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

@article{Ito2014TyrosinasecatalyzedOO,
  title={Tyrosinase‐catalyzed oxidation of rhododendrol produces 2‐methylchromane‐6,7‐dione, the putative ultimate toxic metabolite: implications for melanocyte toxicity},
  author={Shosuke Ito and Makoto Ojika and Toshiharu Yamashita and Kazumasa Wakamatsu},
  journal={Pigment Cell \& Melanoma Research},
  year={2014},
  volume={27}
}
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… 
Tyrosinase‐catalyzed metabolism of rhododendrol (RD) in B16 melanoma cells: production of RD‐pheomelanin and covalent binding with thiol proteins
TLDR
The tyrosinase‐induced metabolism of RD causes melanocyte toxicity, and the covalent binding of RD‐quinone to proteins was 20‐ to 30‐fold greater than dopaquinone.
Human tyrosinase is able to oxidize both enantiomers of rhododendrol
TLDR
The notion that the melanocyte toxicity of RD depends on its tyrosinase‐catalyzed conversion to toxic quinones and the concomitant production of reactive oxygen species is supported.
4‐(4‐Hydroxyphenyl)‐2‐butanol (rhododendrol)‐induced melanocyte cytotoxicity is enhanced by UVB exposure through generation of oxidative stress
TLDR
UVR enhanced RD‐induced cytotoxicity in normal human epidermal melanocytes (NHEMs) via the induction of endoplasmic reticulum (ER) stress and increased generation of intracellular reactive oxygen species (ROS) was detected.
The potent pro‐oxidant activity of rhododendrol–eumelanin induces cysteine depletion in B16 melanoma cells
TLDR
This study examines the changes in glutathione (GSH) and cysteine in B16 cells exposed to RD for up to 24 h and proposes that RD‐eumelanin induces cytotoxicity through its potent pro‐oxidant activity.
The potent pro‐oxidant activity of rhododendrol–eumelanin is enhanced by ultraviolet A radiation
TLDR
The results suggest that RD–eumelanin is cytotoxic to melanocytes through its potent pro‐oxidant activity that is enhanced by UVA radiation.
Roles of reactive oxygen species in UVA‐induced oxidation of 5,6‐dihydroxyindole‐2‐carboxylic acid‐melanin as studied by differential spectrophotometric method
TLDR
The results show that UVA radiation induces the oxidation of DHICA to indole‐5,6‐quinone‐2‐carboxylic acid in eumelanin, which is then cleaved to form a photodegraded, pyrrolic moiety and finally to form free pyrrole‐2,3,5‐tricarboxYlic acid.
Regioselective Hydroxylation of Rhododendrol by CYP102A1 and Tyrosinase
TLDR
E engineered cytochrome P450 102A1 and Ty can be used as effective biocatalysts to produce hydroxylated products, and Ty is a more cost-effective bioc atalyst for industrial applications than engineered CYP102A1.
Biochemical Mechanism of Rhododendrol-Induced Leukoderma
TLDR
It is found that the oxidation of racemic RD by mushroom tyrosinase rapidly produces RD-quinone, which gives rise to secondary quinone products and the results suggest two major mechanisms of cytotoxicity to melanocytes.
NAD(P)H dehydrogenase, quinone 1 (NQO1), protects melanin‐producing cells from cytotoxicity of rhododendrol
TLDR
The results suggest that NQO1 attenuates the cytotoxicity of RD and/or its metabolites and the leukoderma of the skin that may result.
Genome‐wide association study identifies CDH13 as a susceptibility gene for rhododendrol‐induced leukoderma
TLDR
This is the first genome‐wide association study for chemical‐induced vitiligo, and it could be a useful model for studying the disease's genetic aspects.
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