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Survey and mechanism of skin depigmenting and
lightening agents
ARTICLE in PHYTOTHERAPY RESEARCH · NOVEMBER 2006
Impact Factor: 2.4 · DOI: 10.1002/ptr.1954 · Source: PubMed

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Ltd. P. Min-Kyu Shin2 and Hyunsu Bae1. Pakistan. tyrosine. glycosylated. with reports of potential mutagenicity and epidemics of ochronosis. dopaquinone is converted by a series of complex reactions to melanin.2.. hydroquinone (HQ) and azelaic acid (Maeda and Fukuda. Korea 2 The type and amount of melanin synthesized by the melanocyte. particularly ultra-violet light exposure. are a common factor in pigment abnormalities such as melasma. Tyrosinase is synthesized by melanosomal ribosomes found on the rough endoplasmic reticulum (Halaban et al. to 3-4-dihydroxyphenylalanine. Copyright © 2006 John Wiley & Sons. After synthesis.1954 921 REVIEW ARTICLE Survey and Mechanism of Skin Depigmenting and Lightening Agents Shoukat Parvez1†. kojic acid. 921–934 (2006) Published online 14 July 2006 in Wiley SKINInterScience DEPIGMENTATION AND LIGHTENING (www. Mason (1948) and Lerner et al. in humans. Kyung-Hee University #1 Hoegi-Dong. Upon exposure of the skin to UV radiation. 1997). However. This o-quinone is a highly reactive compound and can polymerize spontaneously to form melanin pigmentation. Exogenous causes. E-mail: hbae@khu. Moo-Chang Hong2. Seoul 130-701. and its distribution pattern in the surrounding keratinocytes. It is therefore a good specific marker for the cells.1002/ptr Accepted 12 May 2006 . solar lentigines and ephelides (Maeda and Fukuda. Dongdaemun-Ku. Kyung-Hee University. 1998). tyrosinase. (1949). including their historical background. tyrosinase is glycosylated en route to and within the golgi. furthermore. including their historical background. Chongwoon Cho1. 2003). L-DOPA and the oxidation of L-DOPA to o-dopaquinone.. However. INTRODUCTION Up to 10% of skin cells in the innermost layer of the epidermis produce a dark pigment known as melanin. Ltd. College of Oriental Medicine. melanin.. Some of these. catechins. type of Received 26921–934 February(2006) 2006 Phytother. College of Oriental Medicine. arbutin. such as kojic. #1 Hoegi-Dong. Exposure to certain drugs and chemicals as well as the existence of certain disease states can result in hyperpigmentation. It is subsequently delivered to melanosomes via coated vesicles in an inactive form (Halaban et al. hyperpigmentation. Moonkyu Kang1. Res. 2001. there has been an increasing impetus to find alternative herbal and pharmaceutical depigmenting agents. In this article. Melanin forms through a series of oxidative reactions involving the amino acid tyrosine in the presence of the enzyme tyrosinase. magnesium-L-ascorbyl-2-phosphate (MAP). Korea Department of Physiology. 20. L-DOPA.PHYTOTHERAPY RESEARCH Phytother. Seoul 130-701. 2002). Seoul 130 -701. The first two steps in the pathway are hydroxylation of L-tyrosine † Permanent address: NIBGE. 1991). coppercontaining oxidase with a molecular weight of approximately 60 –70 kDa in mammals. Res. Tyrosinase is a multifunctional. azelaic acid. Hwan-Suck Chung1. arbutin (hydroquinone-beta-D-glucopyranoside) and hydroquinone (HQ) are the most widely prescribed worldwide.kr Copyright © 2006 John Wiley & Sons. Revised 27 March 2006 DOI: 10. which are well known to most dermatologists. Ltd. glycolic and azelaic acids. 1976). Dongdaemun-Ku. a review is presented of several notable depigmenting and lightening agents reported in the literature for use in depigmentation or disorders of hyperpigmentation of skin.. Box 577.wiley. 1981). Korea. Dongdaemun-Ku. * Correspondence to: Dr Hyunsu Bae. 20. biochemical characteristics. In addition.* 1 Purimed R&D Institute. Others have been more recently discovered and are reported in this article. are well known to most dermatologists.1002/ptr. determines the actual color of the skin. and is found exclusively in melanocytes (Strothkemp et al. the clinical importance of mushroom tyrosinase as a recent prospect is discussed in this paper. Among the skin-lightening and depigmenting agents. 1996. hydroxyanisole. A review of the literature reveals that numerous other depigmenting or skin-lightening agents are either in use or in investigational stages.com) DOI: 10. Faisalabad. 1986. Katagiri et al..O. 2002). melanogenesis is initiated with the first step of tyrosine oxidation through an enzyme called tyrosinase (Vámos. it attempts to deal with various aspects of depigmentation and lightening agents from natural products. Tyrosinase catalyses three different reactions in the biosynthetic pathway of melanin in melanocytes: the hydroxylation of tyrosine to L-DOPA and the oxidation of L-DOPA to dopaquinone. Several depigmentation and lightening agents are discussed. Depigmenting agents commonly are prescribed to treat disorders of hyperpigmentation (Kubo. Department of Physiology. hydroquinone. Copyright © 2006 John Wiley & Sons. Others have been discovered and reported in the literature more recently. Keywords: arbutin. type of inhibition and activators from various sources. Kyung-Hee University. biochemical characteristics.. while it is inevitable that this review be selective in its coverage. Jang et al.interscience. The biosynthetic pathway for melanin formation in various life forms has largely been elucidated by Raper (1928).ac. this presents a serious aesthetic problem in human beings (Briganti et al. #1 Hoegi-Dong. N-acetyl-4-S-cysteaminylphenol. Among some of the skinlightening and depigmentation agents are kojic acid.

