Cosmetic industries have an interest in exploring and developing materials that have the potential to regulate melanin synthesis in human skin. Although melanin protects the skin from ultraviolet irradiation, excess melanin can be undesirable, particularly on the face where spots or freckles are associated with an appearance of aging. In this study, we found that ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic acid (11α-OH KA) in Pteris dispar Kunze strongly inhibited melanin synthesis by suppressing tyrosinase gene expression. The melanogenic transcription factor microphthalmia-associated transcription factor (MITF) is required for this suppression. However, 11α-OH KA did not modulate the expression level or activity of MITF. Structure-activity relationship analyses suggested that the 11α-OH, 15-oxo, and 16-en moieties of 11α-OH KA are essential for the suppression of melanin synthesis. On the other hand, the 19-COOH moiety is important for preventing cellular toxicity associated with 11α-OH KA and its related compounds. These results suggest that 11α-OH KA is an attractive target for potential use in the production of cosmetic items.

Keywords:
Melanogenesis, Microphthalmia-associated transcription factor, Tyrosinase, Pteris dispar Kunze
1.
Boissy RE: Melanosome transfer to and translocation in the keratinocyte. Exp Dermatol 2003;12:5-12.
2.
Gilchrest BA, Park HY, Eller MS, Yaar M: Mechanisms of ultraviolet light-induced pigmentation. Photochem Photobiol 1996;63:1-10.
3.
Yamada T, Hasegawa S, Inoue Y, Date Y, Arima M, Yagami A, Iwata Y, Takahashi M, Yamamoto N, Mizutani H, Nakata S, Matsunaga K, Akamatsu H: Accelerated differentiation of melanocyte stem cells contributes to the formation of hyperpigmented maculae. Exp Dermatol 2014;23:652-658.
4.
d'Ischia M, Wakamatsu K, Napolitano A, Briganti S, Garcia-Borron JC, Kovacs D, Meredith P, Pezzella A, Picardo M, Sarna T, Simon JD, Ito S: Melanins and melanogenesis: methods, standards, protocols. Pigment Cell Melanoma Res 2013;26:616-633.
5.
Ando H, Oka M, Ichihashi M, Mishima Y: Protein kinase C and linoleic acid-induced inhibition of melanogenesis. Pigment Cell Res 1990;3:200-206.
6.
Kim DS, Park SH, Kwon SB, Li K, Youn SW, Park KC: (-)-Epigallocatechin-3-gallate and hinokitiol reduce melanin synthesis via decreased MITF production. Arch Pharm Res 2004;27:334-339.
7.
Kahn V: Effect of kojic acid on the oxidation of DL-DOPA, norepinephrine, and dopamine by mushroom tyrosinase. Pigment Cell Res 1995;8:234-240.
8.
Jimbow K, Obata H, Pathak MA, Fitzpatrick TB: Mechanism of depigmentation by hydroquinone. J Invest Dermatol 1974;62:436-449.
9.
Seiji M, Yoshida T, Itakura H, Irimajiri T: Inhibition of melanin formation by sulfhydryl compounds. J Invest Dermatol 1969;52:280-286.
10.
Ni-Komatsu L, Tong C, Chen G, Brindzei N, Orlow S: Identification of quinolines that inhibit melanogenesis by altering tyrosinase family trafficking. Mol Pharmacol 2008;74:1576-1586.
11.
Lin JY, Fisher DE: Melanocyte biology and skin pigmentation. Nature 2007;445:843-850.
12.
Vachtenheim J, Borovanský J: “Transcription physiology” of pigment formation in melanocytes: central role of MITF. Exp Dermatol 2010;19:617-627.
13.
Horike N, Kumagai A, Shimono Y, Onishi T, Itoh Y, Sasaki T, Kitagawa K, Hatano O, Takagi H, Susumu T, Teraoka H, Kusano K, Nagaoka Y, Kawahara H, Takemori H: Downregulation of SIK2 expression promotes the melanogenic program in mice. Pigment Cell Melanoma Res 2010;23:809-819.
14.
Yamahara M, Sugimura K, Kumagai A, Fuchino H, Kuroi A, Kagawa M, Itoh Y, Kawahara H, Nagaoka Y, Iida O, Kawahara N, Takemori H, Watanabe H: Callicarpa longissima extract, carnosol-rich, potently inhibits melanogenesis in B16F10 melanoma cells. J Nat Med 2016;70:28-35.
15.
Bouktaib M, Lebrun S, Atmani A, Rolando C: Hemisynthesis of all the O-monomethylated analogues of quercetin including the major metabolites, through selective protection of phenolic functions. Tetrahedron 2002;58:10001-10009.
16.
Tanaka N, Hata M, Murakami T, Saiki Y, Chen C-M: Weitere Inhaltsstoffe von Pteris dispar Kunze. Chem Pharm Bull 1976;24:1965-1966.
17.
Wu K, Liu Y, Lv Y, Cui L, Li W, Chen J, Liang NC, Li L: Ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic-acid induces apoptosis and cell cycle arrest in CNE-2Z nasopharyngeal carcinoma cells. Oncol Rep 2013;29:2101-2108.
18.
Li L, Chen GG, Lu YN, Liu Y, Wu KF, Gong XL, Gou ZP, Li MY, Liang NC: Ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic-acid inhibits growth of human lung cancer A549 cells by arresting cell cycle and triggering apoptosis. Chin J Cancer Res 2012;24:109-115.
19.
Weilbaecher KN, Motyckova G, Huber WE, Takemoto CM, Hemesath TJ, Xu Y, Hershey CL, Dowland NR, Wells AG, Fisher DE: Linkage of M-CSF signaling to Mitf, TFE3, and the osteoclast defect in Mitfmi/mi mice. Mol Cell 2001;8:749-758.
20.
Wu M, Hemesath TJ, Takemoto CM, Horstmann MA, Wells AG, Price ER, Fisher DZ, Fisher DE: c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi. Genes Dev 2000;14:301-312.
21.
Takeda K, Takemoto C, Kobayashi I, Watanabe A, Nobukuni Y, Fisher DE, Tachibana M: Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance. Hum Mol Genet 2000;9:125-132.
22.
Mansky KC, Sankar U, Han J, Ostrowski MC: Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-κB ligand signaling. J Biol Chem 2002;277:11077-11083.
23.
Sato S, Roberts K, Gambino G, Cook A, Kouzarides T, Goding CR: CBP/p300 as a co-factor for the Microphthalmia transcription factor. Oncogene 1997;14:3083-3092.
24.
Price ER, Horstmann MA, Wells AG, Weilbaecher KN, Takemoto CM, Landis MW, Fisher DE: α-Melanocyte-stimulating hormone signaling regulates expression of microphthalmia, a gene deficient in Waardenburg syndrome. J Biol Chem 1998;273:33042-33047.
25.
Wang X, Liu Y, Chen H, Mei L, He C, Jiang L, Niu Z, Sun J, Luo H, Li J, Feng Y: LEF-1 regulates tyrosinase gene transcription in vitro. PLoS One 2015;10:e0143142.
26.
Saito H, Yasumoto K, Takeda K, Takahashi K, Fukuzaki A, Orikasa S, Shibahara S: Melanocyte-specific microphthalmia-associated transcription factor isoform activates its own gene promoter through physical interaction with lymphoid-enhancing factor 1. J Biol Chem 2002;277:28787-28794.
© 2017 S. Karger AG, Basel
2017
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.