Biochemical Mechanism of Rhododendrol-Induced Leukoderma

• Main Authors: Shosuke Ito, Kazumasa Wakamatsu
• Format: Article
• Language: English
• Published: MDPI AG 2018-02-01
• Series: International Journal of Molecular Sciences
• Subjects: rhododendrol; 4-(4-hydroxyphenyl)-2-butanol; whitening agent: tyrosinase; melanocyte toxicity; sulfhydryl group; glutathione; cysteine; ultraviolet A; reactive oxygen species
• Online Access: http://www.mdpi.com/1422-0067/19/2/552

RS-4-(4-hydroxyphenyl)-2-butanol (rhododendrol (RD))—a skin-whitening ingredient—was reported to induce leukoderma in some consumers. We have examined the biochemical basis of the RD-induced leukoderma by elucidating the metabolic fate of RD in the course of tyrosinase-catalyzed oxidation. We found that the oxidation of racemic RD by mushroom tyrosinase rapidly produces RD-quinone, which gives rise to secondary quinone products. Subsequently, we confirmed that human tyrosinase is able to oxidize both enantiomers of RD. We then showed that B16 cells exposed to RD produce high levels of RD-pheomelanin and protein-SH adducts of RD-quinone. Our recent studies showed that RD-eumelanin—an oxidation product of RD—exhibits a potent pro-oxidant activity that is enhanced by ultraviolet-A radiation. In this review, we summarize our biochemical findings on the tyrosinase-dependent metabolism of RD and related studies by other research groups. The results suggest two major mechanisms of cytotoxicity to melanocytes. One is the cytotoxicity of RD-quinone through binding with sulfhydryl proteins that leads to the inactivation of sulfhydryl enzymes and protein denaturation that leads to endoplasmic reticulum stress. The other mechanism is the pro-oxidant activity of RD-derived melanins that leads to oxidative stress resulting from the depletion of antioxidants and the generation of reactive oxygen radicals.