title: Nobiletin, a polymethoxy flavonoid, reduced endothelin-1 plus SCF-induced pigmentation in human melanocytes.
abstract: Nobiletin is a unique flavonoid having polymethoxy groups and has exhibited anti-inflammatory and antiobesity effects. Here, we examined the inhibition of nobiletin on melanogenesis induced by endothelin-1 (ET) and stem cell factor (SCF) in normal human melanocytes. Nobiletin dose dependently reduced ET plus SCF-stimulated tyrosinase activity without causing cytotoxicity. Nobiletin reduced cAMP-response element-binding protein (CREB) phosphorylation and microphthalmia-associated transcription factor (MITF) expression, which is a key transcription factor for tyrosinase expression in pigmentation induced by ET plus SCF stimulation. Nobiletin treatment effectively decreased ET plus SCF-induced Raf-1, MEK and ERK1/2 phosphorylation and also downregulated the forskolin-induced phosphorylation of CREB. Furthermore, nobiletin inhibited ET plus SCF-triggered production of melanin and expression of MITF/tyrosinase in a three-dimensional human epidermal model. In accordance with protein expression, the expression of genes related to the pigmentation was also increased in the cells stimulated with ET plus SCF and the cotreatment with nobiletin decreased obviously the ET plus SCF-triggered gene expressions of tyrosinase, PMEL, TRP1 and MITF. Nobiletin contributes to hypopigmentation by downregulating MITF and tyrosinase expression through reduced Raf-1 phosphorylation. Our findings implicate nobiletin as a potential new whitening agent.
authors.affiliation: Research Institute for Biological Functions, Chubu University, Kasugai, Aichi, Japan.
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yonezawa
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Teruya
authors.forename: Je-Tae
authors.initials: JT
authors.lastname: Woo
authors.forename: Byung-Yoon
authors.initials: BY
authors.lastname: Cha
mesh_terms: D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D047309:Flavones / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008543:Melanins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D062327:Skin Lightening Preparations / Q000494:pharmacology*; D019089:Stem Cell Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D046509:Tissue Culture Techniques; D058951:gp100 Melanoma Antigen / Q000235:genetics / Q000378:metabolism
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D019332:Endothelin-1; D047309:Flavones; C497234:MITF protein, human; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; C548637:PMEL protein, human; D062327:Skin Lightening Preparations; D019089:Stem Cell Factor; D058951:gp100 Melanoma Antigen; D005576:Colforsin; C008661:nobiletin; D014442:Monophenol Monooxygenase; D019908:Proto-Oncogene Proteins c-raf; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases