title: Rhododenol and raspberry ketone impair the normal proliferation of melanocytes through reactive oxygen species-dependent activation of GADD45.
abstract: Rhododenol or rhododendrol (RD, 4-(4-hydroxyphenyl)-2-butanol) occurs naturally in many plants along with raspberry ketone (RK, 4-(4-hydroxyphenyl)-2-butanone), a ketone derivative, which include Nikko maple tree (Acer nikoense) and white birch (Betula platyphylla). De-pigmenting activity of RD was discovered and it was used as a brightening ingredient for the skin whitening cosmetics. Recently, cosmetics containing RD were withdrawn from the market because a number of consumers developed leukoderma, inflammation and erythema on their face, neck and hands. Here, we explored the mechanism underlying the toxicity of RD and RK against melanocytes using B16F10 murine melanoma cells and human primary epidermal melanocytes. Treatment with RD or RK resulted in the decreased cell viability in a dose-dependent manner which appeared from cell growth arrest. Consistently, ROS generation was significantly increased by RD or RK as determined by DCF-enhanced fluorescence. An antioxidant enzyme, glutathione peroxidase was depleted as well. In line with ROS generation, oxidative damages and the arrest of normal cell proliferation, GADD genes (Growth Arrest and DNA Damage) that include GADD45 and GADD153, were significantly up-regulated. Prevention of ROS generation with an anti-oxidant, N-acetylcysteine (NAC) significantly rescued RD and RK-suppressed melanocyte proliferation. Consistently, up-regulation of GADD45 and GADD153 was significantly attenuated by NAC, suggesting that increased ROS and the resultant growth arrest of melanocytes may contribute to RD and RK-induced leukoderma.
authors: College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea.
authors: Minjeong
authors: M
authors: Kim
authors: AmorePacific Corporation R&D Center, Yongin, Gyeonggi-do 446-729, Republic of Korea.
authors: Heung Soo
authors: HS
authors: Baek
authors: College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea.
authors: Miri
authors: M
authors: Lee
authors: College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea.
authors: Hyeonji
authors: H
authors: Park
authors: AmorePacific Corporation R&D Center, Yongin, Gyeonggi-do 446-729, Republic of Korea.
authors: Song Seok
authors: SS
authors: Shin
authors: Department of Public Health Science, Graduate School, Korea University, Seoul, Republic of Korea. Electronic address: aahhhh@paran.com.
authors: Dal Woong
authors: DW
authors: Choi
authors: College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea. Electronic address: kmLim@ewha.ac.kr.
authors: Kyung-Min
authors: KM
authors: Lim
mesh_terms: D000818:Animals; D000440:Butanols / Q000633:toxicity*; D002074:Butanones / Q000633:toxicity*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008544:Melanocytes / Q000187:drug effects* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000235:genetics; D000097642:GADD45 Proteins
chemical_list: D000440:Butanols; D002074:Butanones; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D051742:Transcription Factor CHOP; D000097642:GADD45 Proteins; C115945:rhododendrol; C035522:raspberry ketone
keywords: B16F10 cell; GADD45; Human melanocytes; Raspberry ketone; Rhododenol