Discovery of Highly Potent Tyrosinase Inhibitor, T1, with Significant Anti-Melanogenesis Ability by zebrafish in vivo Assay and Computational Molecular Modeling

• Published in: Scientific reports Vol. 5; no. 1; p. 7995
• Main Authors: Chen, Wang-Chuan, Tseng, Tien-Sheng, Hsiao, Nai-Wan, Lin, Yun-Lian, Wen, Zhi-Hong, Tsai, Chin-Chuan, Lee, Yu-Ching, Lin, Hui-Hsiung, Tsai, Keng-Chang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.01.2015; Nature Publishing Group
• Subjects: 119/118; 631/92/349; 631/92/606; 631/92/613; 82/47; Acids; Animals; Biosynthesis; Cell Survival - drug effects; Computer applications; Cosmetics; Cytotoxicity; Embryos; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - toxicity; Herbal medicine; Humanities and Social Sciences; Hyperpigmentation; Inhibitory Concentration 50; Kojic acid; Medicine; Melanin; Melanins - biosynthesis; Melanocytes; Melanocytes - drug effects; Melanocytes - metabolism; Mice; Models, Molecular; Molecular Conformation; Molecular modelling; Monophenol Monooxygenase - antagonists & inhibitors; Monophenol Monooxygenase - chemistry; multidisciplinary; Natural products; Pigments; Science; Side effects; Skin; Sulfide; Sulfur; Toxicity; Toxicity Tests, Acute; Zebrafish - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep07995

Tyrosinase is involved in melanin biosynthesis and the abnormal accumulation of melanin pigments leading to hyperpigmentation disorders that can be treated with depigmenting agents. A natural product T1, bis(4-hydroxybenzyl)sulfide, isolated from the Chinese herbal plant, Gastrodia elata , is a strong competitive inhibitor against mushroom tyrosinase (IC 50 = 0.53 μM, K i = 58 ± 6 nM), outperforms than kojic acid. The cell viability and melanin quantification assay demonstrate that 50 μM of T1 apparently attenuates 20% melanin content of human normal melanocytes without significant cell toxicity. Moreover, the zebrafish in vivo assay reveals that T1 effectively reduces melanogenesis with no adverse side effects. The acute oral toxicity study evidently confirms that T1 molecule is free of discernable cytotoxicity in mice. Furthermore, the molecular modeling demonstrates that the sulfur atom of T1 coordinating with the copper ions in the active site of tyrosinase is essential for mushroom tyrosinase inhibition and the ability of diminishing the human melanin synthesis. These results evident that T1 isolated from Gastrodia elata is a promising candidate in developing pharmacological and cosmetic agents of great potency in skin-whitening.