• Mingyeong Kang, See-Hyoung Park, Se Jung Park, Sae Woong Oh, Ju Ah Yoo, Kitae Kwon, Jangsoon Kim, Eunbi Yu, Jae Youl Cho, and Jongsung Lee.
• Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon City, 16419 Gyunggi Do, Republic of Korea.
• Phytomedicine. 2019 May 1; 58: 152877.

BackgroundMelanin plays a crucial role in protecting human skin against exposure to ultraviolet (UV) radiation. However, its overproduction induces hyperpigmentation disorders of the skin.PurposeTo investigate effects of phenylethyl resorcinol as one resorcinol derivative on melanogenesis and its mechanisms using B16F10 mouse melanoma cells and human epidermal melanocytes.MethodsEffects of phenylethyl resorcinol on melanogenesis and its mechanism of action were examined using several in vitro assays (i.e., cell survival, melanin content, cellular tyrosinase activity, real-time PCR analysis, luciferase-reporter assay, Western blot analysis, and ELISAs for cyclic AMP (cAMP), protein kinase A (PKA), cAMP response element binding (CREB) protein, and mitogen-activated protein kinases (MAPKs)).ResultsPhenylethyl resorcinol reduced both melanin content and tyrosinase activity in these cells. Phenylethyl resorcinol also suppressed tyrosinase activity in cell-free tyrosinase enzyme assay. Although phenylethyl resorcinol decreased mRNA levels of tyrosinase and tyrosinase-related protein (TRP)-2, it did not affect mRNA levels of melanogenic gene microphthalmia-associated transcriptional factor (MITF) or TRP-1. Phenylethyl resorcinol had no effects on cAMP signaling or NF-κB signaling based on results of cyclic AMP response element (CRE)-luciferase reporter assay, cAMP production, protein kinase A (PKA) activity, Western blot assays for phosphorylated CRE-binding protein (CREB), NF-κB-luciferase reporter assay, and Western blot assays for phosphorylated NF-κB. However, phenylethyl resorcinol induced activation of activator protein-1 (AP-1) signaling. Specifically, phenylethyl resorcinol increased AP-1 reporter activity and increased phosphorylation of p44/42 MAPK, but not p38 MAPK or c-Jun N-terminal kinase (JNK). MEK1/2 and Src, upstream molecules of p44/42 MAPK were also phosphorylated by phenylethyl resorcinol. In addition, phenylethyl resorcinol-induced decreases in melanin content, tyrosinase activity, and MITF protein levels were attenuated by PD98059, a p44/42 MAPK inhibitor.ConclusionThese data indicate that the anti-melanogenic activity of phenylethyl resorcinol is mediated by activation of p44/42 MAPK, indicating that phenylethyl resorcinol may be a potential therapeutic agent for treating hyperpigmentation skin disorders.Copyright © 2019 Elsevier GmbH. All rights reserved.

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