Leukoderma induced by rhododendrol is different from leukoderma of vitiligo in pathogenesis: A novel comparative morphological study

Abstract

Background Rhododendrol (rhododenol), an inhibitor of tyrosinase activity, is used as a skin‐whitening component. Many cases of leukoderma after the application have been reported, termed rhododenol‐induced leukoderma (RIL). The aim of this study was to clarify the pathogenesis of RIL morphologically through comparison with vitiligo. Methods We examined 14 cases of RIL and 15 cases of vitiligo using routine histopathology and immunohistochemistry. Thirteen cases of RIL, six cases of vitiligo and specimens of the RIL mouse model were evaluated by electron microscopy. Results There were common findings in RIL and vitiligo at the light‐microscopic level: (a) vacuolar changes in the dermo‐epidermal junction, (b) melanophages in the papillary dermis, (c) perifollicular lymphocyte infiltration, (d) loss or decrease of basal melanin pigment and (e) decrease of melanocytes in the lesions. The ultrastructural observations showed specific findings of RIL: (a) remaining melanocytes in depigmented lesions, (b) inhomogeneous melanization in melanocytes and (c) degenerated melanosomes in melanocytes. Some of the findings were observed in a RIL mouse model. Furthermore, it is notable that cell organelles of melanocytes were intact in our RIL cases. Conclusion Morphological changes of RIL targeting melanosomes in melanocytes without degeneration of organelles reflect the reversible clinical course of most cases.

Rhododenol Activates Melanocytes and Induces Morphological Alteration at Sub-Cytotoxic Levels

“…Western blot analysis further confirmed these changes. Taken together, these results may provide an important clue to explain the histological features of remnant melanocytes in the lesion of human RIL which exhibits heterogeneous melanization with intact cell organelles [8].…”

“…However, it is not known what effects the sub-cytotoxic levels of RD can inflict on dermal melanocytes. Focusing on the recent histological study of RD-induced leukoderma patients revealing the paradoxical melanization of remnant melanocytes [8], we hypothesized that sub-cytotoxic level of RD may cause effects on melanocytes distinct from simple cytotoxicity. As shown in our study, sub-cytotoxic levels of RD induced the activation of melanocytes and cytoskeletal changes as can be evidently supported by strong melanization and dendrite formation of remnant melanocytes in Melanoderm™ following the exposure to RD.…”

“…Interestingly, Tsutsumi et al recently reported that RIL exhibits feature different from vitiligo, a hypopigmentary disease [8]. While vacuolar changes, melanophage, perifollicular lymphocyte infiltration, and loss of melanin were commonly observed in both conditions, RIL distinctively exhibited remnant melanocytes in the lesion, with heterogeneous melanization, degenerated melanosomes and intact cell organelles, reflecting the involvement of more complex events in RIL.…”

A Concise Review on the Role of Endoplasmic Reticulum Stress in the Development of Autoimmunity in Vitiligo Pathogenesis

“…In the skin, ER stress may be induced by various endogenous as well as exogenous stressors such as UV irradiation, trauma, and chemical stressors ( Table S3 ). Interestingly, chemical stressors including phenolic derivatives such as rhododendrol, hydroquinone, MBEH (mono benzyl ether of hydroquinone), and 4-TBP (4-tertiary butyl phenol) present in the cosmetic skin whitening agents have been identified to induce UPR mediated melanocyte death ( 80 – 84 ). Importantly, physiological ER stress is required for the maintenance of normal biological functions including keratinocyte differentiation in the skin ( 85 ).…”

Autoantibodies detected in patients with vitiligo vulgaris but not in those with rhododendrol-induced leukoderma

“…Although the cytotoxic effects of rhododendrol metabolites on the melanocytes and degeneration of melanosomes have been proposed, the reason why only 2% of users develop leukoderma remains unclear. The clinical manifestations of leukoderma are similar to those of vitiligo vulgaris, except that leukoderma is apparent at the topical application site [1][2][3][4][5][6][7]. Vitiligo vulgaris is frequently associated with autoantibody-(autoAb-) dependent autoimmune disorders, such as autoimmune thyroiditis or myasthenia gravis.…”