistan.* Correspondence to: Dr Hyunsu Bae, Department of Physiology,

College of Oriental Medicine, Kyung-Hee University, #1 Hoegi-Dong,Dongdaemun-Ku, Seoul 130-701, Korea.E-mail: [email protected]

to 3-4-dihydroxyphenylalanine, L-DOPA and the oxi-dation of L-DOPA to o-dopaquinone. This o-quinoneis a highly reactive compound and can polymerize spon-taneously to form melanin pigmentation; this presentsa serious aesthetic problem in human beings (Brigantiet al., 2003).

Exogenous causes, particularly ultra-violet lightexposure, are a common factor in pigment abnormali-ties such as melasma, solar lentigines and ephelides(Maeda and Fukuda, 1991). Exposure to certaindrugs and chemicals as well as the existence of cer-tain disease states can result in hyperpigmentation.

Depigmenting agents commonly are prescribed totreat disorders of hyperpigmentation (Kubo, 1986;Jang et al., 1997).

In this article, a review is presented of several nota-ble depigmenting and lightening agents reported in theliterature for use in depigmentation or disorders of hyperpigmentation of skin. Among some of the skin-lightening and depigmentation agents are kojic acid,arbutin, catechins, hydroquinone (HQ) and azelaic acid(Maeda and Fukuda, 1996; Katagiri et al., 1998), whichare well known to most dermatologists. Others havebeen more recently discovered and are reported inthis article. However, while it is inevitable that thisreview be selective in its coverage, it attempts to deal

with various aspects of depigmentation and lighten-ing agents from natural products, including their his-torical background, biochemical characteristics, type of

INTRODUCTION

Up to 10% of skin cells in the innermost layer of theepidermis produce a dark pigment known as melanin.Upon exposure of the skin to UV radiation, melanogen-esis is initiated with the first step of tyrosine oxidationthrough an enzyme called tyrosinase (Vámos, 1981).

Tyrosinase is a multifunctional, glycosylated, copper-containing oxidase with a molecular weight of approxi-mately 60–70 kDa in mammals, and is found exclusivelyin melanocytes (Strothkemp et al., 1976). It is therefore

a good specific marker for the cells. Tyrosinase issynthesized by melanosomal ribosomes found on therough endoplasmic reticulum (Halaban et al., 2002).After synthesis, tyrosinase is glycosylated en route toand within the golgi. It is subsequently delivered tomelanosomes via coated vesicles in an inactive form(Halaban et al., 2001; 2002).

The biosynthetic pathway for melanin formation invarious life forms has largely been elucidated by Raper(1928), Mason (1948) and Lerner et al. (1949). The firsttwo steps in the pathway are hydroxylation of L-tyrosine




922 S. PARVEZ ET AL.

Figure 1. Outline of mammalian skin indicating three main layers epidermis, dermis and sub-cutaneous, visible pigmentation resultsfrom the synthesis and distribution of melanin in the melanocytes in the dermis layer of the skin.

The first step is the most critical because the re-mainder of the reaction sequence can proceed sponta-neously at a physiological pH (Halaban et al., 2002).Here, tyrosinase converts tyrosine to dihydroxyphe-nylalanine (DOPA) and then to dopaquinone. Sub-sequently, dopaquinone is converted to dopachromethrough auto-oxidation, and finally to dihydroxyindoleor dihydroxyindole-2-carboxylic acid (DHICA) to formeumelanin (brown-black pigment). The latter reactionoccurs in the presence of dopachrome tautomeraseand DHICA oxidase. In the presence of cysteine orglutathione, dopaquinone is converted to cysteinylDOPA or glutathione DOPA. Subsequently, pheome-lanin, a yellow-red pigment, is formed (Raper, 1928;Kobayashi et al., 1995; Borges et al., 2001) presented insimplified form in Fig 2.

Olivares et al. (2001) recently discovered thatmammalian melanogenesis is not regulated solely bytyrosinase at the enzymatic level, and additionalmelanogenic factors have been identified which canmodulate pigmentation in either a positive or negativefashion.

REGULATION OF MELANOGENESIS

The regulation of pigmentation in mammals is control-led at many different levels and is quite complex withineach level. Melanocytes are initially derived fromthe neural crest and migrate throughout the embryoduring development. These migration patterns areunder strict genetic control and can lead to someinteresting patterns when final melanocyte distributionin the skin is not uniform, as can be seen in zebras andgiraffes (Hearing and Tsukamoto, 1991). Pigmentationis also regulated at the cellular level by melanocytes

synthesizing melanin within melanosomes, which canbe produced in varying sizes, numbers and densities.Lastly, melanogenesis is regulated at the subcellular

inhibitions, activators from various sources and pro-spects for their clinical importance. A number of tyro-sinase inhibitors from both natural and synthetic sources(Fig. 3) that inhibited monophenolase, diphenolaseor both of these activities (Tables 1 and 2) have beenidentified.

MELANIN-FORMATION AND DISTRIBUTION

IN THE SKIN

Visible pigmentation in mammals results from the syn-thesis and distribution of melanin in the skin and hairbulbs (Seiberg et al., 2000; Schaffer and Bolognia, 2001).The formation of pigmentation is demonstrated inFig. 1. Melanins also play a crucial role in the absorp-tion of free radicals generated within the cytoplasmand in shielding the host from various types of ionizingradiations, including UV light. Melanins can be of twobasic types: eumelanins, which are brown or black, andpheomelanins, which are red or yellow (Raper, 1928;Olivares et al., 2001) and whose metabolic pathways

are illustrated in Fig. 2. In mammals, mixtures of bothtypes are typically found. Interestingly, pheomelaninhas the capacity to produce free radicals in response toUV radiation. Since free radicals can inflict cell injury,pheomelanin may actually contribute to intensifyingUV-induced skin damage rather than protecting theskin (Seo et al., 2003).

