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To date, there is accumulating <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> evidence for massive oxidative stress <jats:italic>via<\/jats:italic> hydrogen peroxide (H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>) and peroxynitrite (ONOO<jats:sup>\u2013<\/jats:sup>) in the skin of affected individuals. Autoimmune etiology is the favored theory. Since depletion of the essential amino acid L\u2010tryptophan (Trp) affects immune response mechanisms, we here looked at epidermal Trp metabolism <jats:italic>via<\/jats:italic> tryptophan hydroxylase (TPH) with its downstream cascade, including serotonin and melatonin. Our <jats:italic>in situ<\/jats:italic> immunofluorescence and Western blot data reveal significantly lower TPH1 expression in patients with vitiligo. Expression is also low in melanocytes and keratinocytes under <jats:italic>in vitro<\/jats:italic> conditions. Although <jats:italic>in vivo<\/jats:italic> Fourier transform\u2010Raman spectroscopy proves the presence of 5\u2010hydroxytryptophan, epidermal TPH activity is completely absent. Regulation of TPH <jats:italic>via<\/jats:italic> microphthalmia\u2010associated transcription factor and L\u2010type calcium channels is severely affected. Moreover, dopa decarboxylase (DDC) expression is significantly lower, in association with decreased serotonin and melatonin levels. Computer simulation supports H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\/ONOO<jats:sup>\u2013<\/jats:sup>\u2010mediated oxidation\/nitration of TPH1 and DDC, affecting, in turn, enzyme functionality. Taken together, our data point to depletion of epidermal Trp by Fenton chemistry and exclude melatonin as a relevant contributor to epidermal redox balance and immune response in vitiligo.\u2014Schallreuter, K. U., Salem, M. A. E. L., Gibbons, N. C. J., Martinez, A., Slominski, R., L\u00fcdemann, J., Rokos, H. Blunted epidermal L\u2010tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 1: epidermal H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\/ONOO<jats:sup>\u2013<\/jats:sup>\u2010mediated stress abrogates tryptophan hydroxylase and dopa decarboxylase activities, leading to low serotonin and melatonin levels. <jats:italic>FASEB J.<\/jats:italic> 26, 2457\u20102470 (2012). <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link><\/jats:p>","DOI":"10.1096\/fj.11-197137","type":"journal-article","created":{"date-parts":[[2012,3,14]],"date-time":"2012-03-14T20:18:44Z","timestamp":1331756324000},"page":"2457-2470","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Blunted epidermal L\u2010tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 1: epidermal H<sub>2<\/sub>O<sub>2<\/sub>\/ONOO<sup>\u2013<\/sup>\u2010mediated stress abrogates tryptophan hydroxylase and dopa decarboxylase activities, leading to low serotonin and melatonin levels"],"prefix":"10.1096","volume":"26","author":[{"given":"Karin U.","family":"Schallreuter","sequence":"first","affiliation":[{"name":"Institute for Pigmentary Disorders E. 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