The formation of pigmentation is demonstrated in Fig. (2001) recently discovered that mammalian melanogenesis is not regulated solely by tyrosinase at the enzymatic level. Copyright © 2006 John Wiley & Sons.1002/ptr . diphenolase or both of these activities (Tables 1 and 2) have been identified. 2. dermis and sub-cutaneous. Kobayashi et al. determines the actual color of the skin (Fig. 3) that inhibited monophenolase. Basic information about the pigmentation pathway is helpful prior to a discussion of various skin-lightening agents and their known mechanisms of action. as can be seen in zebras and giraffes (Hearing and Tsukamoto. Outline of mammalian skin indicating three main layers epidermis. 2001) and whose metabolic pathways are illustrated in Fig. Schaffer and Bolognia.. 2002.. Here. Melanins also play a crucial role in the absorption of free radicals generated within the cytoplasm and in shielding the host from various types of ionizing radiations. REGULATION OF MELANOGENESIS The regulation of pigmentation in mammals is controlled at many different levels and is quite complex within each level. 921–934 (2006) DOI: 10. melanogenesis is regulated at the subcellular Phytother.. Figure 1.. and pheomelanins. These migration patterns are under strict genetic control and can lead to some interesting patterns when final melanocyte distribution in the skin is not uniform. mixtures of both types are typically found. Borges et al. Res. 20. 1928. 1). 1995). which are red or yellow (Raper. and finally to dihydroxyindole or dihydroxyindole-2-carboxylic acid (DHICA) to form eumelanin (brown-black pigment). and its distribution pattern in the surrounding keratinocytes. Melanins can be of two basic types: eumelanins. Melanocytes are initially derived from the neural crest and migrate throughout the embryo during development. visible pigmentation results from the synthesis and distribution of melanin in the melanocytes in the dermis layer of the skin. Olivares et al. 2001) presented in simplified form in Fig 2. 2003). 2000.. Olivares et al. PARVEZ ET AL.. 1. Interestingly. 1991).. including UV light. The first step is the most critical because the remainder of the reaction sequence can proceed spontaneously at a physiological pH (Halaban et al. In mammals. 1928. Melanin forms through a series of oxidative reactions involving the amino acid tyrosine in the presence of the enzyme tyrosinase (Shi et al. Kobayashi et al. Pigmentation is also regulated at the cellular level by melanocytes synthesizing melanin within melanosomes.922 S. Lastly. pheomelanin has the capacity to produce free radicals in response to UV radiation. a yellow-red pigment. 1995. pheomelanin may actually contribute to intensifying UV-induced skin damage rather than protecting the skin (Seo et al. dopaquinone is converted to dopachrome through auto-oxidation. and additional melanogenic factors have been identified which can modulate pigmentation in either a positive or negative fashion. A number of tyrosinase inhibitors from both natural and synthetic sources (Fig. Subsequently. numbers and densities. inhibitions. tyrosinase converts tyrosine to dihydroxyphenylalanine (DOPA) and then to dopaquinone. The type and amount of melanin synthesized by the melanocyte. dopaquinone is converted to cysteinyl DOPA or glutathione DOPA. pheomelanin. activators from various sources and prospects for their clinical importance. Since free radicals can inflict cell injury.. which can be produced in varying sizes. 2002). MELANIN-FORMATION AND DISTRIBUTION IN THE SKIN Visible pigmentation in mammals results from the synthesis and distribution of melanin in the skin and hair bulbs (Seiberg et al. Subsequently. which are brown or black. Ltd. is formed (Raper. In the presence of cysteine or glutathione. 2001). The latter reaction occurs in the presence of dopachrome tautomerase and DHICA oxidase.

03 0. 1988 Kubo and Kinst-Hori.1002/ptr . 20..23 0.4-Dihydroxycinnamic acid Oxyresveratrol Kaempferol Trans-cinnamaldehyde Ib 4-Hydroxy-3methoxycinnamic acid 9-Hydroxy-4-methoxypsoraln 5-hydroxymethyl-2-furfural Pulsatillae Radix Competitive Uncompetitive Noncompetitive Competitive Uncompetitive Uncompetitive Noncompetitive Noncompetitive Noncompetitive Mixed Competitive Competitive Competitive Noncompetitive Noncompetitive Competitive Competitive Noncompetitive Noncompetitive Arctostaphylos uva-ursi Gvae grsi Arbutin Type of inhibition Botanical name Source Inhibitor Table 1..04 IC50 (mM) Piao et al. 2002. 1974 Lee.. 1999 No et al. 1974 Lee.. 1987 Kubo et al. 2002 Lee. 2002 Kubo and Hori. Lee. 2000 Madhosingh and Sundberg. 2004 Sharma et al.05 3.03 0..03 0. 921–934 (2006) DOI: 10.97 0. 1998 Lee. 2004 Yagi et al..65 0. et al.. 1999 Madhosingh and Sundberg.1 0. 1999 Lee et al.2 0.. 1994 Lee. 2002 Espin and Jolivet.97 0.68 0. Ltd. 1987 Reference SKIN DEPIGMENTATION AND LIGHTENING 923 Phytother. 1991 No et al. Some depigmenting lightening agents and their mushroom tyrosinase inhibition activities from natural sources 0.26 0.. Noncompetitive Noncompetitive Aloe barbadensis Anacardium occidentale Pimpinella anisum Agaricus bisporus Pimpinella anisum Cuminum cyminum Cuminum cyminum Panax ginseng Thea chinensis Thea chinensis Agaricus hortensis Pulsatilla cernua Morus alba Crocus sativus Cinnamomum cassia Agaricus hortensis Pulsatilla cernua Angelica dahurica Dictyophora indusiata Aloe vera Anacardium occidentale Anise oil Agaricus bisporus Anise oil Cumin seed Cumin seed Ginseng Radix Green tea Green tea Agaricus hortensis Pulsatilla cernua Mori Cortex Croci Stigma Cinnamomi Cortex Angelicae dahuricae Radix Dictyophora indusiata Aloesin Anacardic acid Anisic acid Agaritine Anisaldehyde Cumic acid Cuminaldehyde p-Coumaric acid ECG EGCG Ia 3. Res.Copyright © 2006 John Wiley & Sons.001 0..38 0. 2000 Yagi et al.034 0. 1988 Lim et al.0001 0.98 0.035 0.85 0. 2002 Kubo and Kinst-Hori.