Basic information about the pigmentation pathway ishelpful prior to a discussion of various skin-lighteningagents and their known mechanisms of action. The typeand amount of melanin synthesized by the melanocyte,and its distribution pattern in the surrounding keratin-ocytes, determines the actual color of the skin (Fig. 1).Melanin forms through a series of oxidative reactions

involving the amino acid tyrosine in the presence of the enzyme tyrosinase (Shi et al., 2002; Kobayashiet al., 1995).





Table1

.Somedepigmentinglighteningagentsandtheirmushroom

tyrosinaseinhibition

activitiesfrom

naturalsources

Inhibito

r

Source

Botanicalname

Typeofinhibition

IC 5

0

(m M)

Reference

Arbutin

Gvaegrsi

Arctostaphy

losuva-ursi

Competitive

0.04

Yagietal.,

1987

Uncompetitive

Aloesin

Aloever

a

Aloebarbadensis

Noncompetitive

0.1

Yagietal.,

1987

Anacar

dicacid

Anacard

ium

occidentale

Anacardium

occidentale

Competitive

0.0001

Kuboetal.,1994

Anisicacid

Aniseoi

l

Pimpinellaanisum

Uncompetitive

0.68

Lee,2002

Agaritine

Agaricus

bisporus

Agaricusbisporus

Uncompetitive

0.03

EspinandJolivet,1998

Anisald

ehyde

Aniseoi

l

Pimpinellaanisum

Noncompetitive

0.38

Lee,2002

Cumic

acid

Cumins

eed

Cuminumc

yminum

Noncompetitive

0.26

KuboandK

inst-Hori,1988

Cuminaldehyde

Cumins

eed

Cuminumc

yminum

Noncompetitive

0.05

KuboandK

inst-Hori,1988

p-Coum

aricacid

Ginseng

Radix

Panaxginseng

Mixed

3.65

Lim

etal.,1991

ECG

Greente

a

Theachinensis

Competitive

0.035

Noetal.,1

999

EGCG

Greente

a

Theachinensis

Competitive

0.034

Noetal.,1

999

Ia

Agaricus

hortensis

Agaricusho

rtensis

Competitive

0.03

Madhosing

handSundberg,1974

3,4-Dih

ydroxycinnamicacid

Pulsatillacernua

Pulsatillace

rnua

Noncompetitive

0.97

Lee,2002

Oxyres

veratrol

MoriCortex

Morusalba

Noncompetitive

0.001

Lee,2002

Kaemp

ferol

CrociStigma

Crocussativus

Competitive

0.23

KuboandH

ori,1999

Trans-cinnamaldehyde

Cinnamo

miCortex

Cinnamomu

m

cassia

Competitive

0.85

Leeetal.,2000

Ib

Agaricusho

rtensis

Noncompetitive

0.03

Madhosing

handSundberg,1974

4-Hydroxy-3-

PulsatillaeRadix

Pulsatillace

rnua

Noncompetitive

0.97

Lee,2002;Lee,etal.,2000

meth

oxycinnamicacid

9-Hydroxy-4-methoxypsoraln

Angelica

edahuricaeRadix

Angelicada

hurica

Noncompetitive

0.2

Piaoetal.,

2004

5-hydro

xymethyl-2-furfural

Dictyoph

oraindusiata

Dictyophora

indusiata

Noncompetitive

0.98

Sharmaet

al.,2004





Figure 2. The Raper-Mason melanogenesis pathway in its classical form. Structural formulas are abbreviated as follows: DOPA: L-3,4-dihydroxyphenylalanine; DOPAquinone: 4-(2-carboxy-2-aminoethyl)-1,2-benzoquinone; leucodopachrome: 2,3-dihydro-5,6-dihydroxyindole-2 carboxylate; DOPAchrome: 2-carboxy-2,3-dihydroindole-5,6-quinone; DHICA: 5,6 dihydroxyindole-2-carboxylic acid;DHI: 5,6-dihydroxyindole (Raper, 1928; Kobayashi et al., 1995; Mason, 1948; Olivares et al., 2001 melanogenesis pathway in itsclassical and modified form).

level where the synthesis and expression of variousmelanogenic enzymes and inhibitors play a critical role(Sánchez-Ferrer et al., 1995; Burton, 1994).

Melanocytes work in close harmony with theirneighboring cells in the epidermis. They are influencedby a variety of biological factors including interleukins,

interferons, growth factors, vitamins and prostaglandins,which determine not only whether melanin is synthe-sized, but what type of melanin is produced. Presum-

ably, these factors provide the complex signals thatstimulate pigmentation after trauma, UV exposure, orother environmental stimuli that induce alterations in

Table 2. Some depigmenting and lightening agents and their mushroom tyrosinase inhibition activities from synthetic sources

Inhibitor Type of inhibition IC50 (mM) Reference

Benzoic acid Mixed 0.64 Kubo and Kinst-Hori, 1988Benzaldehyde Noncompetitive 0.82 Kubo and Kinst-Hori, 1988Cupferron Competitive 0.001 Shiino et al., 2001Cinnamaldehyde Noncompetitive 0.97 Lee, 2002Cinnamic acid Mixed 0.7 Lee, 2002Captopril Noncompetitive 0.7 Espin and Wichers, 2001Citral Noncompetitive 1.5 Kubo and Hori, 1999Dimethyl sulfide Competitive 0.014 Pérez-Gilabert et al., 2001Methimazole Mixed 0.7 Andrawis and Kahn, 1996Kojic acid Mixed 0.014 Ha et al., 2001L-Mimosine Competitive 0.34 Cabanes et al., 1987Tiron Competitive 400 Kahn and Andrawis, 1987Tropolone Competitive 0.34 Valero et al., 19912-Methoxycinnamic acid Noncompetitive 0.34 Lee, 20023-Methoxycinnamic acid Noncompetitive 0.35 Lee, 20024-Methoxycinnamic acid Noncompetitive 0.34 Lee, 20024-Substituted benzaldehydes Competitive 0.34 Jiménez et al., 20014-Substituted resorcinol Competitive 0.014 Jiménez and Carmona, 1997p-Hydroxybenzaldehyde Competitive 1.2 Kubo and Hori, 1999





