rhododendrol and Vitiligo

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.

Topics: Butanols; Humans; Hypopigmentation; Melanocytes; Vitiligo

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.. 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.. 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.. Morphological changes of RIL targeting melanosomes in melanocytes without degeneration of organelles reflect the reversible clinical course of most cases.

Topics: Adult; Aged; Aged, 80 and over; Animals; Butanols; Female; Humans; Melanocytes; Mice; Middle Aged; Neoplasms, Experimental; Nevus; Skin Neoplasms; Vitiligo

Rhododendrol (RD), 4-(4-hydroxyphenyl)-2-butanol, inhibits melanin synthesis and has been used for skin-whitening cosmetic products. RD has been very effective in lightening skin pigmentation, but some persons have developed so-called RD vitiligo, in which vitiligo starts on the face, neck and hands where topical RD has been applied and even extended over skin areas where RD has not been applied. RD vitiligo lesions in some patients have lasted for years and have been resistant to conventional vitiligo treatments. We examined the effects of cholecalciferol on RD vitiligo in a blinded randomized clinical trial. Forty-eight female RD vitiligo patients were recruited for the trial and were randomized into two groups: the vitamin D (VD)-intervention group that received daily 5000 IU cholecalciferol for 5 months and the control group. Three blinded investigators scored vitiligo improvement by comparing photographic images of baseline and at 5-month observation. Serum 25(OH)D3 of RD vitiligo patients was not significantly different from age-matched healthy volunteers. Twenty-two in the VD-intervention group and 23 in the control group completed the 5-month observation. Serum 25(OH)D3 levels were significantly increased after the 5-month VD intervention, while the control group did not change. The improvement scores were significantly higher in the VD-intervention group than the control group. The improvement scores were positively correlated with the serum 25(OH)D3 levels after the 5-month intervention period but not before the treatment. This blinded randomized clinical trial showed favor in administrating 5000 IU cholecalciferol daily to RD vitiligo patients.

Topics: Administration, Oral; Adult; Aged; Butanols; Calcifediol; Cholecalciferol; Female; Humans; Middle Aged; Photography; Skin; Skin Lightening Preparations; Treatment Outcome; Vitamins; Vitiligo

Racemic RS-4-(4-hydroxyphenyl)-2-butanol (rhododendrol; trade name: Rhododenol [RD]), which is used in topical skin-lightening cosmetics, was unexpectedly reported in Japan to induce leukoderma or vitiligo called RD-induced leukoderma (RIL) after repeated application. To our knowledge, no studies have investigated chemical-induced vitiligo pathogenesis on a genome-wide scale. Here, we conducted a genome-wide association study (GWAS) for 147 cases and 112 controls. CDH13, encoding a glycosylphosphatidylinositol-anchored protein called T-cadherin (T-cad), was identified as the strongest RIL susceptibility gene. RD sensitivity was remarkably increased by T-cad knockdown in cultured normal human melanocytes. Furthermore, we confirmed tyrosinase upregulation and downregulation of the anti-apoptotic molecules (BCL-2 and BCL-XL), suggesting that T-cad is associated with RD via tyrosinase or apoptotic pathway regulation. Finally, monobenzyl ether of hydroquinone sensitivity also tended to increase with T-cad knockdown, suggesting that the T-cad could be a candidate susceptibility gene for RIL and other chemical-induced vitiligo forms. This is the first GWAS for chemical-induced vitiligo, and it could be a useful model for studying the disease's genetic aspects.

Topics: Alleles; Butanols; Cadherins; Epidermis; Gene Knockdown Techniques; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Melanocytes; Vitiligo

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Antigens, CD; Butanols; Cadherins; Case-Control Studies; Female; Glutamate-Cysteine Ligase; Humans; Immunohistochemistry; Male; Melanocytes; Middle Aged; Monophenol Monooxygenase; Skin; Skin Pigmentation; Vitiligo; Young Adult

Vitiligo is a depigmentation disease characterized by gradual loss of melanin and melanocytes from the epidermis. The mechanism of melanocyte loss is not yet known. In this report, we showed that the expression of discoidin domain receptor 1 and E-cadherin, known adhesion molecules, was variable or absent in the epidermis of rhododendrol-induced leukoderma (RDIL) mice during the depigmentation process. Our findings suggest that melanocyte damage by rhododendrol promotes reduction of adhesion molecules not only in melanocytes but also in keratinocytes, and this is associated with the detachment of melanocytes from the basal layer.