2002 Espin and Wichers.924 S. 1948. 2001 Cabanes et al.5 0. 1928.. Table 2..001 0.014 0.34 400 0. IC50 (mM) 0. Kobayashi et al. 2002 Lee. Mason.4dihydroxyphenylalanine. 2001 melanogenesis pathway in its classical and modified form). DOPAquinone: 4-(2-carboxy-2-aminoethyl)-1.7 0. 2002 Jiménez et al. 1987 Kahn and Andrawis..6-dihydroxyindole (Raper. leucodopachrome: 2. DHICA: 5. 2001 Lee. vitamins and prostaglandins. 1997 Kubo and Hori.7 1.2 Reference Kubo and Kinst-Hori. Some depigmenting and lightening agents and their mushroom tyrosinase inhibition activities from synthetic sources Inhibitor Type of inhibition Benzoic acid Benzaldehyde Cupferron Cinnamaldehyde Cinnamic acid Captopril Citral Dimethyl sulfide Methimazole Kojic acid L-Mimosine Tiron Tropolone 2-Methoxycinnamic acid 3-Methoxycinnamic acid 4-Methoxycinnamic acid 4-Substituted benzaldehydes 4-Substituted resorcinol p-Hydroxybenzaldehyde Mixed Noncompetitive Competitive Noncompetitive Mixed Noncompetitive Noncompetitive Competitive Mixed Mixed Competitive Competitive Competitive Noncompetitive Noncompetitive Noncompetitive Competitive Competitive Competitive level where the synthesis and expression of various melanogenic enzymes and inhibitors play a critical role (Sánchez-Ferrer et al.6-quinone. 1999 Pérez-Gilabert et al. or other environmental stimuli that induce alterations in Phytother. which determine not only whether melanin is synthesized.34 0.6dihydroxyindole-2 carboxylate. Copyright © 2006 John Wiley & Sons.. 921–934 (2006) DOI: 10. 20. 1995. Burton.34 0. DOPAchrome: 2-carboxy-2. Melanocytes work in close harmony with their neighboring cells in the epidermis. 1987 Valero et al.64 0. 1995. but what type of melanin is produced.1002/ptr . 1988 Kubo and Kinst-Hori.34 0. these factors provide the complex signals that stimulate pigmentation after trauma.3-dihydro-5. 1988 Shiino et al. Olivares et al. The Raper-Mason melanogenesis pathway in its classical form.34 0.. Res. Figure 2..7 0. PARVEZ ET AL. UV exposure. 2002 Lee. 1991 Lee. 2001 Jiménez and Carmona.97 0.014 1. Ltd.82 0. 2001 Kubo and Hori.3-dihydroindole-5.014 0. Structural formulas are abbreviated as follows: DOPA: L-3. growth factors.35 0.. Presumably.6 dihydroxyindole-2-carboxylic acid. 1996 Ha et al. 2002 Lee... 1994). They are influenced by a variety of biological factors including interleukins. 1999 interferons. 2001 Andrawis and Kahn. DHI: 5.2-benzoquinone.

a peptide produced by the posterior pituitary.SKIN DEPIGMENTATION AND LIGHTENING the levels of pigment production (Rana et al. CURRENT RESEARCH As the population ages. Hyperpigmentation from other causes such as melasma and post-inflammatory conditions are also of increasing attention as patients realize that its appearance can be improved with treatment (Seo et al. licorice extract and soy will continue to be developed. rather than the density of melanocytes. as mentioned in Tables 1 and 2.. 1996). post-inflammatory hyperpigmentation and other disorders of hyperpigmentation (Yang. Verallo-Rowell et al. which can be easily treated with topical steroids. probably by the skin’s own enzymatic process. the number of melanocytes is the same in all races. they have drawbacks including high cost. 1981). Melanocytes derived from black skin have up to ten times more activity and produce up to ten times more melanin than do melanocytes from white skin (Valverde et al. Anderson et al. 2005). The cosmetic use of bleaching products is considered a common practice in dark-skinned women in many countries in Africa. or melanotropin)... hydroquinone (HQ) is also a ubiquitous chemical readily available in cosmetic and nonprescription forms for skin lightening. (2002) reported that hydroquinone is generally considered very safe. 3.. but more strictly controlled clinical trials are needed to assess their safety and efficacy.. 1996). HQ can be considered a potent melanocyte cytotoxic agent with relatively high melanocytespecific cytotoxicity (Breathnach. and consumers are increasingly requesting treatment for this cosmetic problem (Briganti et al. 1996). Rana et al. Thus. Perhaps the most commonly known melanogenic stimulus is melanocyte-stimulating hormone (MSH. tea. 1993. 2005). as side effects are decreased and the clinical outcomes improved. (2003) and Jablonski and Chaplin (2001) mentioned that the differences in racial skin pigmentation depend upon the quantity of melanin produced and upon the distribution and deposition of melanosomes throughout the epidermis. A rare. a dramatic.1002/ptr . Additional information on the structure of hydroquinone and its analogs is given in Fig. 1989) and causes reversible in-hibition of cellular metabolism by affecting both DNA and RNA synthesis (Penney et al. little is known concerning the relative importance of any step regulating racial pigmentation. branched dendrites (Rana et al. Ltd. Res. and is widely used for the treatment of melanosis and other hyperpigmentary disorders (Palumbo et al. the melanocytes of darkly pigmented skin have thicker. 1989). Exogenous ochronosis has generally been observed in black patients and after the use of high concentrations Phytother. While hydroquinone monotherapy and other prescriptionstrength topicals are fairly effective. and defects in the enzyme’s activity lead to albinism in humans (Masuda et al. 2002). 2005). (1996) found that in black skin... Hydroquinone occurs naturally in many plants as well as in coffee.. which may be extremely difficult to reverse to any degree. the Caribbean and South America... side effect of hydroquinone is the development of exogenous ochronosis. It also seems likely that racial differences in human skin color may primarily be due to differences in tyrosinase activity from varying skin types. 1984).. Masuda et al. the higher level of tyrosinase activity in melanocytes derived from black skin is not due to a greater abundance of tyrosinase. This indicates that the stratum corneum of white skin does not contain any melanin. 925 2003. Kamau et al.. 2004. The cytotoxic effects of HQ are not limited to melanocytes.. number and distribution of melanosomes.. Many of these ingredients are readily available to consumers without a prescription and therefore potential misuse is of concern (Del Giudice and Yves. In fact. 921–934 (2006) DOI: 10. beer and wine (Sang et al. The number of tyrosinase molecules present in white skin melanocytes is equal to that found in highly pigmented black skin types (Valverde et al. Increasing consumer interest in skin care and treatment products derived from natural sources has driven increased research into novel skin depigmenting agents (Jeong and Shim. up to 100-fold increase in melanogenesis results (Spencer et al. 1999). possible skin irritation and the need to limit the duration of use. The following is a discussion of the known skin depigmentation and lightening agents and their mechanisms from the literature. It is considered one of the most effective inhibitors of melanogenesis in vitro and in vivo... Hydroquinone An important industrial chemical. 2003. However. 2005). 1995). 2005). Masuda et al. 2005). 20. Hydroquinone decrease tyrosinase activity by 90% (Verallo-Rowell et al. In the future. identifying a combination of cosmetic compounds that act upon different steps in the pigmentation pathways should be advantageous. longer. Once MSH binds to melanocyte surface receptors. dyspigmentation due to photo aging will become more common. Briganti et al. melanin persists within the horny layer and leaves the skin by natural desquamation. At present. whereas in white skin the pigment is degraded in the granular layer. It is therefore likely that in the future more products containing effective but less irritating ingredients such as kojic acid. This phenolic compound has been successfully used as a skin-lightening agent for the treatment of melasma. But its common side effects are skin irritation or contact dermatitis. 1991. 1996). Masuda et al. Changing demographics and an increase in the nonCaucasian population is also giving rise to an increase in pigmentary disorders (Anderson and Parrish. a sooty hyperpigmentation in the treatment area. There are numerous candidates for depigmenting agents. However. Copyright © 2006 John Wiley & Sons. but serious.. Tyrosinase is the rate-limiting enzyme for melanin synthesis. DIFFERENCES IN RACIAL PIGMENTATION Skin color is a function of the size. although the dose required to inhibit cellular metabolism is much higher for nonmelanotic cells than for melanocytes.

