• 1
    KFDA. Press Release on Functional Cosmetics in Korea. Available at: (2012).
  • 2
    Norlund, J.J., Boissy, R.E., Hearing, V.J., King, R.A. and Ortonne, J.P. The Pigmentary System: Physiology and Pathophysiology, 489502. Oxford University Press, New York (1998).
  • 3
    Gillbro, J.M. and Olsson, M.J. The melanogenesis and mechanisms of skin-lightening agents–existing and new approaches. Int. J. Cosmet. Sci. 33, 210221 (2011).
  • 4
    Briganti, S., Camera, E. and Picardo, M. Chemical and instrumental approaches to treat hyperpigmentation. Pigment Cell Res. 16, 101110 (2003).
  • 5
    Dadzie, O.E. and Petit, A. Skin bleaching: highlighting the misuse of cutaneous depigmenting agents. J. Eur. Acad. Dermatol. Venereol. 23, 741750 (2009).
  • 6
    KFDA. Regulations of cosmetic ingredient assignment, Notification No. 2006-12 of the Korea Food and Drug Administration, (2006).
  • 7
    EC. Directive 2003/15/EC of The European Parliament and of the Council of 27 February 2003 amending Council Directive 76/768/EEC on the approximation of the laws of the Member States relating to cosmetic products, (2003).
  • 8
    Hakozaki, T., Minwalla, L., Zhuang, J. et al. The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. Br. J. Dermatol., 147, 2233 (2002).
  • 9
    Ebanks, J.P., Koshoffer, A., Wickett, R.R., Schwemberger, S., Babcock, G., Hakozaki, T. and Boissy, R.E. Epidermal keratinocytes from light vs. dark skin exhibit differential degradation of melanosomes. J. Invest. Dermatol. 131, 12261233 (2011).
  • 10
    Grimes, P., Nordlund, J.J., Pandya, A.G., Taylor, S., Rendon, M. and Ortonne, J.P. Increasing our understanding of pigmentary disorders. J. Am. Acad. Dermatol. 54(5 Suppl 2), S255S261 (2006).
  • 11
    Kim, D.S., Park, S.H., Kwon, S.B., Youn, S.W. and Park, K.C. Effects of lysophosphatidic acid on melanogenesis. Chem. Phys. Lipids 127, 199206 (2004).
  • 12
    Kim, D.S., Park, S.H., Kwon, S.B., Lee, K.S., Youn, W. and Park, K.C. α(-)-Epigallocatechin-3-gallate and hinokitiol reduce melanin synthesis via decreased MITF production. Arch. Pharm. Res. 27, 334339 (2004).
  • 13
    Solano, F., Briganti, S., Picardo, M. and Ghanem, G. Hypopigmenting agents: an updated review on biological, chemical and clinical aspects. Pigment Cell Res. 19, 550571 (2006).
  • 14
    Hodgkinson, C.A., Moore, K.J., Nakayama, A., Steingrimsson, E., Copeland, N.G., Jenkins, N.A. and Arnheiter, H. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell 74, 395404 (1993).
  • 15
    Steingrimsson, E., Moore, K.J., Lamoreux, M.L. et al. Molecular basis of mouse microphthalmia (mi) mutations helps explain their developmental and phenotypic consequences. Nat. Genet. 8, 256263 (1994).
  • 16
    Bentley, N.J., Eisen, T. and Goding, C.T. Melanocyte-specific expression of the human tyrosinase promoter: activation by the microphthalmia gene product and role of the initiator. Mol. Cell. Biol. 14, 79968006 (1994).
  • 17
    Bertolotto, C., Busca, R., Abbe, P., Bille, K., Aberdam, E., Ortonne, J.P. and Ballotti, R. Different cis-acting elements are involved in the regulation of TRP1 and TRP2 promoter activities by cyclic AMP: pivotalrole of M boxes (GTCATGTGCT) and of microphthalmia. Mol. Cell. Biol. 18, 694702 (1998).
