Introduction

Hydroquinone is often considered the gold standard among traditional topical treatments for hyperpigmentation. However, its use has been associated with a number of adverse effects, including skin irritation, contact dermatitis, and exogenous ochronosis in dark-skinned people. Other commonly available topical agents, such as corticosteroids, are either less effective or more likely to cause local or systemic side effects after long-term use. In the search for novel depigmenting agents, the investigation of natural plant extracts has led to the identification of many potentially active compounds (Table 1)Many plant extracts are more potent inhibitors of melanin formation than hydroquinone, kojic acid, or arbutin and are not associated with cytotoxicity or mutagenicity of melanocytes. Moreover, with natural sources offering a multitude of different extracts and isolated compounds, it is apparent that we are only beginning to realize the potential of natural extracts for skin-lightening applications.

Table 1 - Overview of botanical extracts with depigmenting activity.

Full table

Discussion

Arbutin

Arbutin, a naturally occurring -D-glucopyranoside derivative of hydroquinone, exists in the dried leaves of certain plant species, such as bearberry. The mode of action appears to be by inhibition of melanosomal tyrosinase and DHICA (5,6-dihydroxyindole-2-carboxylic acid) polymerase activities at noncytotoxic concentrations rather than by suppression of the synthesis and expression of this enzyme (Maeda and Fukuda, 1996; Chakraborty et al., 1998). It is thought that the activity of arbutin is driven by the structural homologies that it shares with the substrate tyrosine, which leads to the competitive inhibition of the catalytic function of tyrosinase. Studies have shown that -arbutin (4-hydroxyphenyl -glucopyranoside) demonstrates an even stronger inhibitory effect on human tyrosinase activity than arbutin itself. This effect was achieved without affecting mRNA expression of enzyme in cultured human melanoma cells and a three-dimensional human skin model (Sugimoto et al., 2004). Deoxyarbutin (dA, 4-[tetrahydrofuran-2-yl-oxy]-phenol) has also demonstrated effective inhibition of mushroom tyrosinase in vitro. In a human clinical trial, topical treatment with dA for 12 weeks resulted in a significant or a slight reduction in overall skin lightness and improvement of solar lentigines in a population of light-skinned or dark-skinned individuals, respectively (Boissy et al., 2005). -Arbutin has widely replaced arbutin as the chosen skin-lightening agent in topical skin preparations because it is more effective and stable in producing the desired effects on human skin.

Aloesin

Aloesin, a compound isolated from the aloe plant, has been proven to competitively inhibit tyrosinase from human, mushroom, and murine sources. Studies have shown that tyrosine hydroxylase and DOPA (3,4-dihydroxyphenylalanine) oxidase activities (of tyrosinase from normal human melanocyte cell lysates) are inhibited by aloesin in a dose-dependent manner (Jones et al., 2002). The topical application of aloesin on UV-irradiated (210 mJ) human volar forearm (four times a day for 15 days) showed pigmentation suppression in a dose-dependent manner (Choi et al., 2002). Aloesin, along with arbutin, was observed to synergistically inhibit melanin production by combined mechanisms of noncompetitive and competitive inhibitions of tyrosinase activity (Jin et al., 1999).

Flavonoids

Bioflavonoids can be divided into flavones, flavonols, isoflavones, and flavanones. The effects of many flavonoids on the oxidation of L-DOPA have been studied. Isoflavones, including glycitein, daidzein, and genistein, showed little antityrosinase activity, but 6,7,4'-trihydroxyisoflavone has been identified as a potent tyrosinase inhibitor stronger than kojic acid. Flavanones, such as hesperidin, eriodictyol, and naringenin, have a structure that is similar to that of hydroquinone. When concentrated in nanocapsules, they are protected until they reach the active site of melanin synthesis, where they exert a powerful reducing action and antiradical activity, and act as a substrate competitor for tyrosinase (Tiedtke et al., 2004).

