title: Structural influence on radical formation and sensitizing capacity of alkylic limonene hydroperoxide analogues in allergic contact dermatitis.
abstract: Hydroperoxides are known to be strong contact allergens and a common cause of contact allergy. They are easily formed by the autoxidation of, for example, fragrance terpenes, compounds that are common in perfumes, cosmetics, and household products. A requirement of the immunological mechanisms of contact allergy is the formation of an immunogenic hapten-protein complex. For hydroperoxides, a radical mechanism is postulated for this formation. In our previous investigations of allylic limonene hