Found in the leaves of pear trees and certain plants such as wheat and bearberry, and in lower quantities in cranberry and blueberry leaves (Dermatol. Ther. 2007;20:308-13), arbutin (C12H16O7) is a naturally occurring B-D glucopyranoside consisting of a molecule of hydroquinone bound to glucose (in other words, the beta-D-glucopyranoside of hydroquinone). Arbutin has been used traditionally in Japan as a skin-lightening agent. Its depigmenting mechanism is thought to act by reversibly suppressing melanosomal tyrosinase activity rather than inhibiting the expression and production of tyrosinase (J. Pharmacol. Exp. Ther. 1996;276:765-9). It also acts by inhibiting 5,6-dihydroxyindole-2-carboxylic acid (DHICA) polymerase; the hydrolyzation of the glycosidic bond then results in hydroquinone release in a controlled manner (Dermatol. Clin. 2007;25:353-62; Pigment Cell. Res. 2006;19:550-71). Tyrosinase is the rate-limiting enzyme that controls melanin production and is a unique product of melanocytes. Consequently, agents that inhibit tyrosinase activity, which is a major regulatory step in melanogenesis, prevent the synthesis of the pigment melanin and are therefore considered viable candidates as cosmetic skin-whitening ingredients.
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Arbutin, found in the leaves of the pear tree and in other plants, has been used as a skin-lightening agent in traditional Japanese medicine.
Currently, arbutin is included as an ingredient in several cosmetic products. This column will focus on recent research with arbutin and deoxyarbutin, a synthetic arbutin derivative, created by removing each hydroxyl group, that has shown promising in vitro and in vivo results with a greater inhibition of tyrosinase than its botanical precursor (Exp. Dermatol. 2005;14:601-8). It is important to note that hydroquinone, the standard cosmetic skin-lightening agent, is more potent than arbutin, but it has been associated with cytotoxicity, nephrotoxicity, and genotoxicity (J. Cosmet. Dermatol. 2008;7:189-93) and was banned in Europe in 2000 and is strictly regulated in Asia.
Abutin’s Efficacy Tested
Although arbutin has been reported to be successful for cosmetic and therapeutic purposes, its suitability as an alternative depigmenting agent to hydroquinone has not been firmly established. In a decade-old study, tyrosinase activity diminished in normal human melanocytes treated with arbutin, but an increase of pigmentation was reported (Pigment Cell. Res. 1998;11:12-7). Indeed, Maeda and Fukuda had previously reported that while higher concentrations of arbutin displayed greater efficacy than lower concentrations, a paradoxical hyperpigmentation emerged as a result of postinflammatory hyperpigmentation (J. Pharmacol. Exp. Ther. 1996;276:765-9; Skin Therapy Lett. 2004;9:1-3; Dermatol. Ther. 2007;20:308-13).
In another study in which the inhibitory effect of arbutin and/or aloesin on pigmentation in human skin after UV radiation was examined, the administration of either or both compounds four times a day for 15 days revealed pigmentation suppression of 43.5% by arbutin, 34% by aloesin, and 63.3% by the cotreatment of the skin-lightening agents, compared with the control (Clin. Exp. Dermatol. 2002;27:513-5).
Yang et al. constructed a pigmented skin equivalent model in vitro and then studied the effects on melanocyte cell shape, tyrosinase activity, and melanin formation exerted by aloesin, tea polyphenols, and arbutin. A concentration-dependent inhibitory effect on melanocyte tyrosinase activity and melanin content was achieved by tea polyphenols, aloesin, and arbutin, in descending order, but significantly lower toxicity was associated with aloesin and arbutin (Zhonghua Zheng Xing Wai Ke Za Zhi 2008;24:50-3). Arbutin was also found to be less toxic than hydroquinone in an in vitro study using a melanocyte-keratinocyte coculture model in which four melanogenic-inhibiting compounds (that is, arbutin, hydroquinone, kojic acid, and niacinamide) were compared (Anal. Biochem. 2002;305:260-8).
Antioxidant Properties of Arbutin
Antioxidant activity also plays a role in the effectiveness of arbutin. Bang et al. measured the hydrolytic activity of the primary skin microflora, Staphylococcus epidermidis and Staphylococcus aureus, in order to determine if skin microflora can hydrolyze arbutin to hydroquinone. They found that arbutin was hydrolyzed by all strains, with the hydrolyzed hydroquinone exhibiting greater 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity and tyrosinase inhibition than arbutin. The investigators concluded that the antioxidant activity of hydroquinone allows the main skin microflora to enhance the skin-lightening properties of arbutin (J. Cosmet. Dermatol. 2008;7:189-93).
Lim et al. determined that arbutin both inhibited melanin production in B16 cells induced with alpha–melanocyte stimulating hormone (alpha-MSH) and reduced tyrosinase activity in a cell-free system. The addition of arbutin to brownish guinea pig and human skin tissues also resulted in neutralizing the hyperpigmentary impact of alpha-MSH. The authors concluded that arbutin is a useful skin-whitening agent (Arch. Pharm. Res. 2009;32:367-73).
Potential of Synthetic Arbutin
While the naturally-occurring arbutin has established efficacy in the cosmetic and therapeutic realm, recent evidence suggests that a synthetic version of the botanical is even more effective. Building on previous work in which they demonstrated that deoxyarbutin is a more effective and less toxic skin lightener than hydroquinone, Chawla et al. used standard assays to evaluate the efficacy and reversibility of deoxyarbutin and its derivatives on inhibiting tyrosine hydroxylase and dihydroxyphenylalanine (DOPA) oxidase. They found that the agents, when used in concentrations keeping 95% cell viability in culture, dose-dependently inhibited tyrosine hydroxylase and DOPAoxidase activities, thus suppressing melanin production by healthy melanocytes. Removal of the agents resulted in complete reversal of the depigmenting result. An in vitro test using human and purified mushroom tyrosinase also revealed tyrosinase suppression, which the authors suggested was further evidence that these agents directly inhibit the tyrosinase enzyme. They concluded that deoxyarbutin and its second-generation derivatives impede melanogenesis at safe concentrations by inhibiting tyrosinase, and warrant attention as effective agents to treat hyperpigmentary conditions or to lighten the skin (Br. J. Dermatol. 2008;159:1267-74).