title: The potent pro-oxidant activity of rhododendrol-eumelanin induces cysteine depletion in B16 melanoma cells.
abstract: RS-4-(4-Hydroxyphenyl)-2-butanol (rhododendrol, RD), a skin-whitening agent, is known to induce leukoderma in some people. To explore the mechanism underlying this effect, we previously showed that the oxidation of RD with mushroom or human tyrosinase produces cytotoxic quinone oxidation products. We then examined the metabolism of RD in B16F1 melanoma cells in vitro and detected RD-pheomelanin and RD-quinone bound to non-protein and protein thiols. In this study, we examined the changes in glutathione (GSH) and cysteine in B16 cells exposed to RD for up to 24 h. We find that the levels of cysteine, but not those of GSH, decrease during 0.5- to 3-h exposure, due to oxidation to cystine. This pro-oxidant activity was then examined using synthetic melanins. Indeed, we find that RD-eumelanin exerts a pro-oxidant activity as potent as Dopa-pheomelanin. GSH, cysteine, ascorbic acid, and NADH were oxidized by RD-eumelanin with a concomitant production of H2O2. We propose that RD-eumelanin induces cytotoxicity through its potent pro-oxidant activity.
authors.affiliation: Department of Chemistry, Fujita Health University School of Health Sciences, Toyoake, Japan.
authors.forename: Shosuke
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Masae
authors.initials: M
authors.lastname: Okura
authors.affiliation: Department of Chemistry, Fujita Health University School of Health Sciences, Toyoake, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Wakamatsu
authors.affiliation: Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D000440:Butanols / Q000494:pharmacology*; D003545:Cysteine / Q000172:deficiency* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008543:Melanins / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000440:Butanols; D008543:Melanins; D016877:Oxidants; D017382:Reactive Oxygen Species; C041877:eumelanin; C115945:rhododendrol; D005978:Glutathione; D003545:Cysteine
keywords: cysteine; eumelanin; hydrogen peroxide; pheomelanin; pro-oxidant; rhododendrol