|Figure 1. Inhibition of human tyrosinase by 4-butylresorcinol, kojic acid, arbutin and hydroquinone. The L-DOPA oxidase activity of tyrosinase was determined at various concentrations of the inhibitors to allow for the calculation of IC50 values. Data represent the mean of three independent experiments.||Figure 3. Age spot lightening by 4-butylresorcinol, 4-hexylresorcinol and 4-phenylethylresorcinol. The spots were treated twice daily for 12 weeks with a formula containing the respective inhibitor. Efficacy was evaluated after 4, 8 and 12 weeks. Data represent the mean of 14 subjects. *P < 0.05: statistically significant vs. the untreated control age spots.|
|resorcinol (Fig. 3). Within 8 weeks, 4-butylresorcinol significantly reduced the appearance of age spots while 4-hexylresorcinol or 4-phenylethylresorcinol showed significant effects after 12 weeks (all in comparison to vehicle). Epi-Flash photographs revealed visible improvement in the appearance of age spots after 12 weeks of treatment with 4-butylresorcinol. Control age spots remained unchanged (not shown).
In a second study, subjects applied 1% 4-butylresorcinol to age spots of the volar forearm using a spot applicator. Control age spots were treated with a spot applicator containing the vehicle. Already after 4 weeks of treatment, the treated spots were lighter than the control spots. Improvement continued over the entire treatment period, and after 16 weeks some of the spots were undistinguishable from the surrounding skin (Fig. 4). After treatment, the age spots were monitored for several weeks. Even after 4 weeks without treatment, the age spots previously treated with 4-butylresorcinol were still significantly lighter than the vehicletreated spots.
|Figure 2. Inhibition of melanin production in MelanoDermskin models by 4-butylresorcinol, kojic acid, arbutin and hydroquinone. Melanin content of skin models was determined after 13 days of cultivation in the presence of various inhibitor concentrations. Data represent the mean of five independent experiments.|
|comparison of the dose–response curves of hydroquinone and 4-butylresorcinol reveals that at concentrations above 20 lmol ⁄ L, 4-butylresorcinol is slightly more effective than hydroquinone, at concentrations below 20 lmol ⁄ L hydroquinone is slightly more effective than 4-butylresorcinol.||Discussion
Inhibition of tyrosinase activity is the most effective way to reduce hyperpigmentation. However, most topical products with tyrosinase inhibitors lack clinical efficacy. This is no surprise, as most screenings for inhibitors have been performed with the only commercially available enzyme, tyrosinase from the mushroom Agaricus bisporus.9,10 This is mainly due to considerable difficulties to extract sufficient amounts of human tyrosinase from biological
sources. In fact, many substances described as inhibitors of tyrosinase were only tested on mushroom tyrosinase and are, thus, very
Elderly subjects treated age spots twice daily either with a formula
containing 4-butylresorcinol, 4-hexylresorcinol or 4-phenylethyl
Figure 4. Clinical Study – monitoring of a treated age spot during treatment with a spot applicator. Photographs of age spots were taken at baseline and after 8, 12 and 16 weeks of treatment. The arrows mark the treated age spot. For comparison, untreated spots were included in the photographed area.
