title: Oxidative stress via hydrogen peroxide affects proopiomelanocortin peptides directly in the epidermis of patients with vitiligo.
abstract: The human skin holds the capacity for autocrine processing of the proopiomelanocortin (POMC)-derived peptides. Recent data demonstrated the presence and functionality of ACTH, alpha- and beta-melanocyte-stimulating hormone (MSH), and beta-endorphin in the regulation of skin pigmentation, and a role has been put forward for alpha-MSH as an effective antioxidant. In patients with vitiligo, decreased epidermal POMC processing and low alpha-MSH levels were documented previously. These patients accumulate hydrogen peroxide (H2O2) in the 10(-3) M range in their epidermis. Therefore, we examined the involvement of H2O2 on POMC-derived peptides as possible targets for oxidation by this reactive oxygen species. To address this, we employed immunofluorescence labelling, dot blot analysis, Fourier transform Raman spectroscopy, functionality studies, and computer simulation of the peptide structures. We demonstrate H2O2-mediated oxidation of epidermal ACTH, alpha-MSH, and beta-endorphin in vitiligo owing to oxidation of methionine residues in the sequences of these peptides. Moreover, we show that oxidized beta-endorphin loses its function in the promotion of pigmentation in melanocytes. These changes are reversible upon the reduction of H2O2 levels by a pseudocatalase PC-KUS. Moreover, oxidation of alpha-MSH can be prevented by the formation of a 1:1 complex with the abundant cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin. Thus, using vitiligo, we demonstrate that H2O2 can affect pigmentation via epidermal POMC peptide redox homeostasis.
authors.affiliation: Clinical and Experimental Dermatology/Department of Biomedical Sciences, University of Bradford, Bradford, UK.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Spencer
authors.forename: Nicholas C J
authors.initials: NC
authors.lastname: Gibbons
authors.forename: Hartmut
authors.initials: H
authors.lastname: Rokos
authors.forename: Eva M J
authors.initials: EM
authors.lastname: Peters
authors.forename: John M
authors.initials: JM
authors.lastname: Wood
authors.forename: Karin U
authors.initials: KU
authors.lastname: Schallreuter
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000737:chemistry / Q000187:drug effects; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D003198:Computer Simulation; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism*; D005583:Fourier Analysis; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D008543:Melanins / Q000096:biosynthesis; D008954:Models, Biological; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D012880:Skin Pigmentation; D013059:Spectrum Analysis, Raman; D014820:Vitiligo / Q000378:metabolism* / Q000503:physiopathology; D000521:alpha-MSH / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D001615:beta-Endorphin / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism
chemical_list: D008543:Melanins; D010446:Peptide Fragments; D001708:Biopterins; D000521:alpha-MSH; D001615:beta-Endorphin; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D006861:Hydrogen Peroxide; C038109:pseudocatalase; D002374:Catalase; C003402:sapropterin