2003; Anderson et al., 1993; Masuda et al., 2005).Changing demographics and an increase in the non-Caucasian population is also giving rise to an increasein pigmentary disorders (Anderson and Parrish, 1981).Increasing consumer interest in skin care and treatmentproducts derived from natural sources has drivenincreased research into novel skin depigmenting agents(Jeong and Shim, 2004; Masuda et al., 2005). While

hydroquinone monotherapy and other prescription-strength topicals are fairly effective, they have draw-backs including high cost, possible skin irritation andthe need to limit the duration of use. It is thereforelikely that in the future more products containingeffective but less irritating ingredients such as kojicacid, licorice extract and soy will continue to be devel-oped, as mentioned in Tables 1 and 2. In the future,identifying a combination of cosmetic compoundsthat act upon different steps in the pigmentation path-ways should be advantageous, as side effects aredecreased and the clinical outcomes improved. Thereare numerous candidates for depigmenting agents,but more strictly controlled clinical trials are neededto assess their safety and efficacy.

The following is a discussion of the known skindepigmentation and lightening agents and their mecha-nisms from the literature.

Hydroquinone

An important industrial chemical, hydroquinone(HQ) is also a ubiquitous chemical readily availablein cosmetic and nonprescription forms for skin light-ening. It is considered one of the most effectiveinhibitors of melanogenesis in vitro and in vivo, andis widely used for the treatment of melanosis andother hyperpigmentary disorders (Palumbo et al., 1991;Verallo-Rowell et al., 1989). This phenolic compoundhas been successfully used as a skin-lightening agentfor the treatment of melasma, post-inflammatoryhyperpigmentation and other disorders of hyperpig-mentation (Yang, 1999). Hydroquinone decreasetyrosinase activity by 90% (Verallo-Rowell et al., 1989)and causes reversible in-hibition of cellular metabolismby affecting both DNA and RNA synthesis (Penneyet al., 1984).

Hydroquinone occurs naturally in many plants aswell as in coffee, tea, beer and wine (Sang et al., 2005).The cytotoxic effects of HQ are not limited to melan-

ocytes, although the dose required to inhibit cellularmetabolism is much higher for nonmelanotic cells thanfor melanocytes. Thus, HQ can be considered a potentmelanocyte cytotoxic agent with relatively high melanocyte-specific cytotoxicity (Breathnach, 1996). Additionalinformation on the structure of hydroquinone and itsanalogs is given in Fig. 3.

Kamau et al. (2002) reported that hydroquinone isgenerally considered very safe. But its common sideeffects are skin irritation or contact dermatitis, whichcan be easily treated with topical steroids. A rare, butserious, side effect of hydroquinone is the developmentof exogenous ochronosis, a sooty hyperpigmentation inthe treatment area, which may be extremely difficult to

reverse to any degree.Exogenous ochronosis has generally been observed inblack patients and after the use of high concentrations

the levels of pigment production (Rana et al., 1996).Perhaps the most commonly known melanogenicstimulus is melanocyte-stimulating hormone (MSH,or melanotropin), a peptide produced by the posteriorpituitary. Once MSH binds to melanocyte surfacereceptors, a dramatic, up to 100-fold increase inmelanogenesis results (Spencer et al., 2005).

DIFFERENCES IN RACIAL PIGMENTATION

Skin color is a function of the size, number and distri-bution of melanosomes, rather than the density of melanocytes. In fact, the number of melanocytes is thesame in all races. However, the melanocytes of darklypigmented skin have thicker, longer, branched dendrites(Rana et al., 1996).

Briganti et al. (2003) and Jablonski and Chaplin(2001) mentioned that the differences in racial skinpigmentation depend upon the quantity of melaninproduced and upon the distribution and deposition of melanosomes throughout the epidermis. At present,little is known concerning the relative importance of any step regulating racial pigmentation.

Tyrosinase is the rate-limiting enzyme for melaninsynthesis, and defects in the enzyme’s activity leadto albinism in humans (Masuda et al., 2005). It alsoseems likely that racial differences in human skin colormay primarily be due to differences in tyrosinase activ-ity from varying skin types. Melanocytes derived fromblack skin have up to ten times more activity and pro-duce up to ten times more melanin than do melanocytesfrom white skin (Valverde et al., 1995). However, thehigher level of tyrosinase activity in melanocytesderived from black skin is not due to a greater abun-dance of tyrosinase. The number of tyrosinase moleculespresent in white skin melanocytes is equal to that foundin highly pigmented black skin types (Valverde et al.,1996).

Rana et al. (1996) found that in black skin, melaninpersists within the horny layer and leaves the skin bynatural desquamation, whereas in white skin the pigmentis degraded in the granular layer, probably by theskin’s own enzymatic process. This indicates that thestratum corneum of white skin does not containany melanin.

The cosmetic use of bleaching products is considereda common practice in dark-skinned women in many

countries in Africa, the Caribbean and South America.Many of these ingredients are readily available to con-sumers without a prescription and therefore potentialmisuse is of concern (Del Giudice and Yves, 2002).

CURRENT RESEARCH

As the population ages, dyspigmentation due tophoto aging will become more common, and con-sumers are increasingly requesting treatment for thiscosmetic problem (Briganti et al., 2003; Masuda et al.,2005). Hyperpigmentation from other causes such as

melasma and post-inflammatory conditions are alsoof increasing attention as patients realize that its ap-pearance can be improved with treatment (Seo et al.,





Figure 3. The chemical structures of known skin whitening and lightening agents.

of HQ for many years. Although this condition isuncommon under normal usage, in some cultureswhere light skin is considered desirable, hydroqui-none used at high concentrations or for prolongedperiods, even at low concentrations, may result inthe development of this serious side effect (Kamau,

2002). Alternating the use of hydroquinone with oneof the alternative agents in 4-month cycles will helpto prevent side effects such as irritation as well asdecrease the risk of exogenous ochronosis (Baumann,2004).

