Abrogating effect of a xanthophyll carotenoid astaxanthin on the stem cell factor-induced stimulation of human epidermal pigmentation

Arch Dermatol Res. 2012 Dec;304(10):803-16. doi: 10.1007/s00403-012-1248-y. Epub 2012 May 26.

Abstract

We established a model for the stem cell factor (SCF)-associated stimulation of human epidermal equivalent (HEE) pigmentation. The addition of SCF (at 5 nM) gradually stimulated the visible pigmentation of HEEs over 14 days of treatment. A time course study using real-time RT-PCR and western blotting analysis demonstrated that the expression of all melanocyte-specific genes and proteins examined was gradually up-regulated over 7-10 days of treatment with SCF. The addition of astaxanthin (Ax) at concentrations of 1, 4, or 8 μM markedly abolished the SCF- but not the endothelin (EDN)1-elicited increase in visible pigmentation over 14 days in a dose-dependent manner, with almost complete inhibition at 8 μM. While no degeneration of the epidermal tissue was visible at day 14 by HE staining, melanin deposition throughout the epidermis was markedly reduced in the Ax-treated HEEs at day 14 compared to untreated controls. Ax significantly reduced the eumelanin content of HEEs to the non-SCF-stimulated level at concentrations of 4 or 8 μM compared with untreated controls. Real-time RT-PCR and western blotting of Ax-treated HEEs revealed that the SCF-stimulated expression of tyrosinase (TYR), TYR-related protein-1 (TYRP1), and Pmel17, as well as microphthalmia-associated transcription factor (MITF), is significantly suppressed by Ax at the transcriptional and translational levels. Studies using cultured normal human melanocytes revealed that pre-treatment with Ax interrupts the SCF- but not the EDN1-induced stimulation of TYR activity, and there was no direct inhibitory effect of Ax on TYR activity in vitro. These findings indicate that Ax attenuates SCF-stimulated pigmentation by directly interrupting SCF-associated intracellular signaling linkages through increased expression of MITF, which leads to the stimulated expression of melanogenic genes and proteins in a reactive oxygen species depletion-independent mechanism.

MeSH terms

  • Cells, Cultured
  • Endothelin-1 / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • Epidermis / drug effects*
  • Gene Expression Regulation / drug effects
  • Humans
  • Hyperpigmentation / metabolism*
  • Melanocytes / drug effects
  • Melanocytes / metabolism*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Microphthalmia-Associated Transcription Factor / genetics
  • Microphthalmia-Associated Transcription Factor / metabolism
  • Monophenol Monooxygenase / genetics
  • Monophenol Monooxygenase / metabolism
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism
  • Skin Pigmentation / drug effects*
  • Stem Cell Factor / antagonists & inhibitors*
  • Stem Cell Factor / pharmacology
  • Xanthophylls / pharmacology
  • gp100 Melanoma Antigen / metabolism

Substances

  • Endothelin-1
  • Membrane Glycoproteins
  • Microphthalmia-Associated Transcription Factor
  • Stem Cell Factor
  • Xanthophylls
  • gp100 Melanoma Antigen
  • astaxanthine
  • Oxidoreductases
  • TYRP1 protein, human
  • Monophenol Monooxygenase