Mechanism of action of 4-substituted phenols to induce vitiligo and antimelanoma immunity.

Arthur Kammeyer,Walbert J Bakker,Nico P M Smit,Danielle Ratsma,Wouter Ouwerkerk,Sebas D Pronk,Rosalie M Luiten,Karin J Willemsen

doi:10.1111/pcmr.12774

Arthur Kammeyer, Walbert J Bakker + Show 6 more

Open Access

https://doi.org/10.1111/pcmr.12774

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Abstract

Monobenzone is a 4‐substituted phenol that can induce vitiligo and antimelanoma immunity. We investigated the influence of the chemical structure on the biological activity of a series of structurally related 4‐substituted phenols. All phenols inhibited cellular melanin synthesis, and eight of ten phenols inhibited tyrosinase activity, using the MBTH assay. These phenols also induced glutathione (GSH) depletion, indicative of quinone formation and protein thiol binding, which can increase the immunogenicity of melanosomal proteins. Specific T‐cell activation was found upon stimulation with phenol‐exposed pigmented cells, which also reacted with unexposed cells. In contrast, 4‐tertbutylphenol induced immune activation was not restricted to pigment cells, analogous to contact sensitization. We conclude that 4‐substituted phenols can induce specific T‐cell responses against melanocytes and melanoma cells, also acting at distant, unexposed body sites, and may confer a risk of chemical vitiligo. Conversely, these phenols may be applicable to induce specific antimelanoma immunity.

Highlights

Many phenolic compounds are held responsible for skin bleaching or leukoderma (Bleehen, Pathak, Hori, & Fitzpatrick, 1968; Fisher, 2001)
Besides the effects of tyrosinase activity, we further investigated the inhibitory effects of the phenols on the melanin synthesis by pigmented cells in culture
The CD4 T cell responses upon stimulation with phenol‐exposed or unexposed cells are shown in Supporting Information Figure S1. These results show that phenol‐exposed melanoma cells induce more T‐cell activation, than unexposed cells

Summary

| INTRODUCTION

Many phenolic compounds are held responsible for skin bleaching or leukoderma (Bleehen, Pathak, Hori, & Fitzpatrick, 1968; Fisher, 2001). Skin contact with phenols or catechols, such as monobenzyl ether of hydroqui‐ none (MBEH or monobenzone, in this study referred to as 4‐ben‐ zyloxyphenol, BOP), can induce local depigmentation that can spread to distant, unexposed body sites (occupational vitiligo). This depigmentation is clinically and histologically indistinguish‐ able from vitiligo (Boissy & Manga, 2004; Vrijman et al, 2013). | 541 the release of exosomes containing melanosomal proteins, which are taken up by dendritic cells, leading to their activation These dendritic cells induce a specific immune response against melano‐ cytes, resulting in vitiligo. As previously shown for monobenzone, the immunizing potential of these phenols may be applicable to raise immune responses against melanoma

| MATERIALS & METHODS

Findings

| DISCUSSION