title: Tyrosinase-Catalyzed Oxidation of the Leukoderma-Inducing Agent Raspberry Ketone Produces (E)-4-(3-Oxo-1-butenyl)-1,2-benzoquinone: Implications for Melanocyte Toxicity.
abstract: The exposure of human skin to 4-(4-hydroxyphenyl)-2-butanone (raspberry ketone, RK) is known to cause chemical/occupational leukoderma. RK has a structure closely related to 4-(4-hydroxyphenyl)-2-butanol (rhododendrol), a skin whitening agent that was found to cause leukoderma in the skin of consumers in 2013. Rhododendrol is a good substrate for tyrosinase and causes a tyrosinase-dependent cytotoxicity to melanocytes, cells that are responsible for skin pigmentation. Therefore, it is expected that RK exerts its cytotoxicity to melanocytes through the tyrosinase-catalyzed oxidation to cytotoxic o-quinones. The results of this study demonstrate that the oxidation of RK by mushroom tyrosinase rapidly produces 4-(3-oxobutyl)-1,2-benzoquinone (RK-quinone), which is converted within 10-20 min to (E)-4-(3-oxo-1-butenyl)-1,2-benzoquinone (DBL-quinone). These quinones were identified as their corresponding catechols after reduction by ascorbic acid. RK-quinone and DBL-quinone quantitatively bind to the small thiol N-acetyl-l-cysteine to form thiol adducts and can also bind to the thiol protein bovine serum albumin through its cysteinyl residue. DBL-quinone is more reactive than RK-quinone, as judged by their half-lives (6.2 min vs 10.5 min, respectively), and decays rapidly to form an oligomeric pigment (RK-oligomer). The RK-oligomer can oxidize GSH to GSSG with a concomitant production of hydrogen peroxide, indicating its pro-oxidant activity, similar to that of the RD-oligomer. These results suggest that RK is cytotoxic to melanocytes through the binding of RK-derived quinones to thiol proteins and the pro-oxidant activity of the RK-oligomer.
authors.affiliation: Department of Chemistry, Fujita Health University School of Health Sciences , Toyoake, Aichi 470-1192, Japan.
authors.forename: Shosuke
authors.identifier: 0000-0001-9182-5144
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Chemistry, Fujita Health University School of Health Sciences , Toyoake, Aichi 470-1192, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Hinoshita
authors.affiliation: Department of Chemistry, Fujita Health University School of Health Sciences , Toyoake, Aichi 470-1192, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Suzuki
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University , Nagoya 464-8601, Japan.
authors.forename: Makoto
authors.identifier: 0000-0002-6671-8598
authors.initials: M
authors.lastname: Ojika
authors.affiliation: Department of Chemistry, Fujita Health University School of Health Sciences , Toyoake, Aichi 470-1192, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Wakamatsu
mesh_terms: D016227:Benzoquinones / Q000633:toxicity*; D002384:Catalysis; D007659:Ketones / Q000378:metabolism*; D008544:Melanocytes / Q000187:drug effects*; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D010084:Oxidation-Reduction
chemical_list: D016227:Benzoquinones; D007659:Ketones; D014442:Monophenol Monooxygenase