Review Article THE RECENT UPDATE OF DEOXYARBUTIN: A SKIN DEPIGMENTATION AGENT WITH TYROSINASE INHIBITION TARGETING MUCHTARIDI MUCHTARIDI 1* , MENTARI LUTHFIKA DEWI 1 1 Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Jl, Universitas Padjadjaran, Jl KM 21.5 Bandung Sumedang, Jatinangor, 45363, West Java Email: muchtaridi@unpad.ac.id Received: 28 Jan 2020, Revised and Accepted: 29 Feb 2020 ABSTRACT Melanin is produced through the process of melanogenesis, which serves to protect the skin from the damaging effects of UV radiation. Abnormal accumulation of melanin will aesthetically disturb even interfere with health. One of the clinical manifestations of abnormal accumulation of melanin is the incidence of melasma. Some of the tyrosinase enzyme inhibitor agents most widely used as Hydroquinone, Kojic acid and Arbutin do not give satisfactory results and cause serious side effects. Hydroquinone is known to cause ochronosis exogenous and cytotoxic. Kojic acid is known to cause allergies and mutagenic, while arbutinisis is known to have cytotoxic properties lower than hydroquinone, but less satisfactory depigmentation activity. There was a compound that has been synthesized by removing the hydroxy group of arbutin, known as deoxyarbutin (4- [Tetrahydro-2H-Pyrans-2-yl) oxy] phenol). Deoxyarbutin (dA) shows Ki 10-fold is lower than hydroquinone and 350-fold is lower than arbutin. IC50dA is 17.5+0.5 µmol/l, while the IC50 hydroquinone is 73.7+9.1 µmol/l. In terms of security, dA indicates that cell viability is 95% higher than hydroquinone. However, dA is thermolabile and photolabile. Several studies have shown satisfactory results to improve the stability of dA, that these compounds are considerable potential for further development as a depigmentation agent. The aim of this review is to describe how the potency of dA as a tyrosinase inhibitor interferes melanogenesis process through the latest depigmentation agent, its safety, efficacy and stability. Keywords: Melanin, Deoxyarbutin, Tyrosinase inhibitor, Skin depigmenting agent © 2020 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) DOI: http://dx.doi.org/10.22159/ijap.2020v12i3.36957. Journal homepage: https://innovareacademics.in/journals/index.php/ijap INTRODUCTION Melanin is a biopolymer synthesized by the melanocyte cells in the cell organelles called melanosomes in epidermal layers of the skin [1-3]. Mature melanosomes are then transferred via intermediary dendrites into ceratine, resulting in the dark-colored coating on the corneum layer of skin epidermis [4-7]. Naturally, melanin serves as a photoprotective agent that protects DNA from damage due to UV radiation [8-10]. Melanin synthesized process is a combination of enzymatic catalysis and chemical reactions with tyrosinase [11-14] as the major enzyme. Moreover, tyrosinase can cause enzymatic browning in raw fruits, vegetables, and beverages. This enzyme plays a critical role in changing substrates in the form of L-tyrosine into L-dihydroxyphenylalanine (L-DOPA) via hydroxylation reaction, and the change of L-DOPA becomes dopaquinone through oxidation [15, 16]. This quinone compound is highly reactive and can polymerize spontaneously that at the end of the reaction it forms the melanin compounds. The formation of melanin is responsible for skin pigmentation condition that would interfere with the aesthetics of human [17-19]. Moreover, hyperpigmentation is caused by the accumulation of excess melanin production. It can cause quite serious skin problems, such as melasma, post-inflammatory melanoderma, solar lentigo, ochronosis exogenous, and dermatosis papu-losanigra [20-23]. Inhibition of the enzymatic activity of tyrosinase, both competitive and non- competitive, is widely used as a key strategy in the development of depigmentation agent, either as cosmetics or the treatment of hyperpigmentation problems [24-27]. Some of the most used tyrosinase enzyme inhibitor agents are hydroquinone [11, 28, 29], kojic acid [30-33], and arbutin [34-38]. Hydroquinone is a tyrosinase inhibitor agent that has been used for a long time and become the gold standard in the treatment of hyperpigmentation in the USA [39, 40]. However, the use of hydroquinone in cosmetic preparations has been banned by FDA, and only allowed for the use of physician prescription. The FDA requested the use of hydroquinone is not exceeded more than 1.5– 2.0% in skin cosmetics product. This is due to the effect that hydroquinone can cause ochronosis exogenous and cytotoxic in the presence of reactive metabolites, such as, hydroxyl benzoquinone and p-benzoquinone [41-45]. Natural product that contains stilbenes, uses tyrosinase inhibitors as skin whitening agents [46]. Sapindus mukorossi that grows in tropical and sub-tropical regions of Asia has weak bioactivity against tyronase with IC50 values of 17.8% and 12.3% at 10 μg/ml [47]. Curcumin-Mn and Zn has a potent as anti-tyrosinase capacity as a depigmentation agent [48] that can be studied further. In the previous study, Celastrus paniculatus seed oil exhibited superior tyrosinase inhibition activity than the standard ascorbic acid, kojic acid and arbutin [49]. Senol et al. found natural anti- tyronase from the aerial parts of 33 Turkish Scutellaria species. However, the plant’s activity is moderate, ranged from 39.57% to 51.58% inhibition [50]. The plants from common tropical plant species in the Indian subcontinent and Southeast Asia have been observed as a skin whitening treatment, and it has sub-nano molar activity. However, the IC50 is 60 times higher than kojic acid [51]. Tyrosinase inhibitory activity also is shown by the enzymatic hydrolysates of the collagen that obtained from the skin of squid (Todarodespacificus) [52]. Hydroquinone has very effective to inhibit melanogenesis thus can be used as a depigmentation agent. However, metabolite results from oxidation of hydroquinone by tryrosinase cause seriously adverse effects. DNA is damaged by hydroquinone as showed in studies against rodent models [53]. Furthermore, hydroquinone is banned in European Union, US FDA, and also in Indonesia for the cosmetic active ingredient. Some derivatives of hydroquinone has become much better than hydroquinone due to the decreasing its cytotoxycity, such us arbutin derivatives [54]. Kojic acid is an effective tyrosinase inhibitor agent both in vitro and in vivo [55-58]. However, these compounds have been banned in Japan for causing allergies and mutagenic [59]. Arbutin has been traditionally used by Japanese people to treat skin pigmentation disorders [60]. It is known to be an effective agent to address skin hyperpigmentation disorders. Its cytotoxic properties against melanocyte cells are lower than I In nt te e r rn na a t ti io o n na al l J Jo ou u r rn na a l l o of f A Ap pp p l li ie e d d P Ph h a ar rm m a ac ce e u u t ti ic cs s ISSN- 0975-7058 Vol 12, Issue 3, 2020