Discovery of highly potent tyrosinase inhibitor, T1, with significant anti-melanogenesis ability by zebrafish in vivo assay and computational molecular modeling

Wang-Chuan Chen, Tien-Sheng Tseng, Nai-Wan Hsiao, Yun-Lian Lin, Zhi-Hong Wen, Chin-Chuan Tsai, Yu-Ching Lee, Hui-Hsiung Lin, Keng-Chang Tsai

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

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, Ki = 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.
Original languageEnglish
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 2015

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Monophenol Monooxygenase
Melanins
Zebrafish
Gastrodia
Agaricales
Skin Lightening Preparations
Hyperpigmentation
Melanocytes
Biological Products
Sulfur
Cosmetics
Copper
Catalytic Domain
Cell Survival
Pharmacology
Ions
Skin

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Discovery of highly potent tyrosinase inhibitor, T1, with significant anti-melanogenesis ability by zebrafish in vivo assay and computational molecular modeling. / 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.

In: Scientific Reports, Vol. 5, 2015.

Research output: Contribution to journalArticle

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. / Discovery of highly potent tyrosinase inhibitor, T1, with significant anti-melanogenesis ability by zebrafish in vivo assay and computational molecular modeling. In: Scientific Reports. 2015 ; Vol. 5.
@article{66412cbd9cce4e1089bdc04d99062765,
title = "Discovery of highly potent tyrosinase inhibitor, T1, with significant anti-melanogenesis ability by zebrafish in vivo assay and computational molecular modeling",
abstract = "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, Ki = 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.",
author = "Wang-Chuan Chen and Tien-Sheng Tseng and Nai-Wan Hsiao and Yun-Lian Lin and Zhi-Hong Wen and Chin-Chuan Tsai and Yu-Ching Lee and Hui-Hsiung Lin and Keng-Chang Tsai",
note = "被引用次數:2 Export Date: 28 March 2016 通訊地址: Tsai, K.-C.; National Research Institute of Chinese Medicine, Ministry of Health and WelfareTaiwan 參考文獻: Seo, S.Y., Sharma, V.K., Sharma, N., Mushroom tyrosinase: Recent prospects (2003) J Agric Food Chem, 51, pp. 2837-2853; Prota, G., Progress in the chemistry of melanins and related metabolites (1988) Med Res Rev, 8, pp. 525-556; Spritz, R.A., Hearing, Jr.V.J., Genetic disorders of pigmentation (1994) Adv Hum Genet, 22, pp. 1-45; Lindquist, N.G., Accumulation of drugs on melanin (1973) Acta Radiol Diagn (Stockh), 325, pp. 1-92; Solano, F., Briganti, S., Picardo, M., Ghanem, G., Hypopigmenting agents: An updated review on biological, chemical and clinical aspects (2006) Pigment Cell Res, 19, pp. 550-571; Briganti, S., Camera, E., Picardo, M., Chemical and instrumental approaches to treat hyperpigmentation (2003) Pigment Cell Res, 16, pp. 101-110; Pawelek, J.M., Korner, A.M., The biosynthesis of mammalian melanin (1982) Am Sci, 70, pp. 136-145; Passi, S., Nazzaro-Porro, M., Molecular basis of substrate and inhibitory specificity of tyrosinase: Phenolic compounds (1981) Br J Dermatol, 104, pp. 659-665; Solomon, E.I., Sundaram, U.M., MacHonkin, T.E., Multicopper Oxidases and Oxygenases (1996) Chem Rev, 96, pp. 2563-2606; Cabanes, J., Garcia-Canovas, F., Lozano, J.A., Garcia-Carmona, F., A kinetic study of the melanization pathway