Hesperidin

Hesperidin is a bioflavonoid existing extensively in the peel and membranes of citrus fruits. Studies by Zhu and colleagues have demonstrated hesperidin's potent ability to inhibit melanin synthesis without cytotoxicity. This work found dose-dependent inhibition of tyrosinase activity (vs control) of hesperidin in melanoma B16 cells and human primary melanocytes (Figure 1, Zhang et al., 2008). In addition, hesperidin was found to protect against UVA-induced damage of fibroblasts and oxidative damage of collagen (Proteggente et al., 2003). Thus, hesperidin offers potential skin-lightening benefits, including improved overall skin tone and antiyellowing effects.

Figure 1.

Inhibitory effect of hesperidin on tyrosinase activity in human primary melanocyte.

Full figure (31K)

Niacinamide

Niacinamide is a biologically active form of niacin (vitamin B3) found widely in many root vegetables and yeasts, and it is also an important precursor of NADH (nicotinamide adenine dinucleotide) and NADPH (nicotinamide adenine dinucleotide phosphate). The large number of cellular enzyme reactions in which these cofactors participate may be the basis for the variety of cosmetic benefits, including barrier enhancement observed from the topical use of niacinamide (Hakozaki et al., 2002). Using cocultures of human melanocytes and keratinocytes, investigators have shown that niacinamide inhibits the transfer of melanosomes from melanocytes to keratinocytes. Results of clinical studies using topically applied niacinamide have demonstrated a reversible reduction in hyperpigmented lesions and increased skin lightness compared with vehicle alone after 4 weeks of use. In a separate clinical study, topical niacinamide was also shown to decrease collagen oxidation products and improve aging-induced yellowing or sallowness (Bissett et al., 2004).

Licorice extracts

Licorice extracts have several active compounds that may stimulate or suppress melanogenesis. Glabridin, the main ingredient in the hydrophobic fraction of licorice extract, inhibits tyrosinase activity in cultured B16 murine melanoma cells, at concentrations from 0.1 to 1.0 g ml^-1, without affecting DNA synthesis. Other active compounds, such as glabrene, isoliquiritigenin licuraside, isoliquiritin, and licochalcone A, isolated from licorice extracts, were also shown to inhibit tyrosinase activity (Fu et al., 2005; Nerya et al., 2003). Liquiritin has no effect on tyrosinase; however, it causes depigmentation by other mechanisms, and studies demonstrate that a 20% liquiritin cream applied at 1 g day^-1 for 4 weeks is therapeutically effective in melasma (Amer and Metwalli, 2000).

Mulberry

Dried mulberry (Morus alba) leaves (85% ethanol extract) have been shown to inhibit tyrosinase activity. Additionally, several phenolic flavonoids, such as gallic acid and quercetin, and fatty acids, such as linoleic acid and palmitic acid, have been isolated from its leaves. Mulberroside F (moracin M-6, 3'-di-O-beta-D-glucopyranoside), the active component, showed inhibitory effects on tyrosinase activity and on melanin formation in melan-a cells. This compound also exhibited superoxide scavenging activity that is involved in the protection against auto-oxidation (Lee et al., 2002; Katsube et al., 2006), suggesting a role for Morus alba as a component of lightening cosmetics.

Polyphenols

Polyphenols are a class of compound that have antioxidant capacity and are found widely within plants. The inhibition of melanogenesis has been observed with many types of polyphenol plant extracts. Proanthocyanidins or procyanidins, classified as polyphenols, exist in red wine and cranberry juice; grape seeds are another especially rich source. The antioxidative activities of proanthocyanidins were found to be much stronger than the activity of vitamin C or E in aqueous systems. Ellagic acid is another natural polyphenol that is widely found in fruits and vegetables. The extract of the rinds of pomegranate contains 90% ellagic acid and showed inhibitory activity against mushroom tyrosinase in vitro. The mechanism of action may be inhibition of the proliferation of melanocytes and melanin synthesis by tyrosinase in melanocytes (Yoshimura et al., 2005).

