Alpha Arbutin

What is Alpha-Arbutin?

Alpha-Arbutin is a glycosylated hydroquinone that was first discovered in bearberry (Arctostapylos uva-ursi) and then in the leaves of lingonberry, Chinese pear, creeping saxifrage, strawberry tree, marjoram, evergreen. It is a phenolic secondary metabolite produced by plants as a response against infectious disease and environmental stress.¹ It is a well studied active that has the following benefits:

• helps brighten Acne marks, Sun Spots and other pigmentation
• supports other anti-aging actives²
• Acts as a minor antioxidant³

How does alpha-Arbutin (α-AB) regulate pigmentation?

Skin pigmentation is produced through a process that is mainly regulated by an enzyme called Tyrosinase. Tyrosinase converts L-tyrosine to L-dopaquinone⁴, which is converted to a series of products until it finally becomes Eumelanin (brown or black pigment you see in the skin). Alpha-Arbutin works by acting as an alternative substrate for Tyrosinase, diverting the enzyme from catalyzing melanin production.

It is structurally similar to Hydroquinone (HQ), an effective anti-hyperpigmentation active that can cause irritation and exogenous ochronosis.⁵ When Tyrosinase is uncoupled by inhibitors such as HQ, it produces H2O2, which is thought to be the cause of adverse effects in using HQ.⁶ In alpha-arbutin, a sugar molecule is attached to Hydroquinone, and this confers tolerability and increased stability to the molecule. In various skin models, it has been shown that α-AB does not hydrolyze to HQ.⁷ Skin models are sterile skin equivalents that are excellent representations of the skin; however, they do not account for the processes that our microbiome does to actives that are applied to the skin. In this case, it has been noted that Staphylococcus aureus and Staphylococcus epidermidis hydrolyze arbutin to Hydroquinone, possibly accounting for the increased effect of arbutin in clinical trials compared to in-vitro results.⁸

α-AB has also been tested in various preliminary screening methods through purified tyrosinases, yielding good results. Studies that used cell-based tyrosinases are more reliable than those performed using cell-free and mushroom tyrosinases.^9,10 In various cell-cultures, α-AB was shown to inhibit the catalytic conversion of L-tyrosine to L-Dopaquinone and prevent the oxidation of L-DOPA to L-DOPAquinone.^{11,12,13,14,15}

In addition to tyrosinase inhibition, AB also inhibited 5,6-dihydroxyindole-2-carboxylic acid (DHICA) polymerase activity (pmel 17/silver protein), which is one of the downstream enzymes in producing melanin.¹⁶

In the same study, it was proposed that it is possible that AB may also inhibit L-tyrosine uptake by cells as well as compete with tyrosine at the active site of Tyrosinase. Most of these studies argue that inhibition of Tyrosinase is due to post-translational modification. Another interesting study, however, conducted an experiment using differentiating melanocytes compared to differentiated melanocytes.¹⁷ The results show that HQ downregulated the early stage of melanocyte differentiation (in which neural crest cells were generated) and the late stage of differentiation (in which melanogenesis became active). On the other hand, AB had no effect on the differentiation of melanocytes, but surprisingly, it markedly suppressed the expression of Tyr gene. This means that, contrary to previous studies, AB affects the transcription of tyrosine gene, in addition to the competitive inhibitory effect on Tyrosinase in differentiating melanocytes. For this reason, it is not a surprise that both AB and HQ had the same melanin content on the cultures. It should be noted that Arbutin at higher concentrations can potentially cause paradoxical hyperpigmentation.¹⁸ In one experiment, higher concentrations of AB caused an increase in pigmentation by augmenting melanogenic mechanisms other than Tyrosinase.¹⁹ However, this study was only done in 3 days as opposed to weeks.

How does AB help in anti-aging?

AB was found to increase cell viability in cultured cells, and it was also able to suppress Lactate Dehydrogenase (LDH) release as a result of exposure to UV. It is also shown to downregulate catalase and MMP-2, which are some of the key enzymes in the degradation of the Extracellular Matrix (ECM).²⁰ Collagen degradation, as part of ECM degradation, leads to the visible appearance of fine lines and wrinkles.

AB was also shown to protect cells from radiation-induced apoptosis by decreasing intracellular hydroxyl radical production, as evidenced by the significant dissipation of MMP after 24 hours of treatment.²¹ How well this translates clinically is still up for debate, and there are far superior actives that decrease MMP and prevent ECM degradation.

Does it penetrate the skin?

Multiple studies using skin models show that α-AB has good penetration, and was able to inhibit melanogenesis and decrease melanin production.^22,23,24

What are the results of studies done?

These studies show that although HQ is superior to AB, AB is significantly less cytotoxic than HQ.   

What’s Regimen’s take on alpha-Arbutin?

We think that AB is an excellent supplementary ingredient in anti-pigmentation serums. Alone in a product, it might not have enough Tyrosinase inhibiting ability to decrease pigmentation, especially in skins with a darker color. Look for products that have combination active ingredients to maximize the regulation of pigmentation.