between L-tyrosine and dopachrome (1987) Biochim Biophys Acta, 923, pp. 187-195; Cass, A.E., Hill, H.A., Copper proteins and copper enzymes (1980) Ciba Found Symp, 79, pp. 71-91; Zhang, X., Hu, X., Hou, A., Wang, H., Inhibitory effect of 2, 4, 2', 4'-tetrahydroxy-3-(3-methyl-2-butenyl)-chalcone on tyrosinase activity and melanin biosynthesis (2009) Biol Pharm Bull, 32, pp. 86-90; Park, K.H., Inhibitory effect of ammonium tetrathiotungstate on tyrosinase and its kinetic mechanism (2006) Chem Pharm Bull (Tokyo), 54, pp. 1266-1270; Chen, Q.X., Kubo, I., Kinetics of mushroom tyrosinase inhibition by quercetin (2002) J Agric Food Chem, 50, pp. 4108-4112; Jones, K., Hughes, J., Hong, M., Jia, Q., Orndorff, S., Modulation of melanogenesis by aloesin: A competitive inhibitor of tyrosinase (2002) Pigment Cell Res, 15, pp. 335-340; Kubo, I., Kinst-Hori, I., Flavonols from saffron flower: Tyrosinase inhibitory activity and inhibition mechanism (1999) J Agric Food Chem, 47, pp. 4121-4125; Reish, O., Townsend, D., Berry, S.A., Tsai, M.Y., King, R.A., Tyrosinase inhibition due to interaction of homocyst(e)ine with copper: The mechanism for reversible hypopigmentation in homocystinuria due to cystathionine beta-synthase deficiency (1995) Am J Hum Genet, 57, pp. 127-132; Shimizu, K., Kondo, R., Sakai, K., Inhibition of tyrosinase by flavonoids, stilbenes and related 4-substituted resorcinols: Structure-activity investigations (2000) Planta Med, 66, pp. 11-15; Funasaka, Y., Komoto, M., Ichihashi, M., Depigmenting effect of alpha-tocopheryl ferulate on normal human melanocytes (2000) Pigment Cell Res, 13, pp. 170-174; Mishima, Y., Hatta, S., Ohyama, Y., Inazu, M., Induction of melanogenesis suppression: Cellular pharmacology and mode of differential action (1988) Pigment Cell Res, 1, pp. 367-374; Smith, C.J., O'Hare, K.B., Allen, J.C., Selective cytotoxicity of hydroquinone for melanocyte-derived cells is mediated by tyrosinase activity but independent of melanin content (1988) Pigment Cell Res, 1, pp. 386-389; Maeda, K.F.M., In vitro effectiveness of several whitening cosmetic components in human melanocytes (1991) J. Soc. Cosmet. Chem., 42, pp. 361-368; Arandt, K.A.F.T.B., Topical use of hydroquinine as a depigmenting agent (1965) J. Am. Med. Assoc., 194, pp. 117-119; Fitzpatrick, T.B., Arndt, K.A., El-Mofty, A.M., Pathak, M.A., Hydroquinone and psoralens in the therapy of hypermelanosis and vitiligo (1966) Arch Dermatol, 93, pp. 589-600; Kligman, A.M., Willis, I., A new formula for depigmenting human skin (1975) Arch Dermatol, 111, pp. 40-48; Heilgemeir, G.P., Balda, B.R., [Irreversible toxic depigmentation. Observations following use of hydroquinonemonobenzylether-containing skin bleaching preparations] (1981) MMW Munch Med Wochenschr, 123, pp. 47-48; Breathnach, A.C., Nazzaro-Porro, M., Passi, S., Zina, G., Azelaic acid therapy in disorders of pigmentation (1989) Clin Dermatol, 7, pp. 106-119; Verallo-Rowell, V.M., Verallo, V., Graupe, K., Lopez-Villafuerte, L., Garcialopez, M., Double-blind comparison of azelaic acid and hydroquinone in the treatment of melasma (1989) Acta Derm Venereol Suppl (Stockh), 143, pp. 58-61; Jimbow, K., N-acetyl-4-S-cysteaminylphenol as a new type of depigmenting agent for the melanoderma of patients with melasma (1991) Arch Dermatol, 127, pp. 1528-1534; Funayama, M., Effects of alpha-and