Ginseng

P-coumaric acid, extracted from the fresh leaves of Panax ginseng, was shown to inhibit the oxidation of L-tyrosine more strongly than the inhibition of tyrosinase demonstrated by L-DOPA (Lim et al., 1999). Treatment with Radix ginseng in the presence of various concentrations of Radix trichosanthis suppressed tyrosinase activity and melanin content but increased cell proliferation slightly in B16 melanoma cells, raising the possibility that this combination may be effective as a skin-lightening agent (Im et al., 2003).

Gingko

Extracts from the leaves of the gingko tree have shown potent free radical scavenger activity when applied to the skin. Ginkgo flavone glycosides, mostly quercetin and kaempferol derivatives, can inhibit tyrosinase activity by chelating copper in the enzyme (Hibatallah et al., 1999; Xie et al., 2003).

Herbs used in traditional Chinese medicine

There are many kinds of traditional Chinese medicine prescriptions aimed at the treatment of hyperpigmentary disorders. The inhibitory actions of the extracts of 219 different traditional Chinese medicine herbs on tyrosinase activity were studied, and 11 ethanolic extracts and 8 aqueous extracts showed inhibitory effects on tyrosinase superior or similar to that of arbutin (Lei et al., 1999; Zhang et al., 1999; Wang et al., 2000). Further research investigated the effects and mechanisms of action of screened herbs. Ammonium glycyrrhizinate (18-GL), aloesin, icariin, piceid, salidroside, and epigallocatechin-3-gallate were found to significantly inhibit melanogenesis without cytotoxic effects in vitro. Most of these worked primarily by inhibiting tyrosinase activities competitively or noncompetitively (Lei et al., 2002; Rlu et al., 2003; Wang et al., 2004; Yue et al., 2005). A human trial is currently underway to study the effects of treatment with hesperidin and glycyrrhiza cinnamic acid, a naturally occurring aromatic fatty acid of low toxicity, which has a long history of human use. It is known that cinnamic acid does not influence fungal growth but decreases the yield of pigment from the mycelium. Cinnamic acid and aloesin are mixed-type inhibitors of tyrosinase activity, and sophorcarpidine functions as an uncompetitive inhibitor. Tan et al. (2002) demonstrated that sophorcarpidine, aloin, and cinnamic acid can bind not only to the enzyme but also to the enzyme–substrate complex, leading to inactivation of tyrosinase.

Conclusion

During the past decades, thousands of plant extracts have been screened, and hundreds of compounds were identified as potential skin-lightening ingredients. It is clear that natural sources and extracts represent a repository of ingredients that can be used in topical treatments to achieve improvement of hyperpigmentation and the overall appearance of skin. More and more in vitro studies are showing that these ingredients may also provide additional potential for protective cosmeceutical use, through antioxidant efficacy and protection of macromolecules, such as collagen from UV irradiation. However, only a few have been incorporated into topically applied cosmetics or cosmeceuticals, often due to lack of parallel human clinical trials. The results of the research by these authors and others indicate the real possibility that natural plant extracts may offer the potential to significantly expand the choices for skin-lightening ingredients and address the need for better ways to treat hyperpigmentation.

Conflict of Interest

W.Y. Zhu received an honorarium for consultant's services from Procter & Gamble toward the preparation of this paper.

