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Effects of Rhododendrol and Its Metabolic Products on Melanocytic Cell Growth

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Effects of Rhododendrol and Its Metabolic Products on Melanocytic Cell Growth Journal of Dermatological Science 80 (2015) 142–149 Contents lists available at ScienceDirect Journal of Dermatological Science journal homepage: www.jdsjournal.com Effects of rhododendrol and its metabolic products on melanocytic cell growth Masae Okura a, Toshiharu Yamashita a,*, Yasue Ishii-Osai a, Momoko Yoshikawa a, Yasuyuki Sumikawa a, Kazumasa Wakamatsu b, Shosuke Ito b a Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan b Department of Chemistry, Fujita Health University School of Health Sciences, Toyoake 470-1192, Japan ARTICLE INFO ABSTRACT Article history: Background: Rhododendrol (RD), a skin-whitening agent, is believed to be associated with cases of Received 6 March 2015 cosmetics-related leukoderma that have been reported in Japan. Recently, we have shown that RD is Received in revised form 10 June 2015 catalyzed by tyrosinase to produce putative toxic metabolites RD-catechol and RD-cyclic catechol. Accepted 21 July 2015 Objective: To examine the cytotoxicity and production of reactive oxygen species (ROS) in melanocytic cells by RD and its metabolic products. Keywords: Methods: The growth inhibitory effect of RD or its metabolite on the normal human epidermal Rhododendrol melanocyte (NHEM) and B16F1 cells was assessed by cell counting or WST assay. ROS production was Leukoderma detected by flow cytometry and confocal microscopy after cells were treated with 20,70-dichloro- Tyrosinase Cytotoxicity fluorescein and RD or its metabolite. Reactive oxygen species Results: Growth of NHEM derived from African American (NHEMb) and B16F1 cells was suppressed by 300 mM or more RD. Growth inhibitory activity of RD (IC50 of B16F1: 671 mM) was weaker than hydroquinone (IC50 of B16F1: 28.3 mM) or resveratrol (IC50 of B16F1: 27.1 mM). Flow cytometric analysis detected ROS production in the NHEMb and B16F1 cells exposed to RD. However, neither RD nor H2O2 increased the subG1 fraction of these melanocytic cells. RD-catechol and RD-cyclic catechol inhibited growth of NHEMb and B16F1 cells much more strongly than did RD. RD-catechol, as well as RD, produced ROS detected by both flow cytometry and immunostaining, while RD-cyclic catechol produced a hardly detectable amount of ROS in B16F1 cells. Conclusions: These results suggest that RD exerts the cytotoxicity in melanocytic cells through its oxidative metabolites and that ROS plays a role in RD-mediated cytotoxicity. ß 2015 The Authors. Published by Elsevier Ireland Ltd. on behalf of Japanese Society for Investigative Dermatology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). 1. Introduction essential for the first step of melanin biosynthesis, the conversion of L-tyrosine to 3,4-dihydroxyphenylalanine (L-DOPA) and subse- Melanin pigment is produced in the melanocytes and trans- quent oxidation to dopaquinone [2]. Dopaquinone is a highly ferred to the surrounding epidermal keratinocytes to protect reactive intermediate and gives rise to eumelanin production with genomic DNA from ultraviolet light [1]. Overproduction and the participation of tyrosinase-related protein-1 (TYRP-1) and accumulation of melanin pigment in the epidermis and/or dermis TYRP-2 [3,4], while intervention of L-cysteine switches to causes cutaneous hyperpigmentation such as freckles, melasma, pheomelanin production [2,5]. Pheomelanin has been reported senile lentigines and acquired bilateral dermal melanocytosis. to be cytotoxic due to the production of reactive oxygen species Thus, the inhibition of melanogenesis has been the focus of medical (ROS) [6–8]. Thus, suppression of excess amounts of melanin and treatment and cosmetics especially on the sun-exposed areas. suppression of intracellular ROS is necessary biochemical abilities Melanogenesis is regulated by the key enzyme, tyrosinase, which is of safe and ideal skin-whitening agent. More than ten kinds of skin-whitening compounds have been produced and used as cosmetic ingredients. These quasi-drugs Abbreviations: RD, rhododendrol; NHEM, normal human epidermal melanocytes; prevent or improve hyperpigmentation by inhibiting tyrosinase ROS, reactive oxygen species; DOPA, dihydroxyphenylalanine. activity (ascorbic acid, kojic acid, arbutin and ellagic acid) or * Corresponding author at: Department of Dermatology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo 060-8543, Japan. decreasing tyrosinase protein (linoleic acid) [9]. They have been E-mail address: [email protected] (T. Yamashita). used as cosmetic ingredients without causing the prominent http://dx.doi.org/10.1016/j.jdermsci.2015.07.010 0923-1811/ß 2015 The Authors. Published by Elsevier Ireland Ltd. on behalf of Japanese Society for Investigative Dermatology. This is an open access article under the CC BY- NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). M. Okura et al. / Journal of Dermatological Science 80 (2015) 142–149 143 leukoderma on the application sites. The 4-tertiary-butylphenol (4- reported that RD was incorporated into the