4‐(4‐Hydroxyphenyl)‐2‐butanol (rhododendrol)‐induced melanocyte cytotoxicity is enhanced by UVB exposure through generation of oxidative stress

Abstract

4-(4-Hydroxyphenyl)-2-butanol (rhododendrol, RD), a skin-whitening agent, was reported to cause skin depigmentation in some users, which is attributed to its cytotoxicity to melanocyte. It was reported that cytotoxicity to melanocyte is possibly mediated by oxidative stress in a tyrosinase activity-dependent manner. We examined the effect of UV radiation (UVR) on RD-induced melanocyte cytotoxicity as an additional aggravating factor. UVR enhanced RD-induced cytotoxicity in normal human epidermal melanocytes (NHEMs) via the induction of endoplasmic reticulum (ER) stress. Increased generation of intracellular reactive oxygen species (ROS) was detected. Pretreatment with N-acetyl cysteine (NAC), antioxidant and precursor of glutathione significantly attenuated ER stress-induced cytotoxicity in NHEMs treated with RD and UVR. Increase in cysteinyl-RD-catechol and RD-pheomelanin in NHEMs treated with RD and UVR suggested that, after UVR excitation, RD or RD metabolites are potent ROS-generating substances and that the tendency to produce RD-pheomelanin during melanogenesis amplifies ROS generation in melanocytes. Our results help to elucidate the development mechanisms of RD-induced leukoderma and provide information for innovation of safe skin-whitening compounds.

Biochemical Mechanism of Rhododendrol-Induced Leukoderma

“…In addition, autophagy may be involved in resistance to the cytotoxicity of RD [ 8 ]. Although UVB appears to augment the cytotoxicity of RD [ 45 , 54 , 55 ], how UVB interacts with RD metabolites directly or indirectly has yet to be examined. Also, the role of UVA in RD-induced cytotoxicity remains to be confirmed by in vitro studies.…”

“…In a collaborative study with Chikako Nishigori of Kobe University [ 45 ], we examined the metabolism of RD in human epidermal melanocytes exposed to UVB irradiation. Higher levels of CyS-RDC and RD-pheomelanin were found in melanocytes treated with RD and UVB compared to the RD only-treated cells.…”

“…How the binding of RD-quinone (2) to protein-SH induces cytotoxicity to melanocytes is a matter of conjecture. A number of studies have shown that RD induces endoplasmic reticulum (ER) stress and the apoptosis that follows [ 8 , 36 , 45 , 54 , 55 ]. Sasaki et al [ 36 ] found that the gene expression level of CCAAT-enhancer-binding protein homologous protein (CHOP), a transcription factor with a major role in unfolded protein response (UPR)-induced cell death, was up-regulated in melanocytes exposed to RD and this up-regulation was tyrosinase-dependent.…”

“…Arase et al [ 55 ] reported the augmentation of UVB-induced apoptosis of melanocytes exposed to RD and the suppression of NF-κB activation by TNFα that depends on tyrosinase activity. Goto et al [ 45 ] reported that UVB radiation enhanced RD-induced cytotoxicity in melanocytes via the induction of ER stress. An in vivo study by Abe et al [ 47 ] also suggested the involvement of ER stress using biopsy samples from RD exposed mice.…”

“…Kim et al [ 61 ] showed approximately 10-fold increased levels of ROS generation in RD-exposed B16F10 cells using a fluorescence assay. Furthermore, Goto et al [ 45 ] reported that ROS generation was synergistically enhanced in normal human melanocytes treated with RD and UVB compared to cells treated with RD alone.…”