References

1. Amer M, Metwalli M (2000) Topical liquiritin improves melasma. Int J Dermatol 39:299–301 | Article | PubMed | ChemPort |
2. Bissett DL, Miyamoto K, Sun P, Li J, Berge CA (2004) Topical niacinamide reduces yellowing, wrinkling, red blotchiness, and hyperpigmented spots in aging facial skin. Int J Cosmet Sci 26:231–238 | Article | ChemPort |
3. Boissy RE, Visscher M, DeLong MA (2005) DeoxyArbutin: a novel reversible tyrosinase inhibitor with effective in vivo skin lightening potency. Exp Dermatol 14:601–608 | Article | PubMed | ChemPort |
4. Chakraborty AK, Funasaka Y, Komoto M, Ichihashi M (1998) Effect of arbutin on melanogenic proteins in human melanocytes. Pigment Cell Res 11:206–212 | Article | PubMed | ISI | ChemPort |
5. Choi S, Lee SK, Kim JE, Chung MH, Park YI (2002) Aloesin inhibits hyperpigmentation induced by UV radiation. Clin Exp Dermatol 27:513–515 | Article | PubMed | ChemPort |
6. Fu B, Li H, Wang X, Lee FS, Cui S (2005) Isolation and identification of flavonoids in licorice and a study of their inhibitory effects on tyrosinase. J Agric Food Chem 53:7408–7414 | Article | PubMed | ChemPort |
7. Funayama M, Arakawa H, Yamamoto R, Nishino T, Shin T, Murao S (1995) Effects of alpha- and beta-arbutin on activity of tyrosinases from mushroom and mouse melanoma. Biosci Biotechnol Biochem 59:143–144 | PubMed | ChemPort |
8. Hakozaki T, Minwalla L, Zhuang J, Chhoa M, Matsubara A, Miyamoto K et al. (2002) The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. Br J Dermatol 147:20–31 | Article | PubMed | ChemPort |
9. Hibatallah J, Carduner C, Poelman MC (1999) In-vivo and in-vitro assessment of the free-radical-scavenger activity of Ginkgo flavone glycosides at high concentration. J Pharm Pharmacol 51:1435–1440 | Article | PubMed | ChemPort |
10. Im SJ, Kim KN, Yun YG, Lee JC, Mun YJ, Kim JH et al. (2003) Effect of Radix Ginseng and Radix Trichosanthis on the melanogenesis. Biol Pharm Bull 26:849–853 | Article | PubMed | ChemPort |
11. Jin YH, Lee SJ, Chung MH, Park JH, Park YI, Cho TH et al. (1999) Aloesin and arbutin inhibit tyrosinase activity in a synergistic manner via a different action mechanism. Arch Pharm Res 22:232–236 | PubMed | ChemPort |
12. Jones K, Hughes J, Hong M, Jia Q, Orndorff S (2002) Modulation of melanogenesis by aloesin: a competitive inhibitor of tyrosinase. Pigment Cell Res 15:335–340 | Article | PubMed | ChemPort |
13. Katsube T, Imawaka N, Kawano Y, Yamazakib Y, Shiwakuc K, Yamane Y (2006) Antioxidant flavonol glycosides in mulberry (Morus alba L) leaves isolated based on LDL antioxidant activity. Food Chem 97:25–31 | Article | ChemPort |
14. Kubo I, Kinst-Hori I, Chaudhuri SK, Kubo Y, Sanchez Y, Ogura T (2000) Flavonols from Heterotheca inuloides: tyrosinase inhibitory activity and structural criteria. Bioorg Med Chem 8:1749–1755 | Article | PubMed | ChemPort |
15. Lee SH, Choi SY, Kim H, Hwang JS, Lee BG, Gao JJ et al. (2002) Mulberroside F isolated from the leaves of Morus Alba inhibits melanin biosynthesis. Biol Pharm Bull 25:1045–1048 | Article | PubMed | ChemPort |
16. Lei TC, Zhu WY, Xia MY, Zhang MH, Fan WX (1999) Extracts from 82 kinds of traditional Chinese herbs are inhibitors to the tyrosinase. Tradit Chin Herbs 30:336–339 | ChemPort |
17. Lei TC, Zhu WY, Xia MY, Zhang MH, Fan WX (2002) Comparative studies on regulation of melanogenesis in the response of murine melanoma cells to ammonium glycyrrhizinate, arbutin and hydroquinone. J Clin Dermatol (China) 29:69–72
18. Lim JY, Ishiguro K, Kubo I (1999) Tyrosinase inhibitory p-coumaric acid from ginseng leaves. Phytother Res 13:371–375 | Article | PubMed | ChemPort |
