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Kazinol U inhibits melanogenesis through the inhibition of tyrosinase‐related proteins via AMP kinase activation
Author(s) -
Lim Jihyun,
Nam Sorim,
Jeong Ji Hye,
Kim Min Jung,
Yang Young,
Lee MyeongSok,
Lee Hee Gu,
Ryu JaeHa,
Lim JongSeok
Publication year - 2019
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14560
Subject(s) - microphthalmia associated transcription factor , tyrosinase , protein kinase a , skin whitening , biology , arbutin , microbiology and biotechnology , zebrafish , transcription factor , chemistry , phosphorylation , biochemistry , pharmacology , enzyme , gene , active ingredient
Background and Purpose Kazinol U is a prenylated flavan isolated from an extract of Broussonetia kazinoki Sieb (Moraceae). Kazinol U has shown cytoprotective effects against cytokine‐induced apoptotic cell death and induces AMP kinase (AMPK) activation through LKB1 activation. However, kazinol U has not been tested as a regulator of melanogenesis, although bark extract of B. kazinoki has been used as a cosmetic ingredient for skin conditioning. Experimental Approach We cultured mouse, human melanoma cells and normal human melanocytes to demonstrate anti‐melanogenic effects of kazinol U. A tyrosinase activity assay, Western blot, RT‐qPCR and a luciferase reporter gene assay were performed to determine the anti‐melanogenic mechanisms of kazinol U. We confirmed its effect on melanogenesis in vivo using zebrafish. Key Results Kazinol U inhibited the expression and activity of tyrosinase, the rate‐limiting enzyme in melanogenesis, and reduced tyrosinase expression and activity in response to cAMP‐inducing agents. Kazinol U reduced the expression of other melanogenic enzymes, such as tyrosinase‐related protein (Tyrp) 1 and Tyrp2, and down‐regulated microphthalmia‐associated transcription factor (MITF), the master regulator of the tyrosinase gene family. Moreover, kazinol U induced phosphorylation of AMPK and MAPK proteins, which are MITF inhibitors. It also exhibited anti‐melanogenic effects in zebrafish, a recently developed in vivo model. Conclusions and Implications Our findings suggest that kazinol U reduces melanogenesis via its inhibitory effect on MITF and its downstream target genes, tyrosinase, Tyrp1 and Tyrp2. This work may provide a basis for the application of kazinol U for the treatment of hyperpigmentation skin disorders.