in some cultures where light skin is considered desirable. ochre-colored fibers in the dermis (Penney et al. Despite its remarkable overall safety. may result in the development of this serious side effect (Kamau.1002/ptr .926 S. 20. PARVEZ ET AL. Ltd. Magnesium ascorbyl phosphate Recently. Contact dermatitis occurs in a small number of patients and responds promptly to topical steroids. In situ experiments demonstrated that VC-PMG cream was absorbed into the epidermis and that 1. The chemical structures of known skin whitening and lightening agents. adverse effect of HQ is exogenous ochronosis.. Histologically. Furthermore. 2002)..6% remained 48 h after application. VC-PMG suppressed melanin formation by tyrosinase and melanoma cells. 3) and a 10% cream of MAP was shown to suppress melanin formation. hydroquinone used at high concentrations or for prolonged periods. Alternating the use of hydroquinone with one of the alternative agents in 4-month cycles will help to prevent side effects such as irritation as well as decrease the risk of exogenous ochronosis (Baumann. physicians should bear in mind the potential adverse effects of HQ. The protective effect of magnesium-L-ascorbyl-2phosphate (MAP) on cutaneous photodamage such as Phytother. 921–934 (2006) DOI: 10. Its lightening effect was significant in 19 of 34 patients with chloasma or senile freckles and in 3 of 25 patients with normal skin (Kameyama et al. Kameyama et al.. This disorder is characterized by progressive darkening of the area to which the HQcontaining cream is applied. Copyright © 2006 John Wiley & Sons. An uncommon. even at low concentrations. Although this condition is uncommon under normal usage. 1996). yet significant. 1984). Res. of HQ for many years. Figure 3. 2004). MAP has been shown to have a protective effect against skin damage induced by UV-B irradiation. This protective effect stems from the conversion of MAP to ascorbic acid (AS) and is effective in reducing skin hyperpigmentation in some patients (Elmore 2005. degeneration of collagen and elastic fibers occurs. A significant lightening effect was seen clinically in 19 of 34 patients with melasma and solar lentigos. Elmore (2005) reported that magnesium-Lascorbyl-2-phosphate (MAP) is a stable derivative of ascorbic acid (Fig. followed by the appearance of characteristic ochronotic deposits consisting of crescent-shaped. 1996).

Furthermore. 2005). In addition. although the mechanism by which this occurs is unknown (Oakley. kojic acid or glabridin. 3) class of chemical agents (Gusarova and Zalem. Bowman Birk inhibitor (BBI) and soybean trypsin inhibitor (STI).There are many studies showing that fermented soy products containing the isoflavones. Free radical scavenging of UV-generated hydroxyl radicals and interference with the arachidonic acid metabolism are possible mechanisms of the melatonin action (Bangha et al. the expected decrease in the level of cutaneous AS was unchanged. However. and the UVB-induced decrease in tissue AS was prevented by intracutaneous MAP administration. Similar results were observed for animals given 100 mg of AS-Na per kg body weight before UVB irradiation. 3). 1996). 1986). but that AS-Na did not pass through the epidermis. MBEH almost always causes a nearly irreversible depigmentation of skin. 2005). 20. However. Monobenzyl ether of hydroquinone Like HQ. 6.. 1986). resulting in interference with cell growth and proliferation (Ferguson et al. It has been suggested that the mechanism of depigmentation by MBEH involves selective melanocytic destruction through free radical formation and competitive inhibition of the tyrosinase enzyme system (Lyon and Beck. max... 2001). adhesive tape. 2000. These serine protease inhibitors inhibit the protease-activated receptor-2 (PAR-2) pathway expressed on keratinocytes. 1966). soy has been shown to lighten and slow the regrowth of unwanted facial hair (Seiberg et al. N-acetyl-4-S-cysteaminylphenol (4-S-CAP) belongs to the phenol/catechols class (Fig. 2003). the author reported it to be more stable and less irritating than HQ (Pearson et al. it also is considered to be cytotoxic. Paine et al. the author reported a 66% improvement after 4 weeks of use. In vitro studies showed that MAP was converted to AS as it crossed the epidermis. may function as weak phytoestrogens (Cassidy et al. When MAP was administered intraperitoneally to mice at a dose of 100 mg of ascorbic acid (AS) per kg body weight immediately before irradiation (15 kJ/m2). These results suggest that MAP protects against UVB irradiation-induced lipid peroxidation and inflammation in cutaneous tissue. 1996. 2006). it forms a melanin-like pigment when exposed to tyrosinase.. daidzein and genistein.SKIN DEPIGMENTATION AND LIGHTENING lipid peroxidation and inflammation induced by ultraviolet B (UVB) exposure (290–320 nm. It is probably oxidized selectively in melanocytes to an o-quinone that can alkylate thiol groups on important cellular enzymes. In a study of 12 patients with melasma who used 4% 4-S-CAP. unlike HQ. several manufacturers are producing facial and body care products that contain total soy to even the skin tone... The cutaneous AS level was significantly higher in the MAP-treated mice than in the controls. Soy There has been a great deal of interest and research into the cosmetic benefits of soy (Seiberg et al. The N-acetyl derivative of 4-S-CAP appears to be an excellent tyrosinase substrate. regardless of the drug administration route. which has six times the anti-tyrosinase activity of kojic acid (Chang et al. Ascorbic acidNa had less of a protective effect than intracutaneous MAP administration. Traces of MBEH have been found in disinfectants.. the expected UVB-induced increases in TBARS and sialic acid were again significantly prevented. Like HQ and MBEH. Currently. which are indices of lipid peroxidation and inflammatory reaction. and it is specific to melanin-synthesizing cells.1002/ptr . is a new type of depigmenting agent for better management of melasma.. 927 production (Ferguson et al. Friedman et al. monobenzyl ether of hydroquinone (MBEH) belongs to the phenol/catechol (Fig. Topically applied melatonin has a clear-cut protective effect against UV-induced erythema. Phytother.. germicides. A known biotransformed compound. N-acetyl-4-S-cysteaminylphenol N-Acetyl-4-S-cysteaminylphenol (1) is an analog of tyrosine that is involved in the pathway of melanin Copyright © 2006 John Wiley & Sons.4'-trihydroxyisoflavone.. 1997). Interference with the PAR-2 pathway has been shown to induce depigmentation by reducing the phagocytosis of melanosomes by keratinocytes. 1997). N-acetyl-4-S-cysteaminylphenol. It is much more stable and less irritating to the skin than hydroquinone. 