19. Lu Y, Zhu WY, Tan C (2006) Effects of sophocarpidine and cinnamic acid on the melanogenesis of melan-a. J Clin Dermatol(China) 35:698–700 | ChemPort |
20. Maeda K, Fukuda M (1996) Arbutin: mechanism of its depigmenting action in human melanocyte culture. J Pharmacol Exp Ther 276:765–769 | PubMed | ISI | ChemPort |
21. Nerya O, Vaya J, Musa R, Izrael S, Ben-Arie R, Tamir S (2003) Glabrene and isoliquiritigenin as tyrosinase inhibitors from licorice roots. J Agric Food Chem 51:1201–1207 | Article | PubMed | ChemPort |
22. Proteggente AR, Basu-Modak S, Kuhnle G, Gordon MJ, Youdim K, Tyrrell R et al. (2003) Hesperetin glucuronide, a photoprotective agent arising from flavonoid metabolism in human skin fibroblasts. Photochem Photobiol 78:256–261 | Article | PubMed | ChemPort |
23. Rlu Y, Zhu WY, Tan C, Liu D, Xu Y (2003) Effects of aloesin on melanogenesis and related gene expressions of Melan-a cell line. J Clin Dermatol (China) 32:502–505
24. Shimogaki H, Tanaka Y, Tamai H, Masuda M (2000) In vitro and in vivo evaluation of ellagic acid on melanogenesis inhibition. Int J Cosmetic Sci 22:291–303 | Article | ChemPort |
25. Shoji T, Masumoto S, Moriichi N, Kobori M, Kanda T, Shinmoto H et al. (2005) Procyanidin trimers to pentamers fractionated from apple inhibit melanogenesis in B16 mouse melanoma cells. J Agric Food Chem 53:6105–6111 | Article | PubMed | ChemPort |
26. Sugimoto K, Nishimura T, Nomura K, Sugimoto K, Kuriki T (2004) Inhibitory effects of alpha-arbutin on melanin synthesis in cultured human melanoma cells and a three-dimensional human skin model. Biol Pharm Bull 27:510–514 | Article | PubMed | ChemPort |
27. Tan C, Zhu W, Lu Y (2002) Aloin, cinnamic acid and sophorcarpidine are potent inhibitors of tyrosinase. Chin Med J (Engl) 115:1859–1862 | PubMed | ChemPort |
28. Tiedtke J, Morel J, Marks O (2004) Depigmentation factor. Bioflavonoids—a safe and effective skin lightener based on encapsulated citrus bioflavonoids. Cosmetochem 2004:12–17
29. Wang DG, Zhu WY, Ma HJ (2004) Effects of 6 kinds of monomers extracted from Chinese medicines including icariin on melanogenesis in Cloudman S91 melanima cells. J Clin Dermatol (China) 33:202–205
30. Wang JH, Lei F, Cui JR (2000) Study on 20 kinds of traditional Chinese herbs on tyrosinase. J Chin Pharmacol 35:232–234
31. Xie LP, Chen QX, Huang H, Wang HZ, Zhang RQ (2003) Inhibitory effects of some flavonoids on the activity of mushroom tyrosinase. Biochemistry (Mosc) 68:487–491 | Article | PubMed | ChemPort |
32. Yoshimura M, Watanabe Y, Kasai K, Yamakoshi J, Koga T (2005) Inhibitory effect of an ellagic acid-rich pomegranate extract on tyrosinase activity and ultraviolet-induced pigmentation. Biosci Biotechnol Biochem 69:2368–2373 | Article | PubMed | ChemPort |
33. Yokota T, Nishio H, Kubota Y, Mizoguchi M (1998) The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation. Pigment Cell Res 11:355–361 | Article | PubMed | ChemPort |
34. Yue XZ, Zhu WY, Ma HJ, Wang DG, Li CR (2005) Effects of epigallocatechin-3-gallate on melanogenesis of human epidermal melanocytes. J Clin Dermatol (China) 34:795–797 | ChemPort |
35. Zhang MH, Zhu WY, Xia MY (1999) Effect of 48 kinds of herbs on the melanogenesis of B16F1O in vitro. Tradit Chin Med Jiangsu Prov 20:44–45
36. Zhang RZ, Zhu WY, Xie F (2008) Effect of hesperidin on B16 and HaCaT cell lines irradiated by Narrowband-UVB light. J Clin Dermatol (China) (in press)

Acknowledgements

This research was supported by the National Natural Science Foundation of China.