tyrosinase-dependent TBP) is known to be the most potent phenolic derivative causing biochemical pathway and produced RD-catechol and RD-cyclic occupational leukoderma [10–12] by inducing apoptosis in catechol in addition to the corresponding ortho-quinones melanocytes [13]. Monobenzyl ether of hydroquinone (MBEH) is [19,20]. Moreover, RD-quinone was bound to non-protein thiols the only drug that the Food and Drug Administration has approved and proteins in B16F1 cells through cysteinyl residues [21]. for depigmentation therapy in the United States. Unlike 4-TBP, In order to elucidate further the molecular mechanism of MBEH induces necrotic cell death in melanocytes without cytotoxicity of RD in melanocytic cells, we have analyzed the activating the caspase cascade or DNA fragmentation [14]. effects of RD and its metabolic products RD-catechol and RD-cyclic RS-4-(4-hydroxyphenyl)-2-butanol (rhododendrol or rhodode- catechol on the growth of melanocytic cells and ROS production in nol, RD) had been used since 2011 as a skin-whitening agent of them. RD-catechol and RD-cyclic catechol showed cytotoxicity cosmetics produced and sold by Kanebo, a cosmetics company in much stronger than RD and RD-catechol as well as RD generated Tokyo, Japan. In July 2013, the cosmetics containing RD were ROS in B16F1 cells. The results obtained suggest that RD exerts its recalled by the company because approximately 2% of users cytotoxic effect through its metabolic products and that the ROS developed depigmentation on their face, neck and/or hands. The production is related to RD-associated cytotoxicity. Special Committee on the Safety of Cosmetics Containing Rhododenol, established by the Japanese Dermatological Associa- 2. Materials and methods tion on July 17, 2013, labeled this cosmetics-associated depig- mentation as RD-induced leukoderma [15]. Clinical characteristics 2.1. Cells and cultures of RD-induced leukoderma show depigmentation of varying severity that develops after the use of cosmetics mainly at the Normal human epidermal melanocytes (NHEMa, Asian/Cauca- site of use. In most cases repigmentation of a part or all the affected sian, newborn, Kurabo Cat KM-4009, Strain No. 00378) were areas is evident after discontinuation [15]. purchased from Kurabo Industries Ltd., Japan and cultured in the Until recently it was considered that depigmentation by RD- medium DermaLife1 BM (LKB-LM0004) supplemented with containing cosmetics resulted from competitive inhibition of DermaLife1M LifeFactors (LMK-LS1041). Pigmented human epi- tyrosinase by RD. However, approximately 20% of the patients dermal melanocytes derived from an African American female are still suffering from leukoderma on the face, neck and/or hands (NHEMb, CC-2586, Lot 237204) were purchased from Lonza without repigmentation. In addition, biopsied samples taken from Walkersville Inc. (MD) and cultured in the medium MBM-4 depigmented lesions of RD-induced leukoderma contain few or no BulletKitTM supplemented with endothelin-3. Mouse melanoma detectable epidermal melanocytes [15]. These clinicopathological B16F1 cells were cultured in Dulbecco’s modified Eagle medium observations suggest that RD exhibits a significant cytotoxicity to supplemented by 10% fetal bovine serum and antibiotics. the epidermal melanocytes by producing cytotoxic metabolites through the tyrosinase-catalyzed oxidation. Tyrosinase is able to 2.2. Assay for cytotoxicity of phenolic compounds oxidize, in addition to L-tyrosine, a number of phenols and catechols to form ortho-quinones [16]. Moreover, Sasaki et al. has reported To examine the cytotoxicity of phenolic compounds to NHEM that RD mediates its cytotoxicity in a tyrosinase-dependent and B16F1 cells, cells were seeded at 1.5 Â 105/6 cm dish and manner, since suppression of tyrosinase results in the depressed cultured for 48 h. Cells were then refed with media containing cytotoxicity[(Fig._1)TD$IG] of RD in melanocytes [17,18]. Recently we have 0–800 mM RD and cultured for five or seven days. Numbers of Fig. 1. RD suppressed growth of NHEMb and B16F1 cells but not that of NHEMa. Cells were cultured with RD (50–800 mM) and numbers of viable cells were counted for five or seven days. 144 M. Okura et al. / Journal of Dermatological Science 80 (2015) 142–149 viable cells were counted using a hemocytometer. To determine methods. For the rhododendrol-catechol, a solution of rhododen- IC50 of the phenolic compounds, 2000 cells/well were seeded in drol (166 mg, 1.0 mmol, dissolved in 1 mL ethanol), ascorbic acid 96-well plates, cultured for 24 h and then refed with the medium (1056 mg, 6 mmol), and Na2HPO4 (852 mg, 6 mmol) was prepared containing RD, arbutin, hydroquinone or resveratrol for a further with 100 mL 50 mM sodium phosphate buffer (pH 5.3). The 72 h. Numbers of viable cells were counted by WST assay (Cell resulting pH was 5.3. The mixture was vigorously shaken at 37 8C Counting Kit-8, Dojindo, Wako Pure Chemical Industries Ltd., upon which mushroom tyrosinase (58 mg; 100,000 U) in 2 mL Japan). buffer was added. After 60 min, HPLC analysis showed that most of the ascorbic acid was consumed while 7% of the substrate 2.3.
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