Topics: Animals; Butanols; Cadherins; Discoidin Domain Receptor 1; Epidermis; Melanocytes; Mice; Vitiligo

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autoantibodies; Butanols; Child, Preschool; Female; Humans; Hypopigmentation; Male; Middle Aged; Skin Lightening Preparations; Vitiligo; Young Adult

Rhododenol (RD), a whitening cosmetic ingredient, was withdrawn from the market due to RD-induced leukoderma (RIL). While many attempts have been made to clarify the mechanism underlying RIL, RIL has not been fully understood yet. Indeed, affected subjects showed uneven skin pigmentation, but the features are different from vitiligo, a skin hypopigmentary disorder, alluding to events more complex than simple melanocyte cytotoxicity. Here, we discovered that rhododenol treatment reduced the number of melanocytes in a pigmented 3D human skin model, Melanoderm™, confirming the melanocyte toxicity of RD. Of note, melanocytes that survived in the RD treated tissues exhibited altered morphology, such as extended dendrites and increased cell sizes. Consistently with this, sub-cytotoxic level of RD increased cell size and elongated dendrites in B16 melanoma cells. Morphological changes of B16 cells were further confirmed in the immunocytochemistry of treated cells for actin and tubulin. Even more provoking, RD up-regulated the expression of tyrosinase and TRP1 in the survived B16 cells. Evaluation of mRNA expression of cytoskeletal proteins suggests that RD altered the cytoskeletal dynamic favoring cell size expansion and melanosome maturation. Collectively, these results suggest that RD not only induces cytotoxicity in melanocytes but also can lead to a profound perturbation of melanocyte integrity even at sub-cytotoxic levels.

Topics: Animals; Butanols; Cell Line, Tumor; Cytoskeletal Proteins; Dose-Response Relationship, Drug; Gene Expression Regulation; Humans; Melanocytes; Mice; Models, Biological; Monophenol Monooxygenase; Trypsin; Vitiligo

Topics: Administration, Oral; Animals; Butanols; Disease Models, Animal; Humans; Janus Kinase Inhibitors; Mice; Mice, Hairless; Mice, Transgenic; Piperidines; Pyrimidines; Pyrroles; Skin Lightening Preparations; Skin Pigmentation; Treatment Failure; Vitiligo

Rhododendrol, 4-(4-hydroxyphenyl)-2-butanol, Rhododenol(®) (RD), a naturally occurring phenolic compound, was developed as a tyrosinase inhibitor for skin-lightening/whitening cosmetics. In 2013, skin depigmentation was reported in consumers using RD-containing skin-brightening cosmetics; this condition is called RD-induced leukoderma.. The etiology of RD-induced leukoderma is still largely unknown. Here, to assess the depigmentation potential of RD, we developed a new mouse model of leukoderma by topically applying RD.. Hairless hk14-SCF Tg mice with melanocytes distributed in the epidermis were used for this study. RD was applied on the dorsal skin of the mice daily for 28 days. Then, immunohistological, biochemical, and electron microscopic analyses were performed on biopsy samples taken from these mice.. The depigmentation in the RD-treated sites appeared on Day 14. Histological examination indicated a loss of epidermal melanocytes at Day 7. On the other hand, the melanocyte number did not decrease in the albino mice having the same background as the hairless hk14-SCF Tg, but without tyrosinase activity. Biochemical analyses showed that the eumelanin content decreased in the RD-treated sites and metabolites of RD-quinone, i.e., non-protein thiol adducts and protein-SH adducts, were produced. Electron microscopic analyses revealed double-membrane-walled structures containing electron-dense material, which might be typical for melanin-containing autophagosomes and a dilated endoplasmic reticulum (ER), which would indicate ER stress.. These data suggested that RD exerted tyrosinase-dependent melanocyte cytotoxicity and that tyrosinase-dependent accumulation of ER stress from activation of the autophagy pathway contributed to melanocyte cytotoxicity.