Despite its remarkable overall safety, physiciansshould bear in mind the potential adverse effects of HQ. Contact dermatitis occurs in a small number of patients and responds promptly to topical steroids.An uncommon, yet significant, adverse effect of HQis exogenous ochronosis. This disorder is characterizedby progressive darkening of the area to which the HQ-containing cream is applied. Histologically, degenera-tion of collagen and elastic fibers occurs, followed by

the appearance of characteristic ochronotic depositsconsisting of crescent-shaped, ochre-colored fibers inthe dermis (Penney et al., 1984).

Magnesium ascorbyl phosphate

Recently, Elmore (2005) reported that magnesium-L-ascorbyl-2-phosphate (MAP) is a stable derivativeof ascorbic acid (Fig. 3) and a 10% cream of MAPwas shown to suppress melanin formation. A signifi-

cant lightening effect was seen clinically in 19 of 34patients with melasma and solar lentigos. Furthermore,MAP has been shown to have a protective effect againstskin damage induced by UV-B irradiation. This pro-tective effect stems from the conversion of MAP toascorbic acid (AS) and is effective in reducing skinhyperpigmentation in some patients (Elmore 2005;Kameyama et al., 1996).

VC-PMG suppressed melanin formation by tyro-sinase and melanoma cells. In situ experiments demon-strated that VC-PMG cream was absorbed into theepidermis and that 1.6% remained 48 h after applica-tion. Its lightening effect was significant in 19 of 34patients with chloasma or senile freckles and in 3 of 25

patients with normal skin (Kameyama et al., 1996).The protective effect of magnesium-L-ascorbyl-2-phosphate (MAP) on cutaneous photodamage such as





lipid peroxidation and inflammation induced by ultra-violet B (UVB) exposure (290–320 nm, max. 312 nm)was investigated using hairless mice. When MAPwas administered intraperitoneally to mice at a doseof 100 mg of ascorbic acid (AS) per kg body weightimmediately before irradiation (15 kJ/m2), the expectedincreases in thiobarbituric acid reactive substance(TBARS) formation in skin and serum sialic acid,

which are indices of lipid peroxidation and inflamma-tory reaction, respectively, were significantly reduced.However, the expected decrease in the level of cutane-ous AS was unchanged. Similar results were observedfor animals given 100 mg of AS-Na per kg body weightbefore UVB irradiation. When MAP was administeredintracutaneously immediately before irradiation, theexpected UVB-induced increases in TBARS and sialicacid were again significantly prevented. Ascorbic acid-Na had less of a protective effect than intracutaneousMAP administration. The cutaneous AS level wassignificantly higher in the MAP-treated mice than inthe controls, and the UVB-induced decrease in tissueAS was prevented by intracutaneous MAP administra-tion. These results suggest that MAP protects againstUVB irradiation-induced lipid peroxidation and inflam-mation in cutaneous tissue, regardless of the drugadministration route. In vitro studies showed that MAPwas converted to AS as it crossed the epidermis,but that AS-Na did not pass through the epidermis.Furthermore, MAP was also converted to AS inserum. These results suggest that the protective effectof MAP on UVB-induced cutaneous damage is dueto the conversion of MAP to AS (Kobayashi et al.,1996).

Monobenzyl ether of hydroquinone

Like HQ, monobenzyl ether of hydroquinone (MBEH)belongs to the phenol/catechol (Fig. 3) class of che-mical agents (Gusarova and Zalem, 1966). However,unlike HQ, MBEH almost always causes a nearlyirreversible depigmentation of skin. Traces of MBEHhave been found in disinfectants, germicides, rubber-covered dish trays, adhesive tape, powdered rubbercondoms and rubber aprons (Urabe and Hori, 1997).MBEH should be used only to eliminate residualareas of normally pigmented skin in patients withrefractory and generalized vitiligo. It has been sug-gested that the mechanism of depigmentation by MBEH

involves selective melanocytic destruction throughfree radical formation and competitive inhibition of the tyrosinase enzyme system (Lyon and Beck,1998).

The phenomenon of repigmentation occurred withina few weeks of discontinuing successful depigmentationtherapy with monobenzyl ether of hydroquinone in apatient with extensive vitiligo. Patients undertakingdepigmentation therapy should be warned that this mayoccur, although the mechanism by which this occurs isunknown (Oakley, 1996; Falabella, 1986).

N -acetyl-4-S-cysteaminylphenol

N -Acetyl-4-S-cysteaminylphenol (1) is an analog of tyrosine that is involved in the pathway of melanin

production (Ferguson et al., 2005). It is probablyoxidized selectively in melanocytes to an o-quinonethat can alkylate thiol groups on important cellularenzymes, resulting in interference with cell growthand proliferation (Ferguson et al., 2005). Like HQand MBEH, N -acetyl-4-S-cysteaminylphenol (4-S-CAP)belongs to the phenol/catechols class (Fig. 3). TheN -acetyl derivative of 4-S-CAP appears to be an

excellent tyrosinase substrate; it forms a melanin-likepigment when exposed to tyrosinase. Like HQ, italso is considered to be cytotoxic. In a study of 12patients with melasma who used 4% 4-S-CAP, theauthor reported a 66% improvement after 4 weeksof use. Furthermore, the author reported it to bemore stable and less irritating than HQ (Pearson et al.,2003).

Topically applied melatonin has a clear-cut protec-tive effect against UV-induced erythema. Free radicalscavenging of UV-generated hydroxyl radicals and in-terference with the arachidonic acid metabolism arepossible mechanisms of the melatonin action (Banghaet al., 1997).

Jimbow et al. (1993) demonstrated that a phenolicthioether, N -acetyl-4-S-cysteaminylphenol, is a newtype of depigmenting agent for better management of melasma. It is much more stable and less irritatingto the skin than hydroquinone, and it is specific tomelanin-synthesizing cells.