312 nm) was investigated using hairless mice. and total soy is now being incorporated into skin care products to improve mottled hyperpigmentation and solar lentigines that frequently result from photodamage. When MAP was administered intracutaneously immediately before irradiation. Like HQ. Jimbow et al. The phenomenon of repigmentation occurred within a few weeks of discontinuing successful depigmentation therapy with monobenzyl ether of hydroquinone in a patient with extensive vitiligo. the expected increases in thiobarbituric acid reactive substance (TBARS) formation in skin and serum sialic acid. was identified as a potent tyrosinase inhibitor. 1986). These results suggest that the protective effect of MAP on UVB-induced cutaneous damage is due to the conversion of MAP to AS (Kobayashi et al. 921–934 (2006) DOI: 10. 1998). thus reducing melanin transfer. powdered rubber condoms and rubber aprons (Urabe and Hori. Res. Falabella. rubbercovered dish trays. were significantly reduced. This mechanism of action is different to that of hydroquinone. Natural soybeans contain the small proteins. It is important to note that this depigmenting effect is available only with fresh soymilk and not with pasteurized soymilk (Friedman et al. 2005). 2000.. A number of attempts have been made by various researchers. (1993) demonstrated that a phenolic thioether. Ltd. MAP was also converted to AS in serum. MBEH should be used only to eliminate residual areas of normally pigmented skin in patients with refractory and generalized vitiligo.7.. respectively. Furthermore. Patients undertaking depigmentation therapy should be warned that this may occur.

Kuo et al. Additionally. glycolic acid results in epidermolysis (Perez-Bernal et al. 20. This protection takes place under the enzymatic action of the detoxification enzyme glutathione S-transferase (GST). In another study. in fact. (2001) discovered that the activation of NF-kappaB induced by kojic acid.. Melanocytes that are treated with kojic acid become nondendritic and have decreased melanin content (Moon et al. Figure 3 illustrates the chemical structure of kojic acid. 1993). which is the rate-limiting. 2001. In one study. The possibility of hydroquinone’s effect on pigmentation being potentiated by the inhibition of GSH production has been examined (Bolognia et al. 2003). it scavenges reactive oxygen species that are released excessively from cells or generated in tissue or blood (Cabanes et al. Licorice extract – glabridin Licorice extract is obtained from the root of Glycyrrhia Glabra Linneva. 1966). Choi et al. glycolic acid has an epidermal discohesive effect which results in a more rapid desquamation of pigmented keratinocytes. resulting in skin depigmentation.. Kojic acid Kojic acid (5-hydoxy-4-pyran-4-one-2-methyl) is a tyrosinase inhibitor derived from various fungal species such as Aspergillus and Penicillium (Burdock et al.. Asanuma et al. 2005). The combination of all-trans-retinoic acid (tretinoin. However. The depigmenting effect of hydroquinone is shown to be potentiated by buthionine sulfoximine (BSO) and cystamine as a result of their reducing intracellular GSH levels. it has been suggested that it should be initiated at low concentrations to avoid skin irritation and exacerbated hyperpigmentation (Jones et al. The use of hydroquinone both prior to and after the peel can lessen the risk of such pigmentary alterations (Baumann. These cytotoxic compounds are responsible for the destruction of pigment cells. It functions by chelating copper at the active site of the tyrosinase enzyme.. melanocytotoxic chemicals which are oxidized in melanocytes to produce highly toxic compounds such as quinones (Kasraee et al. glycolic acid shortens the cell cycle so that pigment is lost more rapidly.. At low concentrations. it has been shown to enhance significantly neutrophil phagocytosis and lymphocyte proliferation stimulated by phytohemagglutinin content. New therapeutic uses are being investigated daily. TRA serves as a potent inhibitor of mammalian GSTs and is known to make cells more susceptible to the cytotoxic effect of chemicals by inhibiting the activity of this enzyme (Asanuma et al. Vitamin C in the ascorbyl form (Fig. Glycolic acid Glycolic acid is an alpha-hydroxy acid derived from sugar cane (Saccharum) and it may have two skin lightening effects. an inhibitor of tyrosinase for the biosynthesis of melanin in melanocytes. 2004). 2002). 2000). Parrish et al. melanin. Kojic acid also acts as a free radical scavenger. It is used widely in Asia both topically as a skin-lightening agent and also in the diet outlined by Lim (1999). TRA) with hydroquinone or 4-hydroxyanisole is also known to produce synergetic skin depigmentation. the addition of glycolic acid to hydroquinone formulations seems to enhance its efficacy (Guevara and Pandya. 2003). 2002. Their results indicate that kojic acid is a potential inhibitor of NF-kappaB activation in human keratinocytes. Ltd. When glycolic acid is used in the treatment of post-inflammatory hyperpigmentation. and thus it has been studied by various researchers (Ames et al. BSO and cystamine are shown to inhibit the activity of GST. 3) has been tested extensively and is reported to inhibit the production of melanin (Carsberg et al.. Also.. However. 2003). GSH was shown to perform several important biological functions. PARVEZ ET AL. The depigmenting efficacy of glabridin has been shown by various researchers to be greater Phytother. 2001). Its type of inhibition activity and IC50 values are mentioned in Table 2. was investigated in human transfectant HaCaT and SCC-13 cells. 2006). Like retinoids. 1994. and recent discoveries show that vitamin C can play important role in the health and beauty of skin (Halliwell and Gutteridge. cells are capable of protecting themselves against cytotoxic agents by intracellular glutathione (GSH). Indeed. Additionally... 2003). including quenching of reactive oxygen species and protection of cells from toxic compounds such as quinones. 1998). essential enzyme in the biosynthesis of the skin pigment.. 2001). Several studies have shown that the removal of superficial layers of epidermis with glycolic acid peels at concentrations of 30%–70% can enhance the penetration of other topical skin lighteners such as hydroquinone (Sarkar et al. Res.. There is an increasing awareness that vitamin C (L-ascorbyl acid) has a wide variety of roles in human health. It also acts as an antioxidant and prevents the conversion of the o-quinone to DL-DOPA and dopamine to its corresponding melanin (Burdock et al. Kojic acid also is consumed widely in the Japanese diet with the belief that it is beneficial to health.. 2003). which is responsible for the conjugation of toxic species to GSH (Moridani. 921–934 (2006) DOI: 10.. an enzyme which is inhibited by cystamine and BSO. Kojic acid also inhibits the catecholase activity of tyrosinase. The first step in the synthesis of GSH is catalysed by gammaglutamylcysteine synthetase.. This agent was also shown to reduce the level of intracellular GSH in certain cells (Kasraee et al. kojic acid was reported to have a high-sensitizing potential and to potentially cause irritant contact dermatitis. Hydroxyanisole Vitamin C Many of the well-known depigmenting agents such as hydroquinone and 4-hydroxyanisole are. 2002).928 S. and they hypothesize that the inhibition of NF-kappaB activation may be involved in the kojic acid induced anti-melanogenic effect. 1995.. 1994). it is useful in patients who cannot tolerate hydroquinone and it may be combined with a topical corticosteroid to reduce irritation (Piamphongsant. Copyright © 2006 John Wiley & Sons.1002/ptr ... Moon et al. 1999). At higher concentrations.