Topics: Administration, Topical; Animals; Asian People; Autophagy; Butanols; Cell Count; Disease Models, Animal; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Epidermal Cells; Epidermis; Heat-Shock Proteins; Humans; MART-1 Antigen; Melanins; Melanocytes; Mice; Mice, Hairless; Mice, Inbred C57BL; Mice, Transgenic; Models, Animal; Monophenol Monooxygenase; Skin Lightening Preparations; Skin Pigmentation; Vitiligo

Many users in Japan of skin brightening/lightening cosmetics containing rhododendrol (RD) have developed leucoderma. Leucoderma appears on skin areas repeatedly treated with RD-containing cosmetics. RD-induced leucoderma (RDIL) presents different degrees of well-defined hypopigmentation. It is crucial to determine the degree of hypopigmentation to differentiate RDIL from vitiligo vulgaris (VV).. To quantitatively evaluate hypopigmentation of RDIL lesions and the recovery of pigmentation, and to compare the hypopigmentation with VV and normal skin.. Sixteen cases of RDIL, nine cases of VV and 15 healthy controls were examined using a novel multispectral camera (MSC) that can simultaneously obtain the reflection intensity at 10-nm wavelength intervals from 400 to 760 nm of the photographed area. ∆Absorbance was calculated by subtracting the log of reflection intensity of the target area from that of a white reflection standard.. Most RDIL lesions showed lower ∆Absorbance than healthy skin and higher ∆Absorbance than VV lesions between 400 and 550 nm. Statistical comparison of the maximum ∆Absorbance from 420 to 460 nm (Max∆Absorbance) for VV, RDIL and control skin showed that the Max∆Absorbance of RDIL was significantly higher than that of VV and lower than that of control skin. The comparison of ∆Absorbance of the same sites in RDIL lesions between the initial visit and 6 months later showed significant improvement after 6 months.. These studies demonstrated quantitative changes in RDIL and its recovery phase and suggested the utility of a MSC in obtaining objective colour information of skin disorders.

Topics: Adult; Aged; Butanols; Case-Control Studies; Diagnosis, Differential; Female; Humans; Hypopigmentation; Japan; Middle Aged; Skin Lightening Preparations; Spectrophotometry; Vitiligo

Topics: Butanols; Cells, Cultured; Dermatitis, Contact; Humans; Melanocytes; Monophenol Monooxygenase; NF-kappa B p50 Subunit; Skin Lightening Preparations; Tumor Necrosis Factor-alpha; Vitiligo

Topics: Adolescent; Adult; Aged; Butanols; Cellular Senescence; Cosmetics; Female; Humans; Hypopigmentation; Imaging, Three-Dimensional; Male; Middle Aged; Nevus; Quality of Life; Vitiligo; Young Adult

Topics: Butanols; CD8-Positive T-Lymphocytes; Chemokine CCL17; Chemokine CCL22; Cosmetics; Humans; Hypopigmentation; Lymphocyte Count; Receptors, CCR4; Skin; Vitiligo

Topics: Biomarkers; Butanols; Frizzled Receptors; Hair Follicle; Humans; Immunohistochemistry; Melanocytes; Skin Lightening Preparations; Skin Pigmentation; Vitiligo

Rhododendrol, an inhibitor of melanin synthesis developed for lightening/whitening cosmetics, was recently reported to induce a depigmentary disorder principally at the sites of repeated chemical contact. Rhododendrol competitively inhibited mushroom tyrosinase and served as a good substrate, while it also showed cytotoxicity against cultured human melanocytes at high concentrations sufficient for inhibiting tyrosinase. The cytotoxicity was abolished by phenylthiourea, a chelator of the copper ions at the active site, and by specific knockdown of tyrosinase with siRNA. Hence, the cytotoxicity appeared to be triggered by the enzymatic conversion of rhododendrol to active product(s). No reactive oxygen species were detected in the treated melanocytes, but up-regulation of the CCAAT-enhancer-binding protein homologous protein gene responsible for apoptosis and/or autophagy and caspase-3 activation were found to be tyrosinase dependent. These results suggest that a tyrosinase-dependent accumulation of ER stress and/or activation of the apoptotic pathway may contribute to the melanocyte cytotoxicity.

Topics: Agaricales; Apoptosis; Butanols; Caspase 3; Catalytic Domain; Cell Survival; Cells, Cultured; Chelating Agents; Copper; Endoplasmic Reticulum Stress; Enhancer Elements, Genetic; Enzyme-Linked Immunosorbent Assay; Gene Expression Profiling; Gene Expression Regulation; Humans; Hypopigmentation; Inhibitory Concentration 50; Interleukin-8; Melanocytes; Monophenol Monooxygenase; Phenylthiourea; Pigmentation; Reactive Oxygen Species; RNA, Small Interfering; Skin Lightening Preparations; Up-Regulation; Vitiligo