title: Tyrosinase-catalyzed oxidation of rhododendrol produces 2-methylchromane-6,7-dione, the putative ultimate toxic metabolite: implications for melanocyte toxicity.
abstract: RS-4-(4-Hydroxyphenyl)-2-butanol (rhododendrol, RD) was used as a skin-whitening agent until it was reported to induce leukoderma in July 2013. To explore the mechanism underlying its melanocyte toxicity, we characterized the tyrosinase-catalyzed oxidation of RD using spectrophotometry and HPLC. Oxidation of RD with mushroom tyrosinase rapidly produced RD-quinone, which was quickly converted to 2-methylchromane-6,7-dione (RD-cyclic quinone) and RD-hydroxy-p-quinone through cyclization and addition of water molecule, respectively. RD-quinone and RD-cyclic quinone were identified as RD-catechol and RD-cyclic catechol after NaBH4 reduction. Autoxidation of RD-cyclic catechol produced superoxide radical. RD-quinone and RD-cyclic quinone quantitatively bound to thiols such as cysteine and GSH. These results suggest that the melanocyte toxicity of RD is caused by its tyrosinase-catalyzed oxidation through production of RD-cyclic quinone which depletes cytosolic GSH and then binds to essential cellular proteins through their sulfhydryl groups. The production of ROS through autoxidation of RD-cyclic catechol may augment the toxicity.
authors.affiliation: Department of Chemistry, Fujita Health University School of Health Sciences, Toyoake, Aichi, Japan.
authors.forename: Shosuke
authors.initials: S
authors.lastname: Ito
authors.forename: Makoto
authors.initials: M
authors.lastname: Ojika
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yamashita
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Wakamatsu
mesh_terms: D000363:Agaricales / Q000201:enzymology; D001578:Benzopyrans / Q000737:chemistry*; D000440:Butanols / Q000009:adverse effects* / Q000737:chemistry*; D002384:Catalysis; D002396:Catechols / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000378:metabolism; D005609:Free Radicals; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008544:Melanocytes / Q000166:cytology* / Q000187:drug effects*; D014442:Monophenol Monooxygenase / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D010100:Oxygen / Q000737:chemistry; D011809:Quinones / Q000737:chemistry*; D062327:Skin Lightening Preparations / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D013056:Spectrophotometry, Ultraviolet; D013481:Superoxides / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: C000598270:2-methylchromane-6,7-dione; D001578:Benzopyrans; D000440:Butanols; D002396:Catechols; D005609:Free Radicals; D011809:Quinones; D062327:Skin Lightening Preparations; D014867:Water; D013481:Superoxides; C115945:rhododendrol; D014442:Monophenol Monooxygenase; D005978:Glutathione; D010100:Oxygen
keywords: melanocyte toxicity; rhododendrol; sulfhydryl group; whitening agent: tyrosinase