title: Rhododenol-induced leukoderma in a mouse model mimicking Japanese skin.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan. Electronic address: a.yuko@med.id.yamagata-u.ac.jp.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Abe
authors.affiliation: Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Okamura
authors.affiliation: Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kawaguchi
authors.affiliation: Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hozumi
authors.affiliation: Department of Tissue and Organ Development, Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Department of Tissue and Organ Development, Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kunisada
authors.affiliation: Department of Chemistry, Fujita Health University School of Health Sciences, Aichi, Japan.
authors.forename: Shosuke
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Chemistry, Fujita Health University School of Health Sciences, Aichi, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Wakamatsu
authors.affiliation: Department of Dermatology, Fujita Health University School of Medicine, Aichi, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Matsunaga
authors.affiliation: Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Tamio
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000287:Administration, Topical; D000818:Animals; D044466:Asian People; D001343:Autophagy / Q000187:drug effects; D000440:Butanols / Q000008:administration & dosage / Q000494:pharmacology*; D002452:Cell Count; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D058965:MART-1 Antigen / Q000378:metabolism; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors; D062327:Skin Lightening Preparations / Q000008:administration & dosage / Q000494:pharmacology*; D012880:Skin Pigmentation / Q000187:drug effects* / Q000502:physiology; D014820:Vitiligo / Q000209:etiology
chemical_list: C000598249:4-(4-hydroxyphenyl)-2-butanol; D000440:Butanols; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D058965:MART-1 Antigen; D008543:Melanins; C548668:Mlana protein, mouse; D062327:Skin Lightening Preparations; C018362:pheomelanin; C041877:eumelanin; C115945:rhododendrol; D014442:Monophenol Monooxygenase
keywords: Cytotoxicity; Depigmentaion; Mouse model; Rhododendrol; Tyrosinase