  • 18
    Price, E.R., Horstmann, M.A., Wells, A.G., Weilbaecher, K.N., Takemoto, C.M., Landis, M.W. and Fisher, D.E. alpha-Melanocyte-stimulating hormone signaling regulates expression of microphthalmia, a gene deficient in Waardenburg syndrome. J. Biol. Chem. 273, 3304233047 (1998).
  • 19
    Yasumoto, K., Yokoyama, K., Takahashi, K., Tomita, Y. and Shibahara, S. Functional analysis of microphthalmia-associated transcription factor in pigment cell-specific transcription of the human tyrosinase family genes. J. Biol. Chem. 272, 503509 (1997).
  • 20
    Kim, D.S., Kim, S.Y., Chung, J.H., Kim, K.H., Eun, H.C. and Park, K.C. Delayed ERK activation by ceramide reduces melanin synthesis in human melanocytes. Cell. Signal. 14, 779785 (2002).
  • 21
    Dooley, T.P., Gadwood, R.C., Kilgore, K. and Thomasco, L.M. Development of an in vitro primary screen for skin depigmentation and antimeanoma agents. Skin Pharmacol. 7, 188200 (1994).
  • 22
    Ilearing, V.J. and Jimenez, M. Analysis of mammalian pigmentation at the molecular level. Pigment Cell Res. 2, 75 (1989).
  • 23
    Yagi, A., Kanbara, T. and Morinobu, N. Inhibition of mushroom tyrosinase by aloe extract. Planta Med. 53, 515517 (1987).
  • 24
    Nagatsu, T., Sudo, Y., Okada, T., Umezawa, H. and Takeuchi, T. Inhibition of melanoma tyrosinase by fusaric acid. Cell. Mol. Life Sci. 28, 625752 (1972).
  • 25
    Kong, K.H., Park, S.Y., Hong, M.P. and Choi, S.H. Expression and characterization of human tyrosinase from a bacterial expression system. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 125, 563569 (2000).
  • 26
    Boissy, R.E., Visscher, M. and deLong, M.A. Deoxyarbutin: a novel reversible tyrosinase inhibition with effective in vivo skin lightening potency. Exp. Dermatol. 14, 601608 (2005).
  • 27
    Vanni, A., Gastaldi, D. and Giunata, G. Kinetic investigations on the double enzymatic activity of the tyrosinase mushroom. Anal. Chim. 80, 3560 (1990).
  • 28
    Lee, C.H., Chung, M.C., Lee, H.J., Lee, K.H. and Kho, Y.H. MR 304-1, A melanin synthesis inhibitor produced by trichodermaharzianum. Korean J. Appl. Microbiol. Biotechnol. 23, 641646 (1995).
  • 29
    Korea Food & Drug Administration. Guideline for Efficacy Evaluation of Functional cosmetics-Whitening cosmetics, 45. KFDA press, Korea (2003).
  • 30
    Korea Food & Drug Administration. Guideline for Efficacy Evaluation of Functional cosmetics-Whitening cosmetics, 56. KFDA press, Korea (2003).
  • 31
    Choi, S.Y., Hwang, J.S., Kim, S.H. and Kim, S.Y. Synthesis, discovery and mechanism of 2,6-dimethoxy-N-(4-methoxyphenyl)benzamide as potent depigmenting agent in the skin. Biochem. Biophys. Res. Commun. 349, 3949 (2006).
  • 32
    Barber, J., Townsend, D., David, P., Olds, M.S. and King, R.A. Dopachromeoxidoreductase: a new enzyme in the pigment pathway. J. Invest. Dermatol. 83, 5149 (1984).
  • 33
    Kosmadaki, M.G., Naif, A. and Park, H.Y. Recent progresses in understanding pigmentation. G. Ital. Dermatol. Venereol. 145, 4755 (2010).
  • 34
    Karg, E., Odh, G., Wittbjer, A., Rosengren, E. and Rosman, H. Hydrogen peroxide as induced of elevated tyrosinase level in melanoma cells. J. Invest. Dermatol. 100, 209213 (1993).
  • 35
    Heo, S.J., Ko, S.C., Kang, S.M. et al. Inhibitory effect of diphlorethohydroxycarmalol on melanogenesis and its protective effect against UV-B radiation-induced cell damage. Food Chem. Toxicol. 48, 13551361 (2010).
