N-(4-bromophenethyl) Caffeamide Inhibits Melanogenesis by Regulating AKT/Glycogen Synthase Kinase 3 Beta/Microphthalmia-associated Transcription Factor and Tyrosinase-related Protein 1/Tyrosinase.
Skin color is primarily produced by melanin, which is a crucial pigment that protects the skin from UV-induced damage and prevents carcinogenesis. However, accumulated melanin in the skin may cause hyperpigmentation and related disorders. Melanin synthesis comprises consecutive oxidative reactions, and tyrosinase is the enzyme that catalyzes the rate-limiting process of melanogenesis. In this study, tyrosinase-related protein 1 (TRP-1) and TRP-2 contributed to melanin formation. N-(4-bromophenethyl) caffeamide ((E)-N-(4-bromophenethyl)-3-(3,4-dihydroxyphenyl)acrylamide; K36H), a caffeic acid phenyl amide derivative, inhibited α-melanocyte-stimulating hormone (α-MSH)-induced melanogenesis and tyrosinase activity in B16F0 cells. In addition, K36H reduced the protein expression of the phospho-cAMP response element binding protein (p-CREB), microphthalmia-associated transcription factor (MITF), tyrosinase, and TRP-1. Moreover, K36H promoted AKT and glycogen synthase kinase 3 beta (GSK3β) phosphorylation, thereby inhibiting MITF transcription activity. Thus, K36H attenuated α-MSH-induced cAMP pathways, contributing to hypopigmentation. The results of a safety assay revealed that K36H did not exhibit cytotoxicity or irritate the skin or eyes. According to these results, K36H may have the potential to be used as a whitening agent in the cosmetic and pharmaceutical industries.
Yueh-Hsiung
YH
Kuo
Chien-Chia
CC
Chen
Ping
P
Lin
Ya-Jhen
YJ
You
Department of Cosmeceutics, China Medical University, Taichung 404, Taiwan. hmchiang@mail.cmu.edu.tw.
Hsiu-Mei
HM
Chiang
D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D002109:Caffeic Acids; D051739:Microphthalmia-Associated Transcription Factor; C549043:N-2-(4-bromophenyl) ethyl caffeamide; D010088:Oxidoreductases; C064056:tyrosinase-related protein-1; D014442:Monophenol Monooxygenase; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3