Yuko Abe1, Ken Okamura2, Masakazu Kawaguchi2, Yutaka Hozumi2, Hitomi Aoki3, Takahiro Kunisada3, Shosuke Ito4, Kazumasa Wakamatsu4, Kayoko Matsunaga5, Tamio Suzuki2. 1. Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan. Electronic address: a.yuko@med.id.yamagata-u.ac.jp. 2. Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan. 3. Department of Tissue and Organ Development, Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, Gifu, Japan. 4. Department of Chemistry, Fujita Health University School of Health Sciences, Aichi, Japan. 5. Department of Dermatology, Fujita Health University School of Medicine, Aichi, Japan.
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.
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.