Department of Chemistry and Cosmetics, Jeju Inside Agency and Cosmetic Science Center, Jeju National University, Jeju 63243, Republic of Korea.
Int J Mol Sci. 2024 Nov 19;25(22):12421. doi: 10.3390/ijms252212421.
Vitiligo is a skin condition characterized by the loss of pigment, resulting in white patches on various parts of the body. It occurs when melanocytes, the cells that are responsible for producing skin pigment, are destroyed or stop functioning. This study aimed to investigate the melanogenic potential of various 4-methylcoumarin (4MC) derivatives, including 6-methoxy-4-methylcoumarin (6M-4MC), 7-methoxy-4-methylcoumarin (7M-4MC), 7-amino-4-methylcoumarin (7A-4MC), 6,7-dihydroxy-4-methylcoumarin (6,7DH-4MC), 7,8-dihydroxy-4-methylcoumarin (7,8DH-4MC), and 6,7-dimethoxy-4-methylcoumarin (6,7DM-4MC), in B16F10 melanoma cells. Our findings revealed that, while 4MC, 7A-4MC, 6,7DH-4MC, and 7,8DH-4MC did not exhibit any effect on melanin production, significant stimulation of melanogenesis was observed with 6M-4MC, 7M-4MC, and 6,7DM-4MC, with 6M-4MC demonstrating the most pronounced effect. 6M-4MC significantly stimulated melanin production and tyrosinase activity in a concentration-dependent manner in B16F10 cells. A Western blot analysis revealed that 6M-4MC increased the expression levels of microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2). Further mechanistic studies showed that 6M-4MC inhibited extracellular signal-regulated kinase (ERK) and protein kinase B (AKT), which led to the upregulation of MITF and TRP proteins and subsequent activation of melanin synthesis. Additionally, 6M-4MC activated GSK3β phosphorylation, reduced β-catenin phosphorylation, and stimulated melanogenesis via the GSK3β/β-catenin pathway. Moreover, a primary skin irritation test was conducted on the upper backs of 32 healthy female volunteers to assess the potential irritation or sensitization from 6M-4MC when applied topically at concentrations of 50 µM and 100 µM. The test results showed no adverse effects on the skin. Collectively, these findings suggest that 6M-4MC may be a promising pigmentation stimulator for use in cosmetics and in the medical treatment of hypopigmentation disorders, particularly in the treatment of skin conditions such as vitiligo.
白癜风是一种皮肤状况，其特征是色素丧失，导致身体各部位出现白色斑块。当负责产生皮肤色素的黑素细胞被破坏或停止功能时，就会发生白癜风。本研究旨在研究各种 4-甲基香豆素（4MC）衍生物的黑素生成潜力，包括 6-甲氧基-4-甲基香豆素（6M-4MC）、7-甲氧基-4-甲基香豆素（7M-4MC）、7-氨基-4-甲基香豆素（7A-4MC）、6,7-二羟基-4-甲基香豆素（6,7DH-4MC）、7,8-二羟基-4-甲基香豆素（7,8DH-4MC）和 6,7-二甲氧基-4-甲基香豆素（6,7DM-4MC）在 B16F10 黑素瘤细胞中的作用。我们的研究结果表明，虽然 4MC、7A-4MC、6,7DH-4MC 和 7,8DH-4MC 对黑色素生成没有任何影响，但 6M-4MC、7M-4MC 和 6,7DM-4MC 显著刺激了黑色素生成，其中 6M-4MC 的作用最为显著。6M-4MC 以浓度依赖性方式显著刺激 B16F10 细胞中黑色素的产生和酪氨酸酶活性。Western blot 分析表明，6M-4MC 增加了小眼畸形相关转录因子（MITF）、酪氨酸酶、酪氨酸酶相关蛋白-1（TRP-1）和酪氨酸酶相关蛋白-2（TRP-2）的表达水平。进一步的机制研究表明，6M-4MC 抑制细胞外信号调节激酶（ERK）和蛋白激酶 B（AKT），导致 MITF 和 TRP 蛋白上调，并随后激活黑色素合成。此外，6M-4MC 通过 GSK3β/β-catenin 通路激活 GSK3β 磷酸化，降低β-连环蛋白磷酸化，刺激黑色素生成。此外，在 32 名健康女性志愿者的上背部进行了一次原发性皮肤刺激试验，以评估在 50µM 和 100µM 浓度下局部应用 6M-4MC 时可能引起的刺激或致敏作用。试验结果显示皮肤无不良反应。总的来说，这些发现表明，6M-4MC 可能是一种有前途的化妆品和治疗色素减退症的药物的色素刺激剂，特别是在治疗白癜风等皮肤疾病方面。