beta-arbutin on activity of tyrosinases from mushroom and mouse melanoma (1995) Biosci Biotechnol Biochem, 59, pp. 143-144; Kim, Y.J., Uyama, H., Tyrosinase inhibitors from natural and synthetic sources: Structure, inhibition mechanism and perspective for the future (2005) Cellular and Molecular Life Sciences: CMLS, 62, pp. 1707-1723; Marrero-Ponce, Y., Prediction of tyrosinase inhibition activity using atom-based bilinear indices (2007) ChemMedChem, 2, pp. 449-478; Parvez, S., Survey and mechanism of skin depigmenting and lightening agents (2006) Phytother Res, 20, pp. 921-934; Curto, E.V., Inhibitors of mammalian melanocyte tyrosinase: In vitro comparisons of alkyl esters of gentisic acid with other putative inhibitors (1999) Biochem Pharmacol, 57, pp. 663-672; Hermanns, J.F., Pierard-Franchimont, C., Pierard, G.E., Skin colour assessment in safety testing of cosmetics. An overview (2000) Int J Cosmet Sci, 22, pp. 67-71; Fuyuno, I., Spotlight turns on cosmetics for Asian skin (2004) Nature, 432, p. 938; Shimizu, K., Yasutake, S., Kondo, R., A new stilbene with tyrosinase inhibitory activity from Chlorophora excelsa (2003) Chemical & Pharmaceutical Bulletin, 51, pp. 318-319; Park, S.H., Terrein: A new melanogenesis inhibitor and its mechanism (2004) Cellular and Molecular Life Sciences: CMLS, 61, pp. 2878-2885; Zhong, S., Depigmentation of melanocytes by the treatment of extracts from traditional Chinese herbs: A cell culture assay (2006) Biol Pharm Bull, 29, pp. 1947-1951; Choi, S.Y., (4-Methoxy-benzylidene)-(3-methoxy-phenyl)-amine, a nitrogen analog of stilbene as a potent inhibitor of melanin production (2002) Chem Pharm Bull (Tokyo), 50, pp. 450-452; Baek, S., Inhibitory effect of dalbergioidin isolated from the trunk of Lespedeza cyrtobotrya on melanin biosynthesis (2008) J Microbiol Biotechnol, 18, pp. 874-879; Yanagihara, M., Inhibitory effect of gnetin C, a resveratrol dimer from melinjo (Gnetum gnemon), on tyrosinase activity and melanin biosynthesis (2012) Biol Pharm Bull, 35, pp. 993-996; Roh, J.S., Han, J.Y., Kim, J.H., Hwang, J.K., Inhibitory effects of active compounds isolated from safflower (Carthamus tinctorius L.) seeds for melanogenesis (2004) Biol Pharm Bull, 27, pp. 1976-1978; Kim, J.H., Kim, M.R., Lee, E.S., Lee, C.H., Inhibitory effects of calycosin isolated from the root of Astragalus membranaceus on melanin biosynthesis (2009) Biol Pharm Bull, 32, pp. 264-268; Kong, Y.H., Inhibitory effects of cinnamic acid on melanin biosynthesis in skin (2008) Biol Pharm Bull, 31, pp. 946-948; Cho, Y., Kim, K.H., Shim, J.S., Hwang, J.K., Inhibitory effects of macelignan isolated from Myristica fragrans HOUTT. on melanin biosynthesis (2008) Biol Pharm Bull, 31, pp. 986-989; Lee, M.Y., The melanin synthesis inhibition and radical scavenging activities of compounds isolated from the aerial part of Lespedeza cyrtobotrya (2010) J Microbiol Biotechnol, 20, pp. 988-994; Kim, J.P., Melanocins A, B and C, new melanin synthesis inhibitors produced by Eupenicillium shearii. 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year = "2015",
doi = "10.1038/srep07995",
language = "English",
volume = "5",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Discovery of highly potent tyrosinase inhibitor, T1, with significant anti-melanogenesis ability by zebrafish in vivo assay and computational molecular modeling