Soy

There has been a great deal of interest andresearch into the cosmetic benefits of soy (Seiberget al., 2000; Friedman et al., 1986). Natural soybeanscontain the small proteins, Bowman Birk inhibitor(BBI) and soybean trypsin inhibitor (STI). Theseserine protease inhibitors inhibit the protease-activatedreceptor-2 (PAR-2) pathway expressed on keratino-cytes. Interference with the PAR-2 pathway hasbeen shown to induce depigmentation by reducingthe phagocytosis of melanosomes by keratinocytes,thus reducing melanin transfer. This mechanism of action is different to that of hydroquinone, kojicacid or glabridin. It is important to note that thisdepigmenting effect is available only with fresh soymilkand not with pasteurized soymilk (Friedman et al.,1986).

A number of attempts have been made by

various researchers, and total soy is now beingincorporated into skin care products to improvemottled hyperpigmentation and solar lentigines thatfrequently result from photodamage. In addition,soy has been shown to lighten and slow the regrowthof unwanted facial hair (Seiberg et al., 2000;Paine et al., 2001).There are many studies showingthat fermented soy products containing the isofla-vones, daidzein and genistein, may function as weakphytoestrogens (Cassidy et al., 2006). A knownbiotransformed compound, 6,7,4'-trihydroxyisoflavone,was identified as a potent tyrosinase inhibitor,which has six times the anti-tyrosinase activity of kojic acid (Chang et al., 2005). Currently, several

manufacturers are producing facial and body careproducts that contain total soy to even the skintone.





Hydroxyanisole

Many of the well-known depigmenting agents such ashydroquinone and 4-hydroxyanisole are, in fact, melano-cytotoxic chemicals which are oxidized in melanocytesto produce highly toxic compounds such as quinones(Kasraee et al., 2003). These cytotoxic compounds areresponsible for the destruction of pigment cells, result-

ing in skin depigmentation. However, cells are capableof protecting themselves against cytotoxic agents byintracellular glutathione (GSH). This protection takesplace under the enzymatic action of the detoxificationenzyme glutathione S-transferase (GST), which isresponsible for the conjugation of toxic species toGSH (Moridani, 2006). The depigmenting effect of hydroquinone is shown to be potentiated by buthioninesulfoximine (BSO) and cystamine as a result of theirreducing intracellular GSH levels. Additionally, BSOand cystamine are shown to inhibit the activity of GST.The combination of all-trans-retinoic acid (tretinoin,TRA) with hydroquinone or 4-hydroxyanisole is alsoknown to produce synergetic skin depigmentation. TRAserves as a potent inhibitor of mammalian GSTs and isknown to make cells more susceptible to the cytotoxiceffect of chemicals by inhibiting the activity of this en-zyme (Asanuma et al., 2003). This agent was also shownto reduce the level of intracellular GSH in certain cells(Kasraee et al., 2003).

In another study, GSH was shown to performseveral important biological functions, including quench-ing of reactive oxygen species and protection of cells from toxic compounds such as quinones. The firststep in the synthesis of GSH is catalysed by gamma-glutamylcysteine synthetase, an enzyme which is in-hibited by cystamine and BSO. The possibility of hydroquinone’s effect on pigmentation being poten-tiated by the inhibition of GSH production hasbeen examined (Bolognia et al., 1995; Asanuma et al.,2003).

Glycolic acid

Glycolic acid is an alpha-hydroxy acid derived fromsugar cane (Saccharum) and it may have two skin light-ening effects. At low concentrations, glycolic acid hasan epidermal discohesive effect which results in a morerapid desquamation of pigmented keratinocytes. Likeretinoids, glycolic acid shortens the cell cycle so that

pigment is lost more rapidly. At higher concentrations,glycolic acid results in epidermolysis (Perez-Bernalet al., 2000).

Several studies have shown that the removal of superficial layers of epidermis with glycolic acidpeels at concentrations of 30%–70% can enhance thepenetration of other topical skin lighteners such ashydroquinone (Sarkar et al., 2002). When glycolic acidis used in the treatment of post-inflammatory hyperpig-mentation, it has been suggested that it should be initi-ated at low concentrations to avoid skin irritation andexacerbated hyperpigmentation (Jones et al., 2002; Choiet al., 2002). The use of hydroquinone both prior to andafter the peel can lessen the risk of such pigmentary

alterations (Baumann, 2004). Also, the addition of glycolic acid to hydroquinone formulations seems toenhance its efficacy (Guevara and Pandya, 2003).

Vitamin C

There is an increasing awareness that vitamin C(L-ascorbyl acid) has a wide variety of roles inhuman health, and thus it has been studied by variousresearchers (Ames et al., 1993). New therapeuticuses are being investigated daily, and recent discover-ies show that vitamin C can play important role in

the health and beauty of skin (Halliwell and Gutteridge,1999). Vitamin C in the ascorbyl form (Fig. 3) hasbeen tested extensively and is reported to inhibitthe production of melanin (Carsberg et al., 1994; Kuoet al., 2005).

Kojic acid

Kojic acid (5-hydoxy-4-pyran-4-one-2-methyl) is atyrosinase inhibitor derived from various fungalspecies such as Aspergillus and Penicillium (Burdocket al., 2001; Parrish et al., 1966). Its type of inhibitionactivity and IC50 values are mentioned in Table 2. Itfunctions by chelating copper at the active site of thetyrosinase enzyme. It also acts as an antioxidant andprevents the conversion of the o-quinone to DL-DOPAand dopamine to its corresponding melanin (Burdocket al., 2001). Melanocytes that are treated with kojicacid become nondendritic and have decreased melanincontent (Moon et al., 2001). Kojic acid also acts as afree radical scavenger. It is used widely in Asia bothtopically as a skin-lightening agent and also in the dietoutlined by Lim (1999).

