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Aloesin
 

While hydroquinone has long been the standard skin whitening agent throughout the world, its reputed cytotoxicity prompted a ban in 2000 in Europe and strict regulation in Asia. In response, in addition to combination treatments that include but rely less on hydroquinone, the armamentarium has expanded to include a wide range of active constituents extracted from plants, including aloesin, arbutin, flavonoids, gentisic acid, hesperidin, licorice, niacinamide, yeast derivatives, and polyphenols, which inhibit melanogenesis through varying mechanisms without inducing melanocytotoxicity.[i] This column will focus on recent research related to the skin-lightening activity of aloesin.


 


A moderately-high-molecular-weight C-glycosylated chromone naturally derived and isolated from Aloe vera, aloesin has been found to dose-dependently inhibit tyrosinase [by blocking both the hydroxylation of tyrosine to 3,4-dihydroxyphenylalanine (DOPA) and oxidation of DOPA to dopaquinone] as well as melanin production in cultured normal melanocytes.[ii] Notably, aloesin (2-acetonyl-8-beta-d-glucopyranosyl-7-hydroxy-5-methylchromone), which is difficult to synthesize, and a few chemically related chromones, particularly the 5-methyl-7-methoxy-2(2-benzyl-3-oxobutyl)-chromone, have been shown to display a more potent inhibitory effect on tyrosinase than arbutin and kojic acid.[iii][iv][v] The activity of aloesin in relationship to tyrosinase is important because tyrosinase is the rate-limiting enzyme in melanin production and, thus, directly impacts skin pigment formation.


 


While aloesin appears to be an important component in the armamentarium against hyperpigmentation disorders, its hydrophilic nature renders it less able than hydroquinone to penetrate the skin.[vi] However, some believe that its slower penetration of the skin endows aloesin with greater potential as a skin-lightening agent for cosmetic purposes.[vii]


 


Although less effective than hydroquinone when used as single therapy, aloesin is safer, and has been most successfully used in hypopigmenting regimens for its syngergistic activity in combination therapies with two or more agents acting on various mechanisms.[viii] In 1999, aloesin and arbutin were shown to act synergistically in suppressing tyrosinase activity, and thus melanin production, in a combined treatment, but through different mechanisms. Aloesin inhibited tyrosinase activity noncompetitively while arbutin acted competitively.[ix]


 


Another good example comes from a 2002 examination of the inhibitory effects of aloesin, arbutin, and a combination of the two agents. Human subjects were exposed to UV radiation on the inner forearm and the treated areas were assigned to four daily treatments for 15 days with vehicle control, aloesin, arbutin, and a combination of aloesin and arbutin. Aloesin blocked pigmentation by 34%, arbutin, by 43.5%, and the combination treatment, 63.3%, as compared to the control. In addition, investigators noted that aloesin dose-dependently inhibited UV-induced pigmentation and concluded that the compound may be a suitable agent for blocking UV-induced melanin formation.[x] In 2004, Yang et al. also investigated the synergistic effects of aloesin and arbutin. They treated normal cultured human melanocytes in vitro with an aloesin and arbutin mixture, which was found to have suppressed tyrosinase activity and resulted in a significant decline in melanin content in the cultured melanocytes. The mixture had little effect on melanocyte viability.[xi]


 


In 2008, most of the same investigators, led this time by Wang, examined the effects of aloesin on melanogenesis in an in vitro pigmented skin equivalent, given recent success in the study of skin metabolism and depigmenting agents in such models, which have been shown to display similar morphological and growth qualities to human skin. The investigators found that aloesin exhibited direct inhibitory effects on melanogenesis and dose-dependently sparked a decline in tyrosinase activity and melanin content. Arbutin also exhibited dose-dependent inhibitory activity, but was less effective than aloesin. Tea polyphenols demonstrated greater inhibitory activity than aloesin. Nevertheless, the authors concluded that aloesin evinced potential as an agent intended to affect pigmentation for cosmetic or therapeutic purposes.[xii]


 


Previously, in 2002, Jones et al. demonstrated that aloesin modulates melanogenesis by competitively inhibiting tyrosinase at the dihydroxyphenylalanine oxidation site, suppressing melanin synthesis in vitro, and that it is a tyrosinase inhibitor from mushroom, human, and murine sources. They also found that aloesin dose-dependently inhibited tyrosine hydroxylase and DOPA oxidase activities of tyrosinase from normal human melanocyte cell lysates. The researchers concluded that aloesin indeed demonstrated potential as a cosmetic or therapeutic agent for altering skin pigmentation.[xiii]


 