AU - Chen, Wang-Chuan

AU - Tseng, Tien-Sheng

AU - Hsiao, Nai-Wan

AU - Lin, Yun-Lian

AU - Wen, Zhi-Hong

AU - Tsai, Chin-Chuan

AU - Lee, Yu-Ching

AU - Lin, Hui-Hsiung

AU - Tsai, Keng-Chang

N1 - 被引用次數:2 Export Date: 28 March 2016 通訊地址: Tsai, K.-C.; National Research Institute of Chinese Medicine, Ministry of Health and WelfareTaiwan 參考文獻: Seo, S.Y., Sharma, V.K., Sharma, N., Mushroom tyrosinase: Recent prospects (2003) J Agric Food Chem, 51, pp. 2837-2853; Prota, G., Progress in the chemistry of melanins and related metabolites (1988) Med Res Rev, 8, pp. 525-556; Spritz, R.A., Hearing, Jr.V.J., Genetic disorders of pigmentation (1994) Adv Hum Genet, 22, pp. 1-45; Lindquist, N.G., Accumulation of drugs on melanin (1973) Acta Radiol Diagn (Stockh), 325, pp. 1-92; Solano, F., Briganti, S., Picardo, M., Ghanem, G., Hypopigmenting agents: An updated review on biological, chemical and clinical aspects (2006) Pigment Cell Res, 19, pp. 550-571; Briganti, S., Camera, E., Picardo, M., Chemical and instrumental approaches to treat hyperpigmentation (2003) Pigment Cell Res, 16, pp. 101-110; Pawelek, J.M., Korner, A.M., The biosynthesis of mammalian melanin (1982) Am Sci, 70, pp. 136-145; Passi, S., Nazzaro-Porro, M., Molecular basis of substrate and inhibitory specificity of tyrosinase: Phenolic compounds (1981) Br J Dermatol, 104, pp. 659-665; Solomon, E.I., Sundaram, U.M., MacHonkin, T.E., Multicopper Oxidases and Oxygenases (1996) Chem Rev, 96, pp. 2563-2606; Cabanes, J., Garcia-Canovas, F., Lozano, J.A., Garcia-Carmona, F., A kinetic study of the melanization pathway between L-tyrosine and dopachrome (1987) Biochim Biophys Acta, 923, pp. 187-195; Cass, A.E., Hill, H.A., Copper proteins and copper enzymes (1980) Ciba Found Symp, 79, pp. 71-91; Zhang, X., Hu, X., Hou, A., Wang, H., Inhibitory effect of 2, 4, 2', 4'-tetrahydroxy-3-(3-methyl-2-butenyl)-chalcone on tyrosinase activity and melanin biosynthesis (2009) Biol Pharm Bull, 32, pp. 86-90; Park, K.H., Inhibitory effect of ammonium tetrathiotungstate on tyrosinase and its kinetic mechanism (2006) Chem Pharm Bull (Tokyo), 54, pp. 1266-1270; Chen, Q.X., Kubo, I., Kinetics of mushroom tyrosinase inhibition by quercetin (2002) J Agric Food Chem, 50, pp. 4108-4112; Jones, K., Hughes, J., Hong, M., Jia, Q., Orndorff, S., Modulation of melanogenesis by aloesin: A competitive inhibitor of tyrosinase (2002) Pigment Cell Res, 15, pp. 335-340; Kubo, I., Kinst-Hori, I., Flavonols from saffron flower: Tyrosinase inhibitory activity and inhibition mechanism (1999) J Agric Food Chem, 47, pp. 4121-4125; Reish, O., Townsend, D., Berry, S.A., Tsai, M.Y., King, R.A., Tyrosinase inhibition due to interaction of homocyst(e)ine with copper: The mechanism for reversible hypopigmentation in homocystinuria due to cystathionine beta-synthase deficiency (1995) Am J Hum Genet, 57, pp. 127-132; Shimizu, K., Kondo, R., Sakai, K., Inhibition of tyrosinase by flavonoids, stilbenes and related 4-substituted resorcinols: Structure-activity investigations (2000) Planta Med, 66, pp. 11-15; Funasaka, Y., Komoto, M., Ichihashi, M., Depigmenting effect of alpha-tocopheryl ferulate on normal human melanocytes (2000) Pigment Cell Res, 13, pp. 170-174; Mishima, Y., Hatta, S., Ohyama, Y., Inazu, M., Induction of melanogenesis suppression: Cellular pharmacology and mode of differential action (1988) Pigment Cell Res, 1, pp. 367-374; Smith, C.J., O'Hare, K.B., Allen, J.C., Selective cytotoxicity of hydroquinone for melanocyte-derived cells is mediated by tyrosinase activity but independent of melanin content (1988) Pigment Cell Res, 1, pp. 386-389; Maeda, K.F.M., In vitro effectiveness of several whitening cosmetic components in human melanocytes (1991) J. Soc. Cosmet. Chem., 42, pp. 361-368; Arandt, K.A.F.T.B., Topical use of hydroquinine as a depigmenting agent (1965) J. Am. Med. Assoc., 194, pp. 117-119; Fitzpatrick, T.B., Arndt, K.A., El-Mofty, A.M., Pathak, M.A., Hydroquinone and psoralens in the therapy of hypermelanosis and vitiligo (1966) Arch Dermatol, 93, pp. 589-600; Kligman, A.M., Willis, I., A new formula for depigmenting human skin (1975) Arch Dermatol, 111, pp. 40-48; Heilgemeir, G.P., Balda, B.R., [Irreversible toxic