However. 929 reduced hyperpigmented lesions and was able to inhibit melanosome transfer and induce skin lightening (Greatens et al. It was also shown that UVB-induced pigmentation and erythema in the skins of guinea-pigs were inhibited by topical applications of 0. particularly when oxygen is limited. isoliquiritin. The depigmenting activity of azelaic acid appears to be mediated by inhibition of mitochondrial oxidoreductase activation and DNA synthesis. Nerya et al.. In another study. Res. whereas liquiritigenin activated the monophenolase activity as a cofactor.4dihydroxyphenylalanine (L-DOPA) became available as a cofactor (Hori et al. 2003. The combined analysis of SDS-polyacrylamide gel electrophoresis and DOPA staining on the large granule fraction of these cells disclosed that glabridin specifically decreased the activities of T1 and T3 tyrosinase isozymes (Yokota et al. Aesculus californica (Kubo and Ying. In a 6-month study by Sarkar et al. 1998). and is effective in the topical treatment of various cutaneous hyperpigmentations characterized by hyperactive melanocyte function (Chakraborty et al. which generally resolve after 2–4 weeks of application (Fitton and Goa 1991). 2001). The isolated flavonoids were identified as liquiritin. Nerya et al.4%). 20. 3.. Niacinamide Niacinamide is the amide form of vitamin B3 that affects pigmentation by inhibiting the transfer of melanosomes from the melanocyte to the epidermal keratinocytes (Minwalla et al.. the reported depigmenting mechanism of arbutin is supportable if a cofactor is not available in the melanocytes. licuraside. Tabibian.SKIN DEPIGMENTATION AND LIGHTENING than that of hydroquinone (Holloway.. 1998) and topical application of 0. Phytother. (2005) of a Glycyrrhiza uralensis extract were performed by measuring the inhibitory activity of tyrosinase and melanin synthesis.5% glabridin inhibited UVB-induced erythema and pigmentation in the skin of guinea-pigs (Baumann.05%) yielded an excellent skin lightening response in up to 70% of patients (Piamphongsant. niacinamide molecules affected the viability of melanocytes and keratinocytes. 2002). Its lightening effect appears to be selective and most apparent in highly active melanocytes.. Five different flavonoids were isolated from licorice to identify and characterize the active components in licorice as new tyrosinase inhibitors for depigmenting agents.01 mM) of l-3. solar keratosis and hyperpigmentation associated with burns and herpes labialis. (2003) mentioned that glabrene and isoliquiritigenin (2′. itching and burning.4-trihydroxychalcone) in the licorice extract can inhibit both mono. Glycyrrhisoflavone and glyasperin C were identified as tyrosinase inhibitors for the first time. 1996). Azelaic acid Azelaic acid is a naturally occurring dicarboxylic acid derived from Pitysporum ovale (Table 1). 1998. Ltd. Arbutin Arbutin (hydroquinone-O-beta-D-glucopyranoside) (1) isolated from the fresh fruit of the California buckeye. 2004. Tomita et al. Glyasperin C showed a stronger tyrosinase inhibitory activity than glabridin and a moderate inhibition of melanin production and could make it a promising candidate in the design of skin-whitening agents. In another study. azelaic acid is generally well tolerated and can be used for extended periods. Recently. (2002) on 132 Asian women with melasma... Its most frequent side effects include transient erythema and cutaneous irritation characterized by scaling. 2004. Copyright © 2006 John Wiley & Sons. and the oxidation was accelerated as soon as catalytic amounts (0. arbutin itself was oxidized as a monophenol substrate at an extremely slow rate. 921–934 (2006) DOI: 10. 2001).. 2002). In conclusion. 1992) is reported by various researchers to inhibit the oxidation of L-DOPA catalysed by mushroom tyrosinase (Table 1). no inhibitory activity was observed for liquiritin. which was shown to have no detectable effect on their DNA synthesis.. isoliquiritin and licochalcone A on diphenolase activity with L-DOPA as the substrate was much lower than that with L-tyrosine and have great potential for use as depigmenting agents (Fu et al.. 1999). with minimal effects in normally pigmented skin (Breathnach. Hori et al. 5% niacinamide gave 35%–68% inhibition of melanosome. liquiritigenin (from Glycyrrhiza uralensis Fisch) and licochalcone A (from Glycyrrhiza inflate Bat) and are all competitive inhibitors. studies by Kim et al. significantly decreased hyperpigmentation and increased skin lightness after 4 weeks of use (Hakozaki et al.1002/ptr . A recent study indicated that arbutin inhibits melanin synthesis by inhibition of tyrosinase activity. This appears to be due to the inhibition of melanosomal tyrosinase activity rather than the suppression of this enzyme’s synthesis and expression (Yang et al. 1990)... 2005). a combination of licorice extract (0.and diphenolase tyrosinase activities. Jones et al. 1996).4′. 2002. and these effects on tyrosinase activity were dose-dependent and correlated to their ability to inhibit melanin formation in melanocytes.. The inhibitory effect of licuraside. The chemical structure of glabridin is shown in Fig. 2005). Maeda and Fukuda (1996) showed that arbutin inhibits the oxidation of L-tyrosine (monophenolase activity) catalysed by mushroom tyrosinase and that it competes for active binding sites in tyrosinase without being oxidized (Maeda and Fukuda. In an in vitro melanocytekeratinocyte model system. In contrast to the above flavonoids. In clinical trials. although it is also a competitive and reversible inhibitor of tyrosinase.05%) and retinoic acid (0. 2004). Figure 3 illustrates the chemical structure of arbutin. Thus.5% glabridin. a mean 4 years of treatment with azelaic acid caused both a greater lightening of pigmented lesions and a reduction in lesion size. 2003) and the inhibitory effect of licorice extract on tyrosinase activity has been noted to be higher than that of glabridin in the extract (Choi et al. betamethasone (0. Fitton and Goa (1991) applied azelaic acid at concentrations of 15% or 20% twice daily for 3 to 12 months and produced clinical and histological resolution in facial lentigo maligna and was successful in treating rosacea.