  • 36
    Gukasyan, G.G. Study of the kinetics of oxidation of monophenols by tyrosinase. The effect of reducers. Biochemistry (Mosc) 67, 277280 (2002).
  • 37
    Ros, J.R., Rodriguez-Lopes, J.N. and Garcia-Canovas, F. Effect of l-ascorbic acid on the monophelase activity of tyrosinase. Biochem. J. 295, 309312 (1993).
  • 38
    Ochiai, Y., Okano, Y., Funasaka, Y. and Ichihashi, M. Effects of a-Toc on In Vitro Aged Melanocytes, 119. The 52nd Annual Meeting of the Central division of Japanese Dermatological Association, Tokyo (2001).
  • 39
    Marmo, V.D., Solano, F., Sels, A., Huez, G., Libert, A., Lejeune, F. and Ghanem, G. Glutathione depletion increases tyrosinase activity in human melanoma cells. J. Invest. Dermatol., 101, 871874 (1993).
  • 40
    Nishiyama, T., Ohnishi, J. and Hashiguchi, Y. Fused heterocyclic antioxidants. antioxidative activities of hydrocumarins in a homogeneous solution. Biosci. Biotechnol. Biochem. 65, 11271133 (2001).
  • 41
    Yamamura, T., Onishi, J. and Nishiyama, T. Antimelanogenic activity of hydrocumarins in cultured normal human melanocytes by stimulating intracellular glutathione synthesis. Arch. Dermatol. Res. 294, 349354 (2002).
  • 42
    Fugita, Y., Uehara, I., Morimoto, Y., Nakashima, M., Hatano, T. and Okuda, T. Studies on inhibition mechanism of autooxidation by tannins and flavonoids. II. Inhibition mechanism of coffee tannin isolated from leaves of Artemisia species on lipoxygenase dependent lipid peroxidation. Yakugaku Zasshi, 108, 129135 (1988).
  • 43
    Yagi, K. Assay for blood plasma or serum. Methods Enzymol. 105, 328331 (1984).
  • 44
    Korea Food & Drug Administration. Guideline for Efficacy Evaluation of Functional cosmetics-Whitening cosmetics, 67. KFDA press, Korea (2003).
  • 45
    Sharlow, E.R., Paine, C., Babiarz, L., Eisinger, M., Shapiro, S.S. and Seiberg, M. The protease activated receptor 2 upregulates keratinocyte phagocytosis. J. Cell Sci. 113, 30933101 (2000).
  • 46
    Seiberg, M., Paine, C., Sharlow, E., Costanzo, M., Andrade-Gordon, P., Eisingera, M. and Shapiro, S. The proteasome-activated receptor 2 regulates pigmentation via keratinocyte.melanocyte interaction. Exp. Cell Res. 254, 2532 (2000).
  • 47
    Seiberg, M., Paine, C., Sharlow, E., Costanzo, M., Andrade-Gordon, P., Eisinger, M. and Shapiro, S.S. Inhibition of melanosome transfer results in skin lightening. J. Invest. Dermatol. 115, 162167 (2000).
  • 48
    Goh, C.L. and Dlova, C.N. A retrospective study on the clinical presentation and treatment outcome of melasma in a tertiary dermatological referral center in Singapore. Singapore Med. J. 40, 5458 (1999).
  • 49
    Grimes, P.E. Melasma: etiologic and therapeutic considerations. Arch. Dermatol. 131, 14531457 (1995).
  • 50
    Sanchez, N.P., Pathak, M.A., Sato, S., Fitzpatrick, T.B., Sanchez, J.L. and Mihm, M.C. Jr. Melasma: a clinical, light microscopic, ultrastructural, and immunofluorescence study. J. Am. Acad. Dermatol. 4, 698710 (1981).
  • 51
    Taylor, S.C. Epidemiology of skin diseases in people of color. Cutis 71, 271275 (2003).
  • 52
    Sodhi, V.K. and Sausker, W.F. Dermatoses of pregnancy. Am. Fam. Physician 37, 131138 (1988).
