title: Chemical mechanisms for skin sensitization by aromatic compounds with hydroxy and amino groups.
abstract: It is well-known that aromatic diamino-, dihydroxy-, and amino-hydroxy compounds, with NH(2) and OH groups in ortho- or para-positions relative to each other, are strong skin sensitizers. In this paper, we analyze published potency and cross-reactivity data, whereby animals sensitized to one of these compounds are challenged with other compounds. The data are consistent with two parallel chemical reaction mechanisms: oxidation to electrophilic (protein reactive) quinones or quinone imines or formation of protein-reactive free radicals such as the Wurster salt, which can be formed by para-phenylene diamine. Compounds with NH(2) and OH groups meta to each other have also been found to be skin sensitizers, in some cases quite strong sensitizers. For these compounds, direct formation of quinones or quinone imines is not possible, and free radicals of the Wurster salt type are not favored. Here, we present a molecular mechanism to rationalize the sensitization potential of such compounds and, using the results of quantum mechanics calculations, show how this mechanism can explain observed structure-potency trends.
authors.affiliation: Safety and Environmental Assurance Centre (SEAC), Unilever, Colworth, Sharnbrook, Bedford, MK44 1LQ, England.
authors.forename: Aynur O
authors.initials: AO
authors.lastname: Aptula
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Enoch
authors.forename: David W
authors.initials: DW
authors.lastname: Roberts
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D005609:Free Radicals / Q000378:metabolism; D006168:Guinea Pigs; D007097:Imines / Q000737:chemistry / Q000633:toxicity; D010084:Oxidation-Reduction; D010636:Phenols / Q000737:chemistry / Q000633:toxicity*; D010655:Phenylenediamines / Q000737:chemistry / Q000633:toxicity; D011485:Protein Binding; D011809:Quinones / Q000737:chemistry / Q000633:toxicity; D012867:Skin / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D005609:Free Radicals; D007097:Imines; D010636:Phenols; D010655:Phenylenediamines; D011809:Quinones