Generation of hydroxyl radicals and singlet oxygen during oxidation of rhododendrol and rhododendrol-catechol

Miyaji, Akimitsu; Gabe, Yu; Kohno, Masahiro; Baba, Toshihide

doi:10.3164/jcbn.16-38

Cited by 18 publications

(16 citation statements)

References 35 publications

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“…Because H 2 O 2 is not produced, it cannot be used to evaluate the potential of substances that cause chemical leukoderma in melanocytes; instead, ·OH generation should be used for such evaluations. The amounts of 1 O 2 generated via rhododendrol and rhododendrol-catechol oxidations with mushroom tyrosinase were reported [31], and they were probably lower than that of 1 O 2 exhibiting cell toxicity [31]. The calculation of cell volume was erroneous in this previous report [31]; however, 1 O 2 was produced by L-tyrosine and L-DOPA in the presence of tyrosinase.…”

Section: Discussionmentioning

confidence: 89%

“…The amounts of 1 O 2 generated via rhododendrol and rhododendrol-catechol oxidations with mushroom tyrosinase were reported [31], and they were probably lower than that of 1 O 2 exhibiting cell toxicity [31]. The calculation of cell volume was erroneous in this previous report [31]; however, 1 O 2 was produced by L-tyrosine and L-DOPA in the presence of tyrosinase. These findings suggest that 1 O 2 generated via rhododendrol and rhododendrol-catechol oxidations with tyrosinase does not cause cell toxicity.…”

Section: Discussionmentioning

confidence: 89%

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In Vitro Methods for Predicting Chemical Leukoderma Caused by Quasi-Drug Cosmetics

Zeng

Takahashi

et al. 2017

Cosmetics

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Skin care cosmetics frequently contain whitening or lightening agents. The present study aimed to establish in vitro methods for predicting chemical leukoderma caused by whitening agents in cosmetics. The risks of chemical leukoderma were predicted based on percutaneous absorption rates, toxic concentrations, and toxicity mechanisms. Thus, in vitro skin permeation rate and cytotoxic concentrations of whitening agents were studied using excised skin and cultured B16 melanoma cells. Pigment cell toxicity was observed using transmission electron microscopy (TEM). The levels of hydroxyl radical (·OH) were measured and the location of ·OH generation sites were determined in cultured B16 melanoma cells. Pigment cells cultured under conditions with high tyrosinase activity developed cytotoxicity when exposed to compounds known to cause leukoderma, while those cultured under conditions with low tyrosinase activity did not. Phenolic compounds that cause leukoderma were applied to the pigment cells at the concentration absorbed percutaneously under conditions with high tyrosinase activity. Cells that were observed using TEM demonstrated a large number of vacuolar degenerations in intracellular melanosomes after treatment with phenolic compounds that are known to cause leukoderma. Hydroxyl radical generation during the tyrosinase reaction was examined, as the whitening agents that inhibit tyrosinase activity serve as tyrosinase substrates. Only phenolic compounds that cause leukoderma generated high amounts of hydroxyl radicals. Thus, the hydroxyl radical is a melanocyte-specific toxin that disrupts tyrosinase-containing melanosomes. Whitening agents that generate high amounts of hydroxyl radicals may cause leukoderma. The in vitro method being reported here can predict the potential of a drug to cause leukoderma and whether the use of a specific whitening agent poses a risk.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 89%

In Vitro Methods for Predicting Chemical Leukoderma Caused by Quasi-Drug Cosmetics

Zeng

Takahashi

et al. 2017

Cosmetics

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“…ROS generation during the tyrosinase-catalyzed oxidation of RD was studied by Miyaji et al [ 72 ]. That study detected hydroxyl radical and singlet oxygen during the tyrosinase-catalyzed oxidation of RD using ESR trapping techniques.…”

Section: Melanocyte Toxicity Of Rd and The Detoxifying Mechanismmentioning

confidence: 99%

Biochemical Mechanism of Rhododendrol-Induced Leukoderma

Ito

Wakamatsu

2018

IJMS

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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.

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“…These results suggest that the generation of RD quinone, and the subsequent formation of oxidized metabolites by the tyrosinase activity, increases oxidative stress owing to glutathione consumption, inactivation of essential proteins for survival by cysteine residue attack, and generation of ROS, ultimately inducing cytotoxicity. In the in vitro tyrosinase reaction, generation of ROS can be confirmed when RD is used as a substrate; 17 however, ROS in cells may or may not be detected, depending on the cells or experiments used. In terms of cell death, both apoptosis and necrosis have been reported; therefore, the results may differ depending on the cells and culture conditions used, such as the RD treatment concentration and time 5,12,14–16 …”

Section: Mechanism Of Rdl Developmentmentioning

confidence: 99%

Rhododendrol‐induced leukoderma update II: Pathophysiology, mechanisms, risk evaluation, and possible mechanism‐based treatments in comparison with vitiligo

Inoue

Katayama

Suzuki

et al. 2021

The Journal of Dermatology

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A small proportion of individuals utilizing cosmetics containing rhododendrol developed leukoderma with various pathological conditions, in some cases indistinguishable from vitiligo. In this review, we investigate and evaluate the major considerations for developing rhododendrol‐induced leukoderma based on data from original or review articles published in the literature to provide a wide range of information regarding the pathophysiology, mechanisms, risk evaluation, and possible mechanism‐based treatments. We compile and discuss the latest information, including data related to the cytotoxicity of rhododendrol, cytoprotective functions, and involvement of the immune system, and consider the possibility of novel treatments based on the differences between individual patients and on the mechanism underlying the onset of the condition. Understanding the pathophysiology of rhododendrol‐induced leukoderma helps not only elucidate the mechanisms of non‐segmental vitiligo onset and progression, but also suggests prevention and treatment.

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Generation of hydroxyl radicals and singlet oxygen during oxidation of rhododendrol and rhododendrol-catechol

Cited by 18 publications

References 35 publications

In Vitro Methods for Predicting Chemical Leukoderma Caused by Quasi-Drug Cosmetics

In Vitro Methods for Predicting Chemical Leukoderma Caused by Quasi-Drug Cosmetics

Biochemical Mechanism of Rhododendrol-Induced Leukoderma

Rhododendrol‐induced leukoderma update II: Pathophysiology, mechanisms, risk evaluation, and possible mechanism‐based treatments in comparison with vitiligo

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