Chawla S, deLong M A, Visscher M O, Wickett R R, Manga P, Boissy R E
Department of Dermatology, University of Cincinnati College of Medicine, and Skin Sciences Institute, Cincinnati Children's Hospital Medical Center, 231 Albert Sabin Way, Mail Location #0592, Cincinnati, OH 45267-0592, USA.
Br J Dermatol. 2008 Dec;159(6):1267-74. doi: 10.1111/j.1365-2133.2008.08864.x. Epub 2008 Sep 20.
Disorders, such as age spots, melasma and hyperpigmentation at sites of actinic damage, emanate from the augmentation of an increased amount of epidermal melanin.
The ineptness of current therapies in treating these conditions, as well as high cytotoxicity, mutagenicity, poor skin penetration and low stability of skin-depigmenting formulations led us to investigate new compounds that meet the medical requirements for depigmentation agents. We have shown previously that the tyrosinase inhibitor deoxyArbutin (dA) is a more effective and less toxic skin lightener than hydroquinone (HQ).
The efficacy and reversibility of dA and its derivatives on inhibiting tyrosine hydroxylase and DOPAoxidase was assessed using standard assays.
dA and its second-generation derivatives inhibit tyrosine hydroxylase and DOPAoxidase activities of tyrosinase dose dependently thereby inhibiting melanin synthesis in intact melanocytes, when used at concentrations that retain 95% cell viability in culture. This depigmenting effect was completely reversible when the compounds were removed. Tyrosinase inhibition was also observed in vitro when tested using human and purified mushroom tyrosinase, establishing that they are direct enzyme inhibitors. Lineweaver-Burk reciprocal plot analysis using mushroom tyrosinase illustrated that dA and its derivatives are more robust competitive inhibitors than HQ, when tyrosine is used as substrate.
Thus, dA and its second-generation derivatives, which inhibit melanogenesis at safe concentrations by specifically acting on the tyrosinase enzyme at a post-translational level, are promising agents to ameliorate hyperpigmented lesions or lighten skin.
诸如老年斑、黄褐斑以及光化性损伤部位的色素沉着等病症，是由表皮黑色素含量增加所致。
当前治疗这些病症的方法效果不佳，且皮肤美白制剂具有高细胞毒性、致突变性、皮肤渗透性差以及稳定性低等问题，这促使我们去研究符合色素沉着抑制剂医学要求的新化合物。我们之前已经表明，酪氨酸酶抑制剂脱氧熊果苷（dA）比氢醌（HQ）是一种更有效且毒性更低的皮肤美白剂。
使用标准检测方法评估dA及其衍生物对酪氨酸羟化酶和多巴氧化酶的抑制效果及可逆性。
当以在培养中保持95%细胞活力的浓度使用时，dA及其第二代衍生物剂量依赖性地抑制酪氨酸酶的酪氨酸羟化酶和多巴氧化酶活性，从而抑制完整黑素细胞中的黑色素合成。当去除这些化合物时，这种色素沉着抑制作用是完全可逆的。在使用人酪氨酸酶和纯化的蘑菇酪氨酸酶进行体外测试时也观察到了酪氨酸酶抑制作用，这表明它们是直接的酶抑制剂。使用蘑菇酪氨酸酶进行的Lineweaver - Burk双倒数作图分析表明，当以酪氨酸作为底物时，dA及其衍生物比HQ是更强效的竞争性抑制剂。
因此，dA及其第二代衍生物通过在翻译后水平特异性作用于酪氨酸酶，在安全浓度下抑制黑色素生成，是改善色素沉着病变或提亮肤色的有前景的药物。