In one study, kojic acid was reported to have ahigh-sensitizing potential and to potentially causeirritant contact dermatitis. However, it is useful inpatients who cannot tolerate hydroquinone and it maybe combined with a topical corticosteroid to reduceirritation (Piamphongsant, 1998). Kojic acid also in-hibits the catecholase activity of tyrosinase, which isthe rate-limiting, essential enzyme in the biosynthesisof the skin pigment, melanin. Kojic acid also is con-sumed widely in the Japanese diet with the belief thatit is beneficial to health. Indeed, it has been shownto enhance significantly neutrophil phagocytosis andlymphocyte proliferation stimulated by phytohemag-glutinin content. Additionally, it scavenges reactiveoxygen species that are released excessively fromcells or generated in tissue or blood (Cabanes et al.,1994).

Moon et al. (2001) discovered that the activationof NF-kappaB induced by kojic acid, an inhibitor of tyrosinase for the biosynthesis of melanin inmelanocytes, was investigated in human transfectantHaCaT and SCC-13 cells. Their results indicate thatkojic acid is a potential inhibitor of NF-kappaB activa-tion in human keratinocytes, and they hypothesize thatthe inhibition of NF-kappaB activation may be involvedin the kojic acid induced anti-melanogenic effect. Fig-ure 3 illustrates the chemical structure of kojic acid.

Licorice extract – glabridin

Licorice extract is obtained from the root of GlycyrrhiaGlabra Linneva. The depigmenting efficacy of glabridinhas been shown by various researchers to be greater





than that of hydroquinone (Holloway, 2003; Neryaet al., 2003) and the inhibitory effect of licorice extracton tyrosinase activity has been noted to be higherthan that of glabridin in the extract (Choi et al., 2002;Jones et al., 2002).

Five different flavonoids were isolated from licoriceto identify and characterize the active components inlicorice as new tyrosinase inhibitors for depigmenting

agents. The isolated flavonoids were identified asliquiritin, licuraside, isoliquiritin, liquiritigenin (fromGlycyrrhiza uralensis Fisch) and licochalcone A (fromGlycyrrhiza inflate Bat) and are all competitive inhibi-tors. In contrast to the above flavonoids, no inhibitoryactivity was observed for liquiritin, whereas liquiritigeninactivated the monophenolase activity as a cofactor. Theinhibitory effect of licuraside, isoliquiritin and licochal-cone A on diphenolase activity with L-DOPA as thesubstrate was much lower than that with L-tyrosine andhave great potential for use as depigmenting agents(Fu et al., 2005).

Nerya et al. (2003) mentioned that glabrene andisoliquiritigenin (2′,4′,4-trihydroxychalcone) in the lico-rice extract can inhibit both mono- and diphenolasetyrosinase activities, and these effects on tyrosinaseactivity were dose-dependent and correlated to theirability to inhibit melanin formation in melanocytes. Inanother study, a combination of licorice extract (0.4%),betamethasone (0.05%) and retinoic acid (0.05%)yielded an excellent skin lightening response in up to70% of patients (Piamphongsant, 1998) and topicalapplication of 0.5% glabridin inhibited UVB-inducederythema and pigmentation in the skin of guinea-pigs(Baumann, 2004; Tabibian, 2001).

Recently, studies by Kim et al. (2005) of a Glycyrrhizauralensis extract were performed by measuring theinhibitory activity of tyrosinase and melanin synthesis,which was shown to have no detectable effect on theirDNA synthesis. Glycyrrhisoflavone and glyasperinC were identified as tyrosinase inhibitors for the firsttime. Glyasperin C showed a stronger tyrosinaseinhibitory activity than glabridin and a moderate inhi-bition of melanin production and could make it apromising candidate in the design of skin-whiteningagents. The combined analysis of SDS-polyacrylamidegel electrophoresis and DOPA staining on the largegranule fraction of these cells disclosed that glabridinspecifically decreased the activities of T1 and T3tyrosinase isozymes (Yokota et al., 1998). It was alsoshown that UVB-induced pigmentation and erythema

in the skins of guinea-pigs were inhibited by topicalapplications of 0.5% glabridin. The chemical structureof glabridin is shown in Fig. 3.

Niacinamide

Niacinamide is the amide form of vitamin B3 thataffects pigmentation by inhibiting the transfer of melanosomes from the melanocyte to the epidermalkeratinocytes (Minwalla et al., 2001). In clinical trials,5% niacinamide gave 35%–68% inhibition of mela-nosome, significantly decreased hyperpigmentationand increased skin lightness after 4 weeks of use

(Hakozaki et al., 2002). In an in vitro melanocyte-keratinocyte model system, niacinamide moleculesaffected the viability of melanocytes and keratinocytes,

reduced hyperpigmented lesions and was able to in-hibit melanosome transfer and induce skin lightening(Greatens et al., 2005).

Arbutin

Arbutin (hydroquinone-O-beta-D-glucopyranoside)

(1) isolated from the fresh fruit of the Californiabuckeye, Aesculus californica (Kubo and Ying, 1992)is reported by various researchers to inhibit the oxida-tion of L-DOPA catalysed by mushroom tyrosinase(Table 1), and is effective in the topical treatment of various cutaneous hyperpigmentations characterizedby hyperactive melanocyte function (Chakrabortyet al., 1998; Hori et al., 2004; Tomita et al., 1990).A recent study indicated that arbutin inhibits melaninsynthesis by inhibition of tyrosinase activity. Thisappears to be due to the inhibition of melanosomaltyrosinase activity rather than the suppression of this enzyme’s synthesis and expression (Yang et al.,1999).

