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

被引：58

作者：

Ito, Shosuke ^{[1
]}

Ojika, Makoto ^{[2
]}

Yamashita, Toshiharu ^{[3
]}

Wakamatsu, Kazumasa ^{[1
]}

机构：

[1] Fujita Hlth Univ, Sch Hlth Sci, Dept Chem, Toyoake, Aichi, Japan

[2] Nagoya Univ, Grad Sch Bioagr Sci, Dept Appl Mol Biosci, Nagoya, Aichi 4648601, Japan

[3] Sapporo Med Univ, Sch Med, Dept Dermatol, Sapporo, Hokkaido, Japan

来源：

PIGMENT CELL & MELANOMA RESEARCH | 2014年 / 27卷 / 05期

基金：

日本学术振兴会;

关键词：

melanocyte toxicity; rhododendrol; sulfhydryl group; whitening agent: tyrosinase; MUSHROOM TYROSINASE; ORTHO-QUINONE; N-PROPIONYL-4-S-CYSTEAMINYLPHENOL; 4-S-CYSTEAMINYLPHENOL; MELANOGENESIS; CHEMISTRY; MECHANISM; CELLS; HYDROXYTYROSOL; SUBSTRATE;

D O I：

10.1111/pcmr.12275

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：744 / 753

页数：10

共 31 条

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