There are several considerations that you have to pay attention to regarding AB, as it was shown in a 2015 study that over 55% of cosmetics from the US are dishonest about labeling products containing AB. Some of these products are labeled with AB, without having AB in them. Some had significantly lower AB content, and some use beta-arbutin. Beta-Arbutin is an isomeric counterpart of alpha-arbutin; however, it is far less stable compared to the alpha isomer.²⁸ Another form of AB (deoxy-Arbutin) was shown to be more effective than α-AB, but it is too unstable to be commercially viable and was undetectable in the formulation after 48 hours.^29,30 Since AB favors neutral solutions, look for products that are within a pH of 6-7 to minimize AB degradation. Since AB is a phenolic compound, it is best to find products that also contain chelating agents such as EDTA to prevent the formation of ion-arbutin complexes.

References:

1. Jurica, K., Karačonji, I. B., Šegan, S., Opsenica, D. M., & Kremer, D. (2015). Quantitative analysis of arbutin and hydroquinone in strawberry tree (Arbutus unedo L., Ericaceae) leaves by gas chromatography-mass spectrometry/Kvantitativna analiza arbutina i hidrokinona u listovima obične planike (Arbutus unedo L., Ericaceae) plinskokromatografskom metodom uz detekciju masenim spektrometrom. Archives of Industrial Hygiene and Toxicology, 66(3), 197–202. ↩︎
2. Chen, K.-C., Chang, H.-H., Ko, W.-S., Wu, C.-L., Chiu, W.-T., Hsieh, C.-L., & Peng, R. Y. (2009). UV-induced damages eliminated by arbutin and ursolic acid in cell model of human dermal fibroblast WS-1 cells. Egyptian Dermatology Online Journal, 5(1), 1. ↩︎
3. Jiang, L., Wang, D., Zhang, Y., Li, J., Wu, Z., Wang, Z., & Wang, D. (2018). Investigation of the pro-apoptotic effects of arbutin and its acetylated derivative on murine melanoma cells. International Journal of Molecular Medicine, 41(2), 1048–1054. ↩︎
4. Hearing, V. J. (2011). Determination of melanin synthetic pathways. The Journal of Investigative Dermatology, 131(E1), E8–E11. ↩︎
5. Hu, Z.-M., Zhou, Q., Lei, T.-C., Ding, S.-F., & Xu, S.-Z. (2009). Effects of hydroquinone and its glucoside derivatives on melanogenesis and antioxidation: Biosafety as skin whitening agents. Journal of Dermatological Science, 55(3), 179–184. ↩︎
6. Boissy, R. E., Visscher, M., & DeLong, M. A. (2005). DeoxyArbutin: a novel reversible tyrosinase inhibitor with effective in vivo skin lightening potency. Experimental Dermatology, 14(8), 601–608.↩︎
7. Sugimoto, K., Nishimura, T., & Kuriki, T. (2007). Development of alpha-arbutin: production at industrial scale and application for a skin-lightening cosmetic ingredient. Trends in Glycoscience and Glycotechnology: TIGG, 19(110), 235. ↩︎
8. Bang, S.-H., Han, S.-J., & Kim, D.-H. (2008). Hydrolysis of arbutin to hydroquinone by human skin bacteria and its effect on antioxidant activity. Journal of Cosmetic Dermatology, 7(3), 189–193. ↩︎
9. Maeda, K., & Fukuda, M. (1996). Arbutin: mechanism of its depigmenting action in human melanocyte culture. The Journal of Pharmacology and Experimental Therapeutics, 276(2), 765–769.↩︎
10. Mann, T., Gerwat, W., Batzer, J., Eggers, K., Scherner, C., Wenck, H., Stäb, F., Hearing, V. J., Röhm, K.-H., & Kolbe, L. (2018). Inhibition of Human Tyrosinase Requires Molecular Motifs Distinctively Different from Mushroom Tyrosinase. The Journal of Investigative Dermatology, 138(7), 1601–1608.↩︎
11. Maeda, K., & Fukuda, M. (1996). Arbutin: mechanism of its depigmenting action in human melanocyte culture. The Journal of Pharmacology and Experimental Therapeutics, 276(2), 765–769.↩︎
12. Chakraborty, A. K., Funasaka, Y., Komoto, M., & Ichihashi, M. (1998). Effect of arbutin on melanogenic proteins in human melanocytes. Pigment Cell Research / Sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society, 11(4), 206–212. ↩︎
13. Lim, Y.-J., Lee, E. H., Kang, T. H., Ha, S. K., Oh, M. S., Kim, S. M., Yoon, T.-J., Kang, C., Park, J.-H., & Kim, S. Y. (2009). Inhibitory effects of arbutin on melanin biosynthesis of α-melanocyte stimulating hormone-induced hyperpigmentation in cultured brownish guinea pig skin tissues. Archives of Pharmacal Research, 32(3), 367–373. ↩︎