Maeda and Fukuda (1996) showed that arbutin inhibitsthe oxidation of L-tyrosine (monophenolase activity)catalysed by mushroom tyrosinase and that it competesfor active binding sites in tyrosinase without beingoxidized (Maeda and Fukuda, 1996). However, arbutinitself was oxidized as a monophenol substrate at anextremely slow rate, and the oxidation was acceleratedas soon as catalytic amounts (0.01 mM) of l-3,4-dihydroxyphenylalanine (L-DOPA) became available asa cofactor (Hori et al., 2004). Thus, the reporteddepigmenting mechanism of arbutin is supportable if acofactor is not available in the melanocytes, particu-larly when oxygen is limited. Figure 3 illustrates thechemical structure of arbutin.

Azelaic acid

Azelaic acid is a naturally occurring dicarboxylicacid derived from Pitysporum ovale (Table 1). Thedepigmenting activity of azelaic acid appears to bemediated by inhibition of mitochondrial oxidoreductaseactivation and DNA synthesis, although it is also acompetitive and reversible inhibitor of tyrosinase.Its lightening effect appears to be selective and mostapparent in highly active melanocytes, with minimaleffects in normally pigmented skin (Breathnach,

1996).In a 6-month study by Sarkar et al. (2002) on132 Asian women with melasma, a mean 4 years of treatment with azelaic acid caused both a greater light-ening of pigmented lesions and a reduction in lesionsize. In another study, Fitton and Goa (1991) appliedazelaic acid at concentrations of 15% or 20% twicedaily for 3 to 12 months and produced clinical andhistological resolution in facial lentigo maligna and wassuccessful in treating rosacea, solar keratosis and hyper-pigmentation associated with burns and herpes labialis.In conclusion, azelaic acid is generally well toleratedand can be used for extended periods. Its mostfrequent side effects include transient erythema and

cutaneous irritation characterized by scaling, itchingand burning, which generally resolve after 2–4 weeksof application (Fitton and Goa 1991).





Green tea

Epidemiologically, it is well known that the consump-tion of green tea may help to prevent cancers inhumans and also to reduce several free radicals includ-ing peroxynitrite (Yang et al., 2006; Yang 1999). Ina recent study to assess the efficacy of the inhibitionof mushroom tyrosinase (monophenol monooxygenase

EC 1.14.18.1), ten kinds of traditional Korean teaswere screened for their tyrosinase inhibitory activity.Green tea was the strongest inhibitor, and its majoractive constituents are (-)-epicatechin 3-O-gallate(ECG), (-)-gallocatechin 3-O-gallate (GCG) and (-)-epigallocatechin 3-O-gallate (EGCG). All are catechinswith a gallic acid group as an active site. The kineticanalysis of the inhibition of tyrosinase revealed acompetitive nature of GCG with this enzyme for L-tyrosine binding at the active site of tyrosinase (Noet al., 1999). Its type of inhibition is mentioned inTable 1.

Phenolic compounds from plant sources, particularlyflavonoids, have long been observed to have antioxi-dant activity with potential benefits for human health.Epigallocatechin gallate (EGCG) is a principle phe-nolic antioxidant found in a variety of plants, includinggreen and black tea.

Melatonin

Melatonin is a hormone that is secreted by the pinealgland in response to sunlight (Chakraborty et al., 1995).In addition to its effects on diurnal rhythms in mam-mals, it has been shown in vitro to inhibit melanogenesisin a dose-related manner. It was found that it did notaffect tyrosinase activity, suggesting that its effectoccurs more proximally in the melanogenesis pathway.Melatonin has been shown to inhibit cyclic AMP-drivenprocesses in pigment cells. The concentration neededfor effective depigmentation in human skin has notyet been established, but a melatonin dosage of 0.6 mg/cm2 has been shown to have antiinflammatory activity.A cosmetic manufacturer is currently marketing atopical melatonin cream as an antioxidant (Tabibian,2001).

The effects of melatonin, N -acetylserotonin andserotonin on the growth and tyrosinase activity of SK-Mel 23 and SK-Mel 28 human melanoma cell lines wereinvestigated. It was found that the growth and tyrosinase

activity of SK-Mel 23 cells were not affected bymelatonin or its precursors. These cell lines possess highaffinity binding sites, which may be non-functional, ortrigger responses other than those investigated herein(Souza et al., 2003).

Miscellaneous – Emblica, Helix aspersa Müller,liquiritin, oleic acid, linoleic acid and tyrostat

Emblica is a compound isolated from Phyllanthusemblica fruits. The tree is native to tropical southeast-ern Asia. The compound is a chelator for iron andcopper, and reduces UV induced skin pigmentation

at a 1% concentration. Liquiritin has shown efficacyin limited clinical trials as a therapeutic depigmentingagent (Amer and Metwalli, 2000).

Unsaturated fatty acids, such as oleic and linoleicacid, suppress pigmentation in vitro (Skolnik et al., 1977).A study showed that linoleic acid in vivo had a lighten-ing effect in UVB induced pigmentation without toxiceffects on melanocytes (Quevedo et al., 1990).

Kubo and Hori (1998) reported that an extract fromthe Chilean snail of the species Helix aspersa Müller(from Gastropoda pulmonata) has been used with suc-

cess in the treatment of melasma and hyperpigmentation(Blanc et al., 2003). Tyrostat, an extract of field dock, aplant native to Canada’s northern prairie region, actsby inhibiting melanin synthesis (Corsaro et al., 1995).

The use of mushroom tyrosinase

For many years mushroom tyrosinase has been studiedfor its use in cosmetics as well as in food industries.However, various recent papers have exposed someaspects of mushroom tyrosinase previously unexploredin clinical studies, as described below.

