Is the whitening mechanism of alpha-arbutin not due to direct inhibition of tyrosinase synthesis?

Despite strict regulations and public health campaigns against their use, their use remains widespread across the globe. This can be attributed to the misleading marketing of harmful skin bleaches, which are widely available in the name of skin lighteners, skin toners, or creams to remove dark spots. In the search for safer alternatives to hydroquinone and other harmful skin lightening agents, extensive research eventually led to the discovery of alpha-arbutin. It acts by inhibiting tyrosinase activity and melanosome maturation. It is currently one of the most popular skin lightening ingredients in the world and has been used to treat many pigmentation disorders. Alpha-arbutin has wide applicability in the cosmetic and pharmaceutical industries and has a high market value. In this paper, the physicochemical properties, safety, mechanism of action, the latest research progress of α-arbutin skin brightening, various combination therapy methods and the current market status of α-arbutin were reviewed. This literature review suggests the future scope of alpha-arbutin as a safer alternative to other harmful skin lighteners.

Alpha arbutin

Arbutin is a natural skin lightener, alpha-arbutin acts as a safer alternative to other harmful skin lighteners. This article introduces in detail. Arbutin is found in many plant families, such as marjoram, cranberries, blueberries, and several types of pears. Arbutin effectively reduces melanin production by inhibiting tyrosinase. There are two isoforms of arbutin, alpha arbutin (4-hydroxyphenyl-α-D-glucoside) and beta arbutin (4-hydroxyphenyl-β-diglucoside). Alpha and β-arbutin have different rotational configurations, but the same formula structure (Couteau et al., 2016). Beta-arbutin is generally extracted from the leaves and peels of various plants. However, alpha-arbutin is not naturally occurring and can be synthesized by microbial enzymes or microbial biosynthesis. Interestingly, alpha-arbutin is more effective than natural arbutin in inhibiting tyrosinase activity (Garcia-Jimenez et al., 2017). At the active site of tyrosinase, the α-glucoside bond exhibits stronger affinity than the β-glucoside bond. The 50% inhibitory concentration (ic50) of α-arbutin for human tyrosinase was 2.0 mM, while the 50% inhibitory concentration (IC50) for natural arbutin was greater than 30 mM. The inhibitory effect of α-arbutin on melanin biosynthesis was studied in cultured melanoma cells and human skin models, and the results showed that α-arbutin could effectively inhibit melanin synthesis without cytotoxicity (Sugimoto et al., 2004). α-arbutin can inhibit mouse melanoma tyrosinase, and its inhibitory effect is 10 times stronger than β-arbutin. α-arbutin does not inhibit the growth of HMV-II cultured human melanoma cells, but can effectively inhibit the synthesis of melanin, suggesting that α-arbutin is effective and safe in the treatment of hyperpigmenemia. Due to its molecular structure, alpha arbutin acts similarly to hydroquinone, but with less irritation and melanocytic toxicity. It also does not cause exogenous aging and is less likely to cause irritation and sensitization, making it a more tolerable alternative to hydroquinone. This protects the skin from sunlight-induced pigmentation and free radicals without increasing the skin’s sensitivity to sun exposure. It lightens skin tone by diluting discoloration caused by inflammation and environmental stress. It also solves the problems of glycosylation, skin yellowing and loss of elasticity caused by sugar. Commercially, alpha-arbutin is synthesized using an enzyme that catalyzes the selective transglycosylation of alpha-heteroheads between a glucose-based donor and hydroquinone as a receptor. In addition to enzymatic biosynthesis, hydroquinone can also synthesize α-arbutin with the help of some microorganisms (Kitao et al., 1994). In this review, we present a new view of alpha-arbutin as a safer alternative to other harmful skin lighteners.

Cellular and molecular mechanisms of alpha arbutin

Tyrosinase is a mixed functional enzyme containing copper. It is widely distributed in nature, including animals, plants, fungi and microorganisms. It helps in the production of melanin, which causes skin pigmentation and protects the skin from skin damage caused by ultraviolet light. Tyrosinase has been reported to catalyze two reactions. First, it triggers the o-hydroxylation of monophenols (tyrosine), converting them to o-diphenol (LDOPA)(monophenolase activity). Secondly, it catalyzes the oxidation of o-diphenol, converting it into o-quinone (diphenol enzyme activity). Tyrosinase plays an important role in the production of melanin. Melanin protects the skin from skin damage caused by ultraviolet light and is responsible for the formation of skin color. However, pigmentation disorders (melasma, freckles, etc.) can cause serious aesthetic problems for humans. α-arbutin is synthesized by enzymatic glycosylation of hydroquinone. It directly inhibits melanosomal tyrosinase activity or competes with tyrosinase as a substrate for active sites, thereby causing skin brightening. The action mechanism of α-arbutin is shown in Figure 3. Qin et al., 2014 studied the mechanism of α-arbutin by investigating the effects of mushroom tyrosinase on the activities of monophenolase and diphenolase. α-arbutin has dual effects on monophenolase and diphenolase activity of mushroom tyrosinase. Alpha-arbutin inhibits the homeostasis reduction of enzyme activity during the monophenolase reaction (suicide inactivation of the active site of tyrosinase). In addition, a characteristic lag period was observed during the oxidation of tyrosine during monophenolase activity. The lag time increased dose-dependent with the increase of α-arbutin concentration. However, in the diphenolase reaction, α-arbutin acts as an activator due to the interaction between α-arbutin and the entry residue of the active site. Here, no lag period was observed during the oxidation of LDopa. In addition, it reduces the impact of suicide inactivation. Based on the above findings, Garcia-Jimenez et al., 2017 conducted an experiment to further understand the mechanism of alpha-arbutin. The authors report that α-arbutin cannot completely inhibit tyrosinase and propose α-arbutin as an alternative competing substrate for tyrosinase, as tyrosinase is able to hydroxylate it, rather than acting as an inhibitor. In another study, the inhibitory effect of alpha-arbutin on melanin biosynthesis in cultured human melanoma cells and in 3D(three-dimensional) human skin models was investigated. We report the concentration-dependent inhibition of alpha-arbutin on melanin synthesis in human melanoma cells HMV-II. α-arbutin inhibited melanin formation at non-cytotoxic concentrations. The authors conclude that α-arbutin directly inhibits melanosomal tyrosinase activity, rather than inhibiting tyrosinase gene expression or cell growth. An alternative mechanism is proposed: the inhibition of α-arbutin on tyrosinase activity may be due to its influence at the post-translational level.

Progress of alpha-arbutin delivery to the skin

Alpha-arbutin is one of the most widely used skin lighteners and is less toxic than hydroquinone. Alpha-arbutin is intrinsically hydrophilic, with a logarithmic P value of − 1.49, and is therefore less permeable throughout the skin. Because the stratum corneum more repels hydrophobic substances, hydrophilic alpha-arbutin has difficulty crossing the skin to reach melanocytes. Due to the advantages of alpha-arbutin compared with other harmful skin lighteners, there is an urgent need to develop various novel delivery systems, such as microneedle systems, nanosystems, Microsystems, lipid systems, etc., to improve the penetration and penetration ability of alpha-arbutin in the skin.

α-arbutin has the advantages of safety, high efficiency and whitening, and has a great prospect. At present, the main technical difficulty is how to develop a better delivery system to improve the penetration and penetration of alpha-arbutin in the skin.

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