and is known to be an autoantigen in various autoimmune disorders.. including green and black tea. The effects of melatonin. To develop such a treatment with a selective cytotoxic response. it will be useful in longitudinal studies to determine the relationship between the clinical features of vitiligo and tyrosinase antibody levels. 921–934 (2006) DOI: 10. Melatonin Melatonin is a hormone that is secreted by the pineal gland in response to sunlight (Chakraborty et al. 1990). Thus. Phenolic compounds from plant sources. 2006. various recent papers have exposed some aspects of mushroom tyrosinase previously unexplored in clinical studies. Prodrug therapy. liquiritin. 1977). but a melatonin dosage of 0. These cell lines possess high affinity binding sites.18. Marker of vitiligo. into cytotoxic drugs in melanoma cells. 1996). N-acetylserotonin and serotonin on the growth and tyrosinase activity of SKMel 23 and SK-Mel 28 human melanoma cell lines were investigated. which may be non-functional. Vitiligo is an autoimmune disease. 2000). or trigger responses other than those investigated herein (Souza et al. characterized by hair hypopigmentation and total melanocyte depletion in the basal layer of the epidermis. This would allow selective conversion of inactive prodrugs. The tree is native to tropical southeastern Asia. Green tea was the strongest inhibitor.1002/ptr . with a high mortality rate among humans due to the failure of melanoma cells to respond to cytotoxic treatment in the form of radiation and chemotherapy. Melatonin has been shown to inhibit cyclic AMP-driven processes in pigment cells. In a recent study to assess the efficacy of the inhibition of mushroom tyrosinase (monophenol monooxygenase EC 1. Malignant melanoma continues to be a serious clinical problem. It was found that the growth and tyrosinase activity of SK-Mel 23 cells were not affected by melatonin or its precursors. The compound is a chelator for iron and copper. However. higher titers of IgG anti-tyrosinase antibodies were found in patients with diffused vitiligo compared with localized vitiligo. Ltd. (-)-gallocatechin 3-O-gallate (GCG) and (-)epigallocatechin 3-O-gallate (EGCG).. such as oleic and linoleic acid. In an attempt to prevent melanocyte destruction. 1999). it has been shown in vitro to inhibit melanogenesis in a dose-related manner. and reduces UV induced skin pigmentation at a 1% concentration. The use of mushroom tyrosinase For many years mushroom tyrosinase has been studied for its use in cosmetics as well as in food industries. These antibodies neither cross-react with other autoantigens of different autoimmune disorders nor block tyrosinase activity. modeled on tyrosine. it is well known that the consumption of green tea may help to prevent cancers in humans and also to reduce several free radicals including peroxynitrite (Yang et al. 2001). Green tea Epidemiologically. and its major active constituents are (-)-epicatechin 3-O-gallate (ECG). Tyrostat.. 2003). Helix aspersa Müller. Therefore. This indicates that tyrosinase acts as an autoantigen and serves as a marker for vitiligo (Baharav et al. have long been observed to have antioxidant activity with potential benefits for human health. Liquiritin has shown efficacy in limited clinical trials as a therapeutic depigmenting agent (Amer and Metwalli. linoleic acid and tyrostat Emblica is a compound isolated from Phyllanthus emblica fruits.6 mg/ cm2 has been shown to have antiinflammatory activity. suggesting that its effect occurs more proximally in the melanogenesis pathway. The concentration needed for effective depigmentation in human skin has not yet been established.930 S. It was suggested that this oral administration is closely linked to the suppression of cellular response to autoantigens (Kemp et al. a plant native to Canada’s northern prairie region. 1997). acts by inhibiting melanin synthesis (Corsaro et al. It was found that it did not affect tyrosinase activity. suppress pigmentation in vitro (Skolnik et al. 20. interference with the biosynthetic pathway which converts tyrosine into melanin (Prota et al. Epigallocatechin gallate (EGCG) is a principle phenolic antioxidant found in a variety of plants.. PARVEZ ET AL.... Its type of inhibition is mentioned in Table 1. an extract of field dock. 1995).. Yang 1999). which resulted in a diminished cell-mediated immune response. which shows that they are not reacting with the catalytic site of the enzyme. 1995). as described below. (2001) administered tyrosinase from A. The kinetic analysis of the inhibition of tyrosinase revealed a competitive nature of GCG with this enzyme for Ltyrosine binding at the active site of tyrosinase (No et al. oleic acid. 1994) by tyrosinase is necessary. metastatic melanoma continues to challenge researchers to find a systemic treatment for cancer. bisporus orally in animal models.14. ten kinds of traditional Korean teas were screened for their tyrosinase inhibitory activity. Kubo and Hori (1998) reported that an extract from the Chilean snail of the species Helix aspersa Müller (from Gastropoda pulmonata) has been used with success in the treatment of melasma and hyperpigmentation (Blanc et al. Res. Such a selective strategy toward the treatment of Phytother.1). Unsaturated fatty acids. These anti-tyrosinase autoantibodies from vitiligo patients’ sera can be recovered by exploiting its affinity toward tyrosinase. particularly flavonoids. In addition to its effects on diurnal rhythms in mammals. Miscellaneous – Emblica... A cosmetic manufacturer is currently marketing a topical melatonin cream as an antioxidant (Tabibian. All are catechins with a gallic acid group as an active site. Copyright © 2006 John Wiley & Sons. Immunological studies of vitiligo showed the generation and presence of autoantibodies directed against melanocyte antigens in the patients’ sera. Zehtab et al. Using solid-phase ELISA on mushroom tyrosinase. Tyrosinase is the enzyme responsible for melanin production in normal melanocytes and melanoma cells.. A study showed that linoleic acid in vivo had a lightening effect in UVB induced pigmentation without toxic effects on melanocytes (Quevedo et al. 2003).

Biochem J 235: 91–96. Contradictory results are available regarding the role of tyrosinase in cancer. Baharav E. but when these cells were incubated in the presence of GHB. superoxide dismutase. tumor suppression was observed only in B-16 melanoma cells and not in L1210 leukemia cells due to the absence of the enzyme tyrosinase. However. Topical liquiritin improves melasma. Anderson RR. Ltd. The optics of human skin. Influence of the application time point. 1981. Among skin-lightening agents. this mutagenic response was inhibited by catalase. Arch Dermatol 129: 1010–1014. γ-L-Glutaminyl-4-hydroxybenzene (GHB). Andrawis A. which contributes to the mutagenicity. different types of compounds from both natural and synthetic sources have been investigated. Review. tyrosinase inhibitors have found an important role in the cosmetic industry for their skin-whitening effect and depigmentation after sunburn. as some papers suggest a tumor-suppressing effect of mushroom tyrosinase. The antitumor effect of L-glutamic acid and γ-(phydroxyanilide) on B-16 melanoma was studied in vivo. 2003.. (1977) reported that a stable phenol. is oxidized by tyrosinase to a quinone and a second oxidation product. Ames BN. 921–934 (2006) DOI: 10. Anderson RR. What You Need to Know. which indicates the role of phenolic and quinoid compounds in the generation of reactive oxygen species. Dopamine. Kilmer SL. 20. Clin Exp Immunol 105: 84 – 88. whereas others predict a possible role in mutagenicity.5-dihydroxy derivative inhibited uracil and leucine incorporation into nucleic acid and proteins of melanoma cells (Wick et al. In the presence of mushroom tyrosinase it inhibited DNA polymerase activity and its 3. Incubation of cultured murine L1210 leukemia and B-16 melanoma cells with purified quinone blocked tumor growth in the mice.). A review of the literature reveals that numerous other depigmenting or skin-lightening agents are in use or under investigation. more concrete studies with human tyrosinase from a clinical point of view are required. arbutin. since the enzyme acts as a marker of this disease. kojic acid. 2001). This will be helpful in in vitro mutagenesis studies including antisense RNA techniques and gene silencing. This result indicates that the cytotoxic effect of GHB is dependent on the presence of tyrosinase. as they are considered to be safe and largely free from adverse side effects. Melatonin and 5-methoxytryptophol (5-ML) in nervous and/ Phytother. there has been increasing impetus to find alternative herbal and pharmaceutical depigmenting agents. Recent studies have indicated a possible negative role of mushroom tyrosinase in the metabolism and bioactivation of agaritine and other mushroom hydrazines. 2003. but still more research has to be done to cure vitiligo in humans. However. 1996. Dermatology 195: 248 – 252. Further development in the biochemical understanding of kinetic characterization and relationships between various isoforms of depigmentation and skin lightening agents is needed. Merimski O. 2000. and the degenerative diseases of aging. Pévet P. Baumann L. To achieve this goal. Fitzpatrick RE. 1997. (1993) found that tyrosinase is responsible for enhancing the mutagenicity of mushroom extract due to the production of phenolic and quinoid compounds. However. hydroquinone (HQ) is one of the most widely prescribed agents in the world. which will help to decrease production of tyrosinase in vivo. Parrish JA. Buisson B. Effect of methimazole on the activity of mushroom tyrosinase.or L-DOPAinduced neurotoxicity: the role of dopamine quinone Copyright © 2006 John Wiley & Sons. Kistler GS. Metwalli M. Suppression of UVinduced erythema by topical treatment with melatonin (N-acetyl-5-methoxytryptamine). But the metabolism or carcinogenicity of hydrazines in animals remains to be elucidated. REFERENCES Amer M. J Invest Dermatol 77: 13 –19. Vogel et al. Proc Natl Acad Sci USA 90: 7915–7922.1002/ptr . Besides use in the treatment of some dermatological disorders associated with melanin hyperpigmentation. Shoenfeld Y et al. Moreover. which offers a highly selective drug delivery system (Jordan et al. Res. whereas the 2. 1980). Hagen TM. which can shed more light on the action mechanism of tyrosinase. The contribution of the mushroom tyrosinase pathway to the mutagenicity or carcinogenicity of hydrazines in animals remains to be elucidated. 2004. Continuing Medical Education monograph. Geronemus R. 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Another important clinical application of mushroom tyrosinase is its role in the treatment of vitiligo. 1993. glycolic acid and azelaic acid are well studied. Shigenaga MK. Ogawa N. Kahn V.SKIN DEPIGMENTATION AND LIGHTENING malignant melanoma is called melanocyte-directed enzyme prodrug therapy (MDEPT). Neurotox Res 5: 165–176. Papaparaskeva-Petrides et al. Researchers in this field have actively sought to identify better depigmenting and lightening agents during the past three decades. in the latter case forming genotoxic metabolites. Vivien-Roels B. Blanc A. Attia J. more concrete studies with a human clinical point of view are required. Farinelli W. Asanuma M. which together suppress mitochondrial energy production and synthesis of nucleic acids and proteins. CONCLUSIONS The above studies show that skin depigmenting and lightening agents continue to be the subjects of extensive research due to their easy availability and vast clinical 931 results. 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