Marker of vitiligo. Vitiligo is an autoimmune disease,characterized by hair hypopigmentation and totalmelanocyte depletion in the basal layer of the epider-mis. Tyrosinase is the enzyme responsible for melaninproduction in normal melanocytes and melanoma cells,and is known to be an autoantigen in various auto-immune disorders. Immunological studies of vitiligoshowed the generation and presence of autoantibodiesdirected against melanocyte antigens in the patients’sera. Using solid-phase ELISA on mushroom tyrosinase,higher titers of IgG anti-tyrosinase antibodies werefound in patients with diffused vitiligo compared withlocalized vitiligo. These anti-tyrosinase autoantibodiesfrom vitiligo patients’ sera can be recovered by exploit-ing its affinity toward tyrosinase. These antibodiesneither cross-react with other autoantigens of differentautoimmune disorders nor block tyrosinase activity,which shows that they are not reacting with the cata-lytic site of the enzyme. This indicates that tyrosinaseacts as an autoantigen and serves as a marker for vitiligo(Baharav et al., 1996). In an attempt to preventmelanocyte destruction, Zehtab et al. (2001) adminis-tered tyrosinase from A. bisporus orally in animalmodels, which resulted in a diminished cell-mediatedimmune response. It was suggested that this oraladministration is closely linked to the suppression of cellular response to autoantigens (Kemp et al., 1997).

Therefore, it will be useful in longitudinal studies todetermine the relationship between the clinical featuresof vitiligo and tyrosinase antibody levels.

Prodrug therapy. Malignant melanoma continues to bea serious clinical problem, with a high mortality rateamong humans due to the failure of melanoma cells torespond to cytotoxic treatment in the form of radiationand chemotherapy. Thus, metastatic melanoma con-tinues to challenge researchers to find a systemictreatment for cancer. To develop such a treatment witha selective cytotoxic response, interference with thebiosynthetic pathway which converts tyrosine into mela-nin (Prota et al., 1994) by tyrosinase is necessary. This

would allow selective conversion of inactive prodrugs,modeled on tyrosine, into cytotoxic drugs in melanomacells. Such a selective strategy toward the treatment of





malignant melanoma is called melanocyte-directed en-zyme prodrug therapy (MDEPT), which offers a highlyselective drug delivery system (Jordan et al., 2001).

Role in cancer. Contradictory results are available re-garding the role of tyrosinase in cancer, as some paperssuggest a tumor-suppressing effect of mushroomtyrosinase, whereas others predict a possible role in

mutagenicity. Vogel et al. (1977) reported that a stablephenol, γ -L-Glutaminyl-4-hydroxybenzene (GHB), isoxidized by tyrosinase to a quinone and a second oxi-dation product, which together suppress mitochondrialenergy production and synthesis of nucleic acids andproteins. Incubation of cultured murine L1210 leukemiaand B-16 melanoma cells with purified quinone blockedtumor growth in the mice, but when these cells wereincubated in the presence of GHB, tumor suppressionwas observed only in B-16 melanoma cells and not inL1210 leukemia cells due to the absence of the enzymetyrosinase. This result indicates that the cytotoxic ef-fect of GHB is dependent on the presence of tyrosinase.The antitumor effect of L-glutamic acid and γ -( p-hydroxyanilide) on B-16 melanoma was studied in vivo.In the presence of mushroom tyrosinase it inhibitedDNA polymerase activity and its 3,4-dihydroxy deriva-tive inhibited thymine, whereas the 2,5-dihydroxy de-rivative inhibited uracil and leucine incorporation intonucleic acid and proteins of melanoma cells (Wicket al., 1980). However, other results indicate a negativeeffect of the mushroom tyrosinase on cancer treatment.Papaparaskeva-Petrides et al. (1993) found that tyrosin-ase is responsible for enhancing the mutagenicity of mushroom extract due to the production of phenolicand quinoid compounds. Moreover, this mutagenic re-sponse was inhibited by catalase, superoxide dismutase,glutathione and dimethyl sulfoxide, which indicates therole of phenolic and quinoid compounds in the genera-tion of reactive oxygen species. The contribution of themushroom tyrosinase pathway to the mutagenicity orcarcinogenicity of hydrazines in animals remains to beelucidated.

CONCLUSIONS

The above studies show that skin depigmenting andlightening agents continue to be the subjects of extensiveresearch due to their easy availability and vast clinical

results. Researchers in this field have actively soughtto identify better depigmenting and lightening agentsduring the past three decades. To achieve this goal,different types of compounds from both natural andsynthetic sources have been investigated. Furthermore,depigmenting and lightening agents for skin-whiteningeffects and depigmentation after sunburn from naturalsources have a great potential in the cosmetics industry,

as they are considered to be safe and largely free fromadverse side effects. However, more concrete studieswith a human clinical point of view are required.

Among skin-lightening agents, hydroquinone (HQ)is one of the most widely prescribed agents in the world.However, with reports of potential mutagenicity andepidemics of ochronosis in African nations, there hasbeen increasing impetus to find alternative herbal andpharmaceutical depigmenting agents. A review of theliterature reveals that numerous other depigmentingor skin-lightening agents are in use or under investiga-tion. Among some of the skin agents, kojic acid, arbutin,glycolic acid and azelaic acid are well studied. Besidesuse in the treatment of some dermatological disordersassociated with melanin hyperpigmentation, tyrosinaseinhibitors have found an important role in the cosmeticindustry for their skin-whitening effect and depigmen-tation after sunburn. However, more concrete studieswith human tyrosinase from a clinical point of view arerequired.

Another important clinical application of mushroomtyrosinase is its role in the treatment of vitiligo, sincethe enzyme acts as a marker of this disease. A numberof studies have been conducted on animal models, butstill more research has to be done to cure vitiligo inhumans. Recent studies have indicated a possible nega-tive role of mushroom tyrosinase in the metabolismand bioactivation of agaritine and other mushroomhydrazines, in the latter case forming genotoxicmetabolites, which contributes to the mutagenicity. Butthe metabolism or carcinogenicity of hydrazines in ani-mals remains to be elucidated.

Further development in the biochemical understand-ing of kinetic characterization and relationships betweenvarious isoforms of depigmentation and skin lighteningagents is needed. Also needed is the x-ray crystallo-graphic structure of tyrosine, which can shed more lighton the action mechanism of tyrosinase. This will behelpful in in vitro mutagenesis studies including anti-sense RNA techniques and gene silencing, which willhelp to decrease production of tyrosinase in vivo.

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