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For prehaptens, this requires oxidative activation to generate electrophiles capable of reacting with skin proteins. While abiotic oxidation is established, enzymatic oxidation remains poorly understood. Because neutrophils can infiltrate the skin and release the heme peroxidase myeloperoxidase (MPO), we investigated whether human MPO contributes to the oxidative activation of selected sensitizers. The study included the hair dye precursor\n                    <jats:italic>p<\/jats:italic>\n                    -phenylenediamine (PPD) and its derivatives toluene-2,5-diamine (PTD) and 2-methoxymethyl-PPD (ME-PPD), together with the phenylpropanoid fragrance molecules eugenol and dihydroeugenol, and the aromatic alcohol cinnamyl alcohol. Molecular docking predicted productive binding orientations of all compounds except cinnamyl alcohol, which adopted a non-productive orientation within the MPO active site. Consistent with these predictions, in chemico experiments showed MPO-catalyzed oxidation of the aromatic diamines and phenylpropanoids with comparable catalytic efficiencies (10-25\u00a0\u00d7\u00a010\n                    <jats:sup>3\u00a0<\/jats:sup>\n                    mM\n                    <jats:sup>\u22121<\/jats:sup>\n                    \u00a0\u00d7\u00a0min\n                    <jats:sup>\u22121<\/jats:sup>\n                    ), whereas cinnamyl alcohol remained unconverted. High-resolution mass spectrometry revealed distinct metabolite profiles, with the aromatic diamines forming mono-, di-, and trimeric oxidation products, including Bandrowski\u2019s Base, whereas phenylpropanoids predominantly yielded monomeric quinone methides and dimers. Increased protein-binding potential was predicted for several observed metabolites using the OECD QSAR Toolbox. Collectively, these results demonstrate that MPO catalyzes the oxidation of a subset of the investigated sensitizers, generating metabolites predicted to exhibit increased protein-binding potential. These findings establish MPO-mediated oxidation as an additional enzymatic pathway that complements well-known abiotic oxidation and expands the current understanding of enzymatic activation in the skin.\n                  <\/jats:p>","DOI":"10.1007\/s00204-026-04549-y","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:45:26Z","timestamp":1790477126000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Human myeloperoxidase-driven activation of skin sensitizing p-phenylenediamine-related aromatic diamines and phenylpropanoids\u2013insights from in chemico and in silico approaches"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9868-4804","authenticated-orcid":false,"given":"Hannah","family":"Deusinger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7427-5352","authenticated-orcid":false,"given":"Philipp","family":"Peslalz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4062-9503","authenticated-orcid":false,"given":"Karma C.","family":"Fussell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4237-6087","authenticated-orcid":false,"given":"Sabine","family":"Langhoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1913-9478","authenticated-orcid":false,"given":"Udo","family":"Bock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0609-8227","authenticated-orcid":false,"given":"Carsten","family":"Goebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3625-0701","authenticated-orcid":false,"given":"Brunhilde","family":"Bl\u00f6meke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,27]]},"reference":[{"key":"4549_CR1","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1038\/jid.2008.209","volume":"129","author":"P Aeby","year":"2009","unstructured":"Aeby P, Sieber T, Beck H, Gerberick GF, Goebel C (2009) Skin sensitization to p-phenylenediamine: the diverging roles of oxidation and N-acetylation for dendritic cell activation and the immune response. 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