cule raised their concern, and consequently the SCCP regards the use of arbutin in cosmetic products as unsafe.18 The published tyrosinase IC50 values for kojic acid vary between less than 20 lmol ⁄ L19 up to more than 100 lmol ⁄ L.20 On human tyrosinase, kojic acid is less effective with an IC50 of about 500 lmol ⁄ L. On MelanoDerms, kojic acid shows a surprisingly steep dose–response curve, from more than 75% inhibition at 900 lmol ⁄ L down to 5% at 150 lmol ⁄ L. This might explain, in part, the very limited efficacy of kojic acid in vivo. Concerning the safety of kojic acid, the European Scientific Committee on Consumer Safety21 now considers kojic acid in concentrations up to 1.0% safe for cosmetic products when applied to healthy skin, this view is shared by the Cosmetic Ingredient Review Expert Panel. The 4-substituted resorcinol motif has been known for a long time as a very powerful chemical moiety for the inhibition of human tyrosinase. Many natural compounds, mainly flavonoids, known as whitening ingredient contain this resorcinol motif.19,24 Unfortunately, the bioavailability of flavonoids is generally very low, and we therefore searched for smaller resorcinols with high effectiveness and good bioavailability. Among these resorcinol derivatives, 4-butylresorcinol has been characterized as a strong tyrosinase25 and TRP-126 inhibitor. We measured an IC50 in the human tyrosinase assay of 21 lmol ⁄ L for 4-butylresorcinol compared with 94 and 131 lmol ⁄ L for 4-hexylresorcinol and 4-phenylethylresorcinol respectively. Also on skin models, 4-butylresorcinol was most effective of all tested substances with an IC50 of 13.5 lmol ⁄ L. Therefore, 4-butylresorcinol was for several clinical studies to prove in vivo efficacy. In comparison with 4- hexylresorcinol and 4-phenylethylresorcinol, 4-butylresorcinol treated age spots showed a faster onset of improvement and also a higher degree of lightening after 12 weeks of treatment. A study with a spot applicator showed continuous improvement over the entire treatment period and even after ceasing treatment, the age spots remained for 4 weeks significantly lighter than control spots. Even 13 weeks later, some of the spots still showed some improvement. Based on these results, a skin care line was developed and
tested under dermatological supervision on Asian women with pigmentary disorders like melasma, age spots or postinflammatory hyperpigmentation.27 The results of the studies demonstrate a significant pigment-reducing efficacy of the test products and a clear clinical benefit of the tested product line in the management of facial hyperpigmentation.
In conclusion, the present data show that 4-butylresorcinol is a powerful human tyrosinase inhibitor with remarkable in vivo effectiveness. Topical products containing 4-butylresorcinol show strong efficacy on age spots, melasma28 and other facial hyperpigmentation.
|effective inhibitors of mushroom tyrosinase, but rather poor inhibitors of human tyrosinase. The objective of this study, there fore, was to compare the inhibitory capacity of arbutin, hydroqui none, kojic acid and 4-butylresorcinol on melanin production using human in vitro test systems and to select the best active ingredient for further in vivo studies. All four substances are known as tyrosinase inhibitors,11 however, the published range of inhibitory activity is extremely broad and divergent. In the medical literature, hydroquinone is considered the gold standard for the treatment of hyperpigmentation. However, there are severe concerns regarding the safety of hydroquinone. Banned in the EU from the use in cosmetics, it is still sold in the USA as over-the-counter drug in formulations with up to 2% hydroquinone. Recently, the FDA also expressed concerns12; however, a fifinal ruling is still pending. The published IC50 values for hydroquinone in the mushroom tyrosinase inhibition cover a wide range from 1.113 to 680 lmol ⁄ L.14 In our human assay, hydroquinone was remarkably ineffective and only marginally inhibited human tyrosinase, barely reaching 50% inhibition at 4400 lmol ⁄ L. Since Palumbo published his results in 199115 hydroquinone is considered a tyrosinase inhibitor; however, the cytotoxic effects seem to be more important for the effificacy of the molecule,2 not only for the adverse effects. This view is substantiated by our results with the MelanoDerm skin models. Here, hydroquinone (IC50 < 40 lmol ⁄ L) is almost as effective as the potent tyrosinase inhibitor 4-butylresorcinol.
Although arbutin is considered a potent tyrosinase inhibitor, the published IC50 values for mushroom tyrosinase range from 40 lmol ⁄ L16 to more than 30,000 lmol ⁄ L.17 On human tyrosinase, we found an IC50 in the millimolar range ( 6500 lmol ⁄ L), and also on MelanoDerm models we measured an IC50 in the same range (>5000 lmol ⁄ L). According to the literature, alphaarbutin seems to be slightly more effective than beta-arbutin, but both are hydroquinone prodrugs and the activity depends on the release of hydroquinone from the molecule.2 The European Union Scientifific Committee on Consumer Products published a critical opinion on arbutin. The release of hydroquinone from the mole
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