College of Pharmacy, Ewha Womans University, Seoul 03760, Korea.
Department of Beauty and Cosmetic Science, College of Health Science, Eulji University, Seongnam-si 13135, Korea.
Int J Mol Sci. 2019 Nov 12;20(22):5665. doi: 10.3390/ijms20225665.
Rhododenol (RD), a whitening cosmetic ingredient, was withdrawn from the market due to RD-induced leukoderma (RIL). While many attempts have been made to clarify the mechanism underlying RIL, RIL has not been fully understood yet. Indeed, affected subjects showed uneven skin pigmentation, but the features are different from vitiligo, a skin hypopigmentary disorder, alluding to events more complex than simple melanocyte cytotoxicity. Here, we discovered that rhododenol treatment reduced the number of melanocytes in a pigmented 3D human skin model, Melanoderm™, confirming the melanocyte toxicity of RD. Of note, melanocytes that survived in the RD treated tissues exhibited altered morphology, such as extended dendrites and increased cell sizes. Consistently with this, sub-cytotoxic level of RD increased cell size and elongated dendrites in B16 melanoma cells. Morphological changes of B16 cells were further confirmed in the immunocytochemistry of treated cells for actin and tubulin. Even more provoking, RD up-regulated the expression of tyrosinase and TRP1 in the survived B16 cells. Evaluation of mRNA expression of cytoskeletal proteins suggests that RD altered the cytoskeletal dynamic favoring cell size expansion and melanosome maturation. Collectively, these results suggest that RD not only induces cytotoxicity in melanocytes but also can lead to a profound perturbation of melanocyte integrity even at sub-cytotoxic levels.
熊果苷（RD）是一种美白化妆品成分，因其诱导的白癜风（RIL）而从市场上撤出。虽然已经有许多尝试来阐明导致 RIL 的机制，但 RIL 尚未得到充分理解。事实上，受影响的受试者表现出不均匀的皮肤色素沉着，但这些特征与白癜风不同，白癜风是一种皮肤色素减退障碍，暗示着比单纯的黑素细胞细胞毒性更复杂的事件。在这里，我们发现熊果苷处理减少了色素沉着的 3D 人皮肤模型（Melanoderm™）中的黑素细胞数量，证实了 RD 对黑素细胞的毒性。值得注意的是，在 RD 处理的组织中存活的黑素细胞表现出形态改变，例如延长的树突和增加的细胞大小。与此一致的是，亚细胞毒性水平的 RD 增加了 B16 黑色素瘤细胞的细胞大小和树突伸长。用处理过的细胞进行肌动蛋白和微管蛋白免疫细胞化学进一步证实了 B16 细胞的形态变化。更具挑衅性的是，RD 在存活的 B16 细胞中上调了酪氨酸酶和 TRP1 的表达。对细胞骨架蛋白的 mRNA 表达的评估表明，RD 改变了细胞骨架动态，有利于细胞大小的扩大和黑素体成熟。总的来说，这些结果表明 RD 不仅诱导黑素细胞的细胞毒性，而且即使在亚细胞毒性水平下也可以导致黑素细胞完整性的深刻破坏。
