title: Rhododendrol, a depigmentation-inducing phenolic compound, exerts melanocyte cytotoxicity via a tyrosinase-dependent mechanism.
abstract: Rhododendrol, an inhibitor of melanin synthesis developed for lightening/whitening cosmetics, was recently reported to induce a depigmentary disorder principally at the sites of repeated chemical contact. Rhododendrol competitively inhibited mushroom tyrosinase and served as a good substrate, while it also showed cytotoxicity against cultured human melanocytes at high concentrations sufficient for inhibiting tyrosinase. The cytotoxicity was abolished by phenylthiourea, a chelator of the copper ions at the active site, and by specific knockdown of tyrosinase with siRNA. Hence, the cytotoxicity appeared to be triggered by the enzymatic conversion of rhododendrol to active product(s). No reactive oxygen species were detected in the treated melanocytes, but up-regulation of the CCAAT-enhancer-binding protein homologous protein gene responsible for apoptosis and/or autophagy and caspase-3 activation were found to be tyrosinase dependent. These results suggest that a tyrosinase-dependent accumulation of ER stress and/or activation of the apoptotic pathway may contribute to the melanocyte cytotoxicity.
authors.affiliation: Innovative Beauty Science Laboratory, Kanebo Cosmetics Inc., Kanagawa, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Sasaki
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kondo
authors.forename: Kohji
authors.initials: K
authors.lastname: Sato
authors.forename: Mai
authors.initials: M
authors.lastname: Umeda
authors.forename: Keigo
authors.initials: K
authors.lastname: Kawabata
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Tamio
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kayoko
authors.initials: K
authors.lastname: Matsunaga
authors.forename: Shintaro
authors.initials: S
authors.lastname: Inoue
mesh_terms: D000363:Agaricales / Q000201:enzymology; D017209:Apoptosis; D000440:Butanols / Q000737:chemistry / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D020134:Catalytic Domain; D002470:Cell Survival; D002478:Cells, Cultured; D002614:Chelating Agents / Q000737:chemistry; D003300:Copper / Q000737:chemistry; D059865:Endoplasmic Reticulum Stress; D004742:Enhancer Elements, Genetic; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D017496:Hypopigmentation / Q000139:chemically induced; D020128:Inhibitory Concentration 50; D016209:Interleukin-8; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010670:Phenylthiourea / Q000737:chemistry; D010858:Pigmentation / Q000187:drug effects*; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D062327:Skin Lightening Preparations / Q000737:chemistry / Q000633:toxicity*; D015854:Up-Regulation; D014820:Vitiligo / Q000188:drug therapy
chemical_list: D000440:Butanols; D002614:Chelating Agents; D016209:Interleukin-8; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D062327:Skin Lightening Preparations; C115945:rhododendrol; D010670:Phenylthiourea; D003300:Copper; D014442:Monophenol Monooxygenase; D053148:Caspase 3
keywords: ER stress; chemical leukoderma; cytotoxicity; depigmentation; rhododendrol; tyrosinase; vitiligo