14. Sugimoto, K., Nishimura, T., & Kuriki, T. (2007). Development of alpha-arbutin: production at industrial scale and application for a skin-lightening cosmetic ingredient. Trends in Glycoscience and Glycotechnology: TIGG, 19(110), 235. ↩︎
15. Sugimoto, K., Nishimura, T., Nomura, K., Sugimoto, K., & Kuriki, T. (2004). Inhibitory Effects of α-Arbutin on Melanin Synthesis in Cultured Human Melanoma Cells and a Three-Dimensional Human Skin Model. Biological & Pharmaceutical Bulletin, 27(4), 510–514. ↩︎
16. Chakraborty, A. K., Funasaka, Y., Komoto, M., & Ichihashi, M. (1998). Effect of arbutin on melanogenic proteins in human melanocytes. Pigment Cell Research / Sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society, 11(4), 206–212. ↩︎
17. Inoue, Y., Hasegawa, S., Yamada, T., Date, Y., Mizutani, H., Nakata, S., Matsunaga, K., & Akamatsu, H. (2013). Analysis of the effects of hydroquinone and arbutin on the differentiation of melanocytes. Biological & Pharmaceutical Bulletin, 36(11), 1722–1730. ↩︎
18. Draelos, Z. D. (2007). Skin lightening preparations and the hydroquinone controversy. Dermatologic Therapy, 20(5), 308–313. ↩︎
19. Nakajima, M., Shinoda, I., Fukuwatari, Y., & Hayasawa, H. (1998). Arbutin increases the pigmentation of cultured human melanocytes through mechanisms other than the induction of tyrosinase activity. Pigment Cell Research / Sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society, 11(1), 12–17. ↩︎
20. Chen, K.-C., Chang, H.-H., Ko, W.-S., Wu, C.-L., Chiu, W.-T., Hsieh, C.-L., & Peng, R. Y. (2009). UV-induced damages eliminated by arbutin and ursolic acid in cell model of human dermal fibroblast WS-1 cells. Egyptian Dermatology Online Journal, 5(1), 1. ↩︎
21. Jiang, L., Wang, D., Zhang, Y., Li, J., Wu, Z., Wang, Z., & Wang, D. (2018). Investigation of the pro-apoptotic effects of arbutin and its acetylated derivative on murine melanoma cells. International Journal of Molecular Medicine, 41(2), 1048–1054. ↩︎
22. Lim, Y.-J., Lee, E. H., Kang, T. H., Ha, S. K., Oh, M. S., Kim, S. M., Yoon, T.-J., Kang, C., Park, J.-H., & Kim, S. Y. (2009). Inhibitory effects of arbutin on melanin biosynthesis of α-melanocyte stimulating hormone-induced hyperpigmentation in cultured brownish guinea pig skin tissues. Archives of Pharmacal Research, 32(3), 367–373. ↩︎
23. Sugimoto, K., Nishimura, T., & Kuriki, T. (2007). Development of alpha-arbutin: production at industrial scale and application for a skin-lightening cosmetic ingredient. Trends in Glycoscience and Glycotechnology: TIGG, 19(110), 235. ↩︎
24. Sugimoto, K., Nishimura, T., Nomura, K., Sugimoto, K., & Kuriki, T. (2004). Inhibitory Effects of α-Arbutin on Melanin Synthesis in Cultured Human Melanoma Cells and a Three-Dimensional Human Skin Model. Biological & Pharmaceutical Bulletin, 27(4), 510–514. ↩︎
25. Draelos, Z. D. (2007). Skin lightening preparations and the hydroquinone controversy. Dermatologic Therapy, 20(5), 308–313. ↩︎
26. Santoso, G. L., Anwar, A. I., Tabri, F., Djawad, K., Madjid, A., & Seweng, A. (2018). The Effectiveness of Combination Serum of Tranexamic Acid, Galactomyces Ferment Filtrate, Niacinamide And Alpha Arbutin in Enhancing Skin Brightness. Int J Med Rev Case Rep, 2, 169–173. ↩︎
27. Anwar, A. I., Wahab, S., Widita, W., Nurdin, A. R., Budhiani, S., & Seweng, A. (2019). Randomized control trial outcomes of tranexamic acid combination serum as a depigmenting agent for the use in healthy individuals. Dermatologic Therapy, 32(6), e13146. ↩︎
28. Avonto, C., Wang, Y.-H., Avula, B., Wang, M., Rua, D., & Khan, I. A. (2016). Comparative studies on the chemical and enzymatic stability of alpha-and beta-arbutin. International Journal of Cosmetic Science, 38(2), 187–193. ↩︎
29. Hu, Z.-M., Zhou, Q., Lei, T.-C., Ding, S.-F., & Xu, S.-Z. (2009). Effects of hydroquinone and its glucoside derivatives on melanogenesis and antioxidation: Biosafety as skin whitening agents. Journal of Dermatological Science, 55(3), 179–184. ↩︎
30. Boissy, R. E., Visscher, M., & DeLong, M. A. (2005). DeoxyArbutin: a novel reversible tyrosinase inhibitor with effective in vivo skin lightening potency. Experimental Dermatology, 14(8), 601–608.↩︎