Tyrosinase-catalyzed oxidation of rhododendrol produces 2-methylchromane-6,7-dione, the putative ultimate toxic metabolite: implications for melanocyte toxicity

Summary 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 H...

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Bibliographic Details
Published in:Pigment cell and melanoma research 2014-09, Vol.27 (5), p.744-753
Main Authors: Ito, Shosuke, Ojika, Makoto, Yamashita, Toshiharu, Wakamatsu, Kazumasa
Format: Article
Language:English
Subjects:
Agaricales - enzymology
Benzopyrans - chemistry
Butanols - adverse effects
Butanols - chemistry
Catalysis
Catechols - chemistry
Chromatography, High Pressure Liquid
Cytosol - metabolism
Free Radicals
Glutathione - metabolism
Humans
melanocyte toxicity
Melanocytes - cytology
Melanocytes - drug effects
Monophenol Monooxygenase - chemistry
Monophenol Monooxygenase - metabolism
Monophenol Monooxygenase - toxicity
Oxidation
Oxygen - chemistry
Quinones - chemistry
rhododendrol
Skin Lightening Preparations - chemistry
Skin Lightening Preparations - metabolism
Skin Lightening Preparations - toxicity
Spectrophotometry, Ultraviolet
sulfhydryl group
Superoxides - chemistry
Toxicity
Water - chemistry
whitening agent: tyrosinase
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Summary:Summary 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.
ISSN:1755-1471
1755-148X
DOI:10.1111/pcmr.12275