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

Pigment Cell Melanoma Res 2014 Sep 27;27(5):744-53. Epub 2014 Jun 27.

Department of Chemistry, Fujita Health University School of Health Sciences, Toyoake, Aichi, Japan.

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.

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http://dx.doi.org/10.1111/pcmr.12275DOI Listing
September 2014
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