  • 53
    Lutfi, R.J., Fridmanis, M., Misiunas, A.L. et al. Association of melasma with thyroid autoimmunity and other thyroidal abnormalities and their relationship to the origin of the melasma. J. Clin. Endocrinol. Metab. 61, 2831 (1985).
  • 54
    Perez, M., Sanchez, J.L. and Aguilo, F. Endocrinologic profile of patients with idiopathic melasma. J. Invest. Dermatol. 81, 543545 (1983).
  • 55
    Resnik, S. Melasma induced by oral contraceptive drugs. JAMA 199, 9599 (1967).
  • 56
    Kang, W.H., Yoon, K.H., Lee, E.S., Kim, J., Lee, K.B., Yim, H., Sohn, S. and Im, S. Melasma: histopathological charateristics in 56 Korean patients. Br. J. Dermatol. 146, 228237 (2002).
  • 57
    Yoshimura, K., Tsukamoto, K., Okazaki, M. et al. Effects of all-trans retinoic acid on melanogenesis in pigmented skin equivalents and monolayer culture of melanocytes. J. Dermatol. Sci. 27, 6875 (2001).
  • 58
    Ando, H., Ryu, A., Hashimoto, A., Oka, M. and Ichashi, M. Linoleic and a-linoleic acid lightens ultraviolet-induced hyperpigmentation of the skin. Arch. Dermatol. Res. 290, 375381 (1998).
  • 59
    Korea Food & Drug Administration. Guideline for Efficacy Evaluation of Functional Cosmetics-Whitening cosmetics, 813. KFDA press, Korea (2003).
  • 60
    Korea Food & Drug Administration. Guideline for Efficacy Evaluation of Functional cosmetics-Whitening cosmetics, 1316. KFDA press, Korea (2003).
  • 61
    Vachtenheim, J. and Borovanský, J. “Transcription physiology” of pigment formation in melanocytes: central role of MITF. Exp. Dermatol. 19, 617627 (2010).
  • 62
    Brenner, M. and Hearing, V.J. Modifying skin pigmentation-approaches through intrinsic biochemistry and exogenous agents. Drug Discov. Today Dis. Mech. 5, e189e199 (2008).
  • 63
    Hearing, V.J. Determination of melanin synthetic pathways. J. Invest. Dermatol. 131(E1), E8E11 (2011).
  • 64
    Page, S., Chandhoke, V. and Baranova, A. Melanin and melanogenesis in adipose tissue: possible mechanisms for abating oxidative stress and inflammation? Obes. Rev. 12, e21e31 (2011).
  • 65
    Ali, S.A., Galgut, J.M. and Choudhary, R.K. On the novel action of melanolysis by a leaf extract of aloe vera and its active ingredient aloin, potent skin depigmenting agents. Planta Med. 78, 761771 (2012).
  • 66
    Kasraee, B., Nikolic, D.S., Salomon, D. et al. Ebselen is a new skin depigmenting agent that inhibits melanin biosynthesis and melanosomal transfer. Exp. Dermatol. 21, 1924 (2012).
  • 67
    Tsilika, K., Levy, J.L., Kang, H.Y. et al. A pilot study using reflectance confocal microscopy (RCM) in the assessment of a novel formulation for the treatment of melasma. J. Drugs Dermatol. 10, 12601264 (2011).
  • 68
    Tirado-Sánchez, A., Santamaría-Román, A. and Ponce-Olivera, R.M. Efficacy of dioic acid compared with hydroquinone in the treatment of melasma. Int. J. Dermatol. 48, 893895 (2009).
  • 69
    Sato, K., Takahashi, H., Iraha, R. and Toriyama, M. Down-regulation of tyrosinase expression by acetylsalicylic acid in murine B16 melanoma. Biol. Pharm. Bull. 31, 3337 (2008).
  • 70
    Dadzie, O.E. and Petit, A. Skin bleaching: highlighting the misuse of cutaneous depigmenting agents. J. Eur. Acad. Dermatol. Venereol. 23, 741750 (2009).
  • 71
    Pandhi, D., Vij, A. and Singal, A. Contact depigmentation induced by propyl gallate. Clin. Exp. Dermatol. 36, 366368 (2011).