depigmentation. Observations following use of hydroquinonemonobenzylether-containing skin bleaching preparations] (1981) MMW Munch Med Wochenschr, 123, pp. 47-48; Breathnach, A.C., Nazzaro-Porro, M., Passi, S., Zina, G., Azelaic acid therapy in disorders of pigmentation (1989) Clin Dermatol, 7, pp. 106-119; Verallo-Rowell, V.M., Verallo, V., Graupe, K., Lopez-Villafuerte, L., Garcialopez, M., Double-blind comparison of azelaic acid and hydroquinone in the treatment of melasma (1989) Acta Derm Venereol Suppl (Stockh), 143, pp. 58-61; Jimbow, K., N-acetyl-4-S-cysteaminylphenol as a new type of depigmenting agent for the melanoderma of patients with melasma (1991) Arch Dermatol, 127, pp. 1528-1534; Funayama, M., Effects of alpha-and beta-arbutin on activity of tyrosinases from mushroom and mouse melanoma (1995) Biosci Biotechnol Biochem, 59, pp. 143-144; Kim, Y.J., Uyama, H., Tyrosinase inhibitors from natural and synthetic sources: Structure, inhibition mechanism and perspective for the future (2005) Cellular and Molecular Life Sciences: CMLS, 62, pp. 1707-1723; Marrero-Ponce, Y., Prediction of tyrosinase inhibition activity using atom-based bilinear indices (2007) ChemMedChem, 2, pp. 449-478; Parvez, S., Survey and mechanism of skin depigmenting and lightening agents (2006) Phytother Res, 20, pp. 921-934; Curto, E.V., Inhibitors of mammalian melanocyte tyrosinase: In vitro comparisons of alkyl esters of gentisic acid with other putative inhibitors (1999) Biochem Pharmacol, 57, pp. 663-672; Hermanns, J.F., Pierard-Franchimont, C., Pierard, G.E., Skin colour assessment in safety testing of cosmetics. An overview (2000) Int J Cosmet Sci, 22, pp. 67-71; Fuyuno, I., Spotlight turns on cosmetics for Asian skin (2004) Nature, 432, p. 938; Shimizu, K., Yasutake, S., Kondo, R., A new stilbene with tyrosinase inhibitory activity from Chlorophora excelsa (2003) Chemical & Pharmaceutical Bulletin, 51, pp. 318-319; Park, S.H., Terrein: A new melanogenesis inhibitor and its mechanism (2004) Cellular and Molecular Life Sciences: CMLS, 61, pp. 2878-2885; Zhong, S., Depigmentation of melanocytes by the treatment of extracts from traditional Chinese herbs: A cell culture assay (2006) Biol Pharm Bull, 29, pp. 1947-1951; Choi, S.Y., (4-Methoxy-benzylidene)-(3-methoxy-phenyl)-amine, a nitrogen analog of stilbene as a potent inhibitor of melanin production (2002) Chem Pharm Bull (Tokyo), 50, pp. 450-452; Baek, S., Inhibitory effect of dalbergioidin isolated from the trunk of Lespedeza cyrtobotrya on melanin biosynthesis (2008) J Microbiol Biotechnol, 18, pp. 874-879; Yanagihara, M., Inhibitory effect of gnetin C, a resveratrol dimer from melinjo (Gnetum gnemon), on tyrosinase activity and melanin biosynthesis (2012) Biol Pharm Bull, 35, pp. 993-996; Roh, J.S., Han, J.Y., Kim, J.H., Hwang, J.K., Inhibitory effects of active compounds isolated from safflower (Carthamus tinctorius L.) seeds for melanogenesis (2004) Biol Pharm Bull, 27, pp. 1976-1978; Kim, J.H., Kim, M.R., Lee, E.S., Lee, C.H., Inhibitory effects of calycosin isolated from the root of Astragalus membranaceus on melanin biosynthesis (2009) Biol Pharm Bull, 32, pp. 264-268; Kong, Y.H., Inhibitory effects of cinnamic acid on melanin biosynthesis in skin (2008) Biol Pharm Bull, 31, pp. 946-948; Cho, Y., Kim, K.H., Shim, J.S., Hwang, J.K., Inhibitory effects of macelignan isolated from Myristica fragrans HOUTT. on melanin biosynthesis (2008) Biol Pharm Bull, 31, pp. 986-989; Lee, M.Y., The melanin synthesis inhibition and radical scavenging activities of compounds isolated from the aerial part of Lespedeza cyrtobotrya (2010) J Microbiol Biotechnol, 20, pp. 988-994; Kim, J.P., Melanocins A, B and C, new melanin synthesis inhibitors produced by Eupenicillium shearii. I. 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PY - 2015

Y1 - 2015

N2 - 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, Ki = 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.

AB - 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, Ki = 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.

U2 - 10.1038/srep07995

DO - 10.1038/srep07995

M3 - Article

VL - 5

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

ER -