title: Mechanisms of melanogenesis inhibition by 2,5-dimethyl-4-hydroxy-3(2H)-furanone.
abstract: BACKGROUND
  Increased production and accumulation of melanin is characteristic of a large number of skin diseases, including acquired hyperpigmentation such as melasma, postinflammatory melanoderma and solar lentigo. Thus, there is a increasing need for the development of depigmenting agents.
  
  
  OBJECTIVE
  To evaluate the depigmenting capacity of 2,5-dimethyl-4-hydroxy-3(2H)-furanone (DMHF) and to elucidate the mechanisms by which it inhibits alpha-melanocyte-stimulating hormone (alpha-MSH)-induced melanogenesis in B16 melanoma cells in vitro.
  
  
  METHODS
  Several experiments were performed in B16 melanoma cells. We studied melanin content, tyrosinase activity and cAMP production, and performed cAMP response element (CRE) luciferase reporter assay and Western blots for proteins involved in melanogenesis.
  
  
  RESULTS
  The melanin content and tyrosinase activity induced by alpha-MSH were inhibited significantly by DMHF. To clarify the mechanism of the depigmenting property of DMHF, we examined the involvement of DMHF in cAMP signalling induced by alpha-MSH. In CRE luciferase reporter assay, CRE reporter activation induced by alpha-MSH was inhibited by DMHF. Additionally, although DMHF did not inhibit cAMP production by alpha-MSH, both CRE binding protein (CREB) phosphorylation and the reduction of glycogen synthase kinase-3beta phosphorylation by alpha-MSH were blocked by DMHF. These data suggest that DMHF inhibits the downstream step of cAMP production induced by alpha-MSH, consequently inhibiting melanogenesis. This suggestion was further confirmed by the fact that the increased production levels of microphthalmia-associated transcription factor, tyrosinase and tyrosinase-related protein-1 induced by alpha-MSH were all reduced by DMHF in B16 melanoma cells.
  
  
  CONCLUSIONS
  Our study shows that DMHF inhibits alpha-MSH-induced melanogenesis by suppressing CREB phosphorylation, which is induced by protein kinase A, and suggests that DMHF may be an effective inhibitor of hyperpigmentation.
authors.affiliation: Biospectrum Life Science Institute, Gyunggi Do, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: E
authors.initials: E
authors.lastname: Jung
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Huh
authors.forename: Y C
authors.initials: YC
authors.lastname: Boo
authors.forename: C G
authors.initials: CG
authors.lastname: Hyun
authors.forename: Y-S
authors.initials: YS
authors.lastname: Kim
authors.forename: D
authors.initials: D
authors.lastname: Park
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000473:pathology; D051739:Microphthalmia-Associated Transcription Factor / Q000096:biosynthesis; D014442:Monophenol Monooxygenase / Q000096:biosynthesis / Q000378:metabolism; D010088:Oxidoreductases / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D000521:alpha-MSH / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D005663:Furans; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; C058427:furaneol; D000521:alpha-MSH; D000242:Cyclic AMP; D010088:Oxidoreductases; C064056:tyrosinase-related protein-1; D014442:Monophenol Monooxygenase