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Numerous medications are used to treat hyperpigmentation. However, several reports have indicated that repeated application of some agents, such as rhododendrol (RD), raspberry ketone (RK) and monobenzone (MB), can be toxic to melanocytes. Although these agents had severe side effects in human trials, no current in vitro methods can predict the safety of such drugs. This study assessed the in vitro effects of five depigmentary compounds including leukoderma-inducing agents. In particular, we determined the effects of different concentrations and exposure times of different depigmentary agents on cell viability and melanogenesis in the presence and absence of ultraviolet B (UVB) radiation. Concentrations of RD, RK and MB that inhibit melanogenesis are similar to concentrations that are cytotoxic; however, concentrations of rucinol (RC) and AP736 that inhibit melanogenesis are much lower than concentrations that are cytotoxic. Furthermore, the concentrations that cause toxic effects depend on exposure duration, and prolonged exposure to RD, RK and MB had more cytotoxic effects than prolonged exposure to RC and AP736. The cytotoxic effects of RD and RK appear to be mediated by apoptosis due to increased expression of caspase-3 and caspase-8; UVB radiation increased the cytotoxicity of these agents and also increased caspase activity. Our results indicate that different leukoderma-inducing compounds have different effects on the viability of normal epidermal melanocytes and suggest that the in vitro assay used here can be used to predict whether an investigational compound that induces leukoderma may lead to adverse effects in human trials.

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Amentoflavone is a well-known biflavonoid that has diverse biological effects. Previously, we reported that amentoflavone suppressed UVB-induced matrix metalloproteinase-1 (MMP-1) expression in normal human fibroblasts (NHF). We investigated the effects of amentoflavone on UVB-induced MMP-1 expression in order to elucidate its mode of action. NHF were treated with amentoflavone for indicated times and doses with UVB irradiation. The expressions of MMP-1 gene and protein were determined by RT-PCR and ELISA, respectively. MAP kinase phosphorylation and the expression of c-Fos protein were determined by Western blot. The treatment of amentoflavone completely blocked the upregulation of MMP-1 which is induced by UVB irradiation in HaCaT-NHF co-culture in a dose-dependent manner as well as in NHF monoculture. Also, amentoflavone inhibited UVB-induced activation of extracellular signal-regulated kinase (ERK) without changing total ERK protein level, and did not affect p38 or JNK activation. Finally, AP-1 transcription factor components, phospho-c-Jun and c-Fos protein expressions were decreased by amentoflavone treatment. The major finding of this study shows that amentoflavone inhibits intracellular cell signaling ERK pathway leading to the prevention of MMP-1 expression in human skin fibroblasts. Therefore, these results strongly suggest that amentoflavone should be investigated as a potential agent for the prevention and the treatment of skin photoaging.