In a wide-ranging study of the anti-inflammatory and antioxidant properties of various Aloe isolates, including cinnamoyl, p-coumaroyl, feruloyl, caffeoyl aloesin, and related compounds, Yagi et al. found that the involvement of the caffeoyl, feruloyl, and coumaroyl groups bound to aloesin was well established, and the contact hypersensitivity response suggested that aloesin prevented UVB-induced immune suppression. In addition, they noted that aloesin inhibited the tyrosine hydroxylase and DOPA oxidase activities of tyrosinase in normal human melanocyte cell lysates.[xiv]


 


Importantly, the Ames test has not shown any genotoxicity or mutagenicity to be associated with aloesin and cell-based assays have revealed no cytotoxicity linked to the Aloe derivative.[xv]


 


Conclusion


Aloesin is a less effective but safe alternative to the use of hydroquinone in the treatment of unwanted hyperpigmentations. Used in combination with other skin-lightening agents, aloesin contributes to treatments that rival hydroquinone in effectiveness. Recent research appears to indicate that greater potential for aloesin as a hypopigmenting ingredient is yet to be realized. Of course, much more research is necessary to determine whether aloesin has a larger and more independent role to play in cosmetic and therapeutic hypopigmentation regimens. At this juncture, this botanical derivative is a u




[i] Zhu W, Gao J. The use of botanical extracts as topical skin-lightening agents for the improvement of skin pigmentation disorders. J Investig Dermatol Symp Proc. 2008 Apr;13(1):20-4.


[ii] Jones K, Hughes J, Hong M, Jia Q, Orndorff S. Modulation of melanogenesis by aloesin: a competitive inhibitor of tyrosinase. Pigment Cell Res. 2002 Oct;15(5):335-40.


[iii] Picardo M, Carrera M. New and experimental treatments of cloasma and other hypermelanoses. Dermatol Clin. 2007 Jul;25(3):353-62.


[iv] Piao LZ, Park HR, Park YK, Lee SK, Park JH, Park MK. Mushroom tyrosinase inhibition activity of some chromones. Chem Pharm Bull (Tokyo). 2002 Mar;50(3):309-11.


[v] Solano F, Briganti S, Picardo M, Ghanem G. Hypopigmenting agents: an updated review on biological, chemical and clinical aspects. Pigment Cell Res. 2006 Dec;19(6):550-71.


[vi] Draelos ZD. Skin lightening preparations and the hydroquinone controversy. Dermatol Ther. 2007 Sep-Oct;20(5):308-13.


[vii] Solano F, Briganti S, Picardo M, Ghanem G. Hypopigmenting agents: an updated review on biological, chemical and clinical aspects. Pigment Cell Res. 2006 Dec;19(6):550-71.


[viii] Solano F, Briganti S, Picardo M, Ghanem G. Hypopigmenting agents: an updated review on biological, chemical and clinical aspects. Pigment Cell Res. 2006 Dec;19(6):550-71.


[ix] Jin YH, Lee SJ, Chung MH, Park JH, Park YI, Cho TH, Lee SK. Aloesin and arbutin inhibit tyrosinase activity in a synergistic manner via a different action mechanism. Arch Pharm Res. 1999 Jun;22(3):232-6.


[x] Choi S, Lee SK, Kim JE, Chung MH, Park YI. Aloesin inhibits hyperpigmentation induced by UV radiation. Clin Exp Dermatol. 2002 Sep;27(6):513-5.


[xi] Yang ZQ, Wang ZH, Tu JB, Li P, Hu XY. The effects of aloesin and arbutin on cultured melanocytes in a synergetic method. Zhonghua Zheng Xing Wai Ke Za Zhi. 2004 Sep;20(5):369-71.


[xii] Wang Z, Li X, Yang Z, He X, Tu J, Zhang T. Effects of aloesin on melanogenesis in pigmented skin equivalents. Int J Cosmet Sci. 2008 Apr;30(2):121-30.


[xiii] Jones K, Hughes J, Hong M, Jia Q, Orndorff S. Modulation of melanogenesis by aloesin: a competitive inhibitor of tyrosinase. Pigment Cell Res. 2002 Oct;15(5):335-40.


[xiv] Yagi A, Takeo S. Anti-inflammatory constituents, aloesin and aloemannan in Aloe species and effects of tanshinon VI in Salvia miltiorrhiza on heart. Yakugaku Zasshi. 2003 Jul;123(7):517-32.


[xv] Picardo M, Carrera M. New and experimental treatments of cloasma and other hypermelanoses. Dermatol Clin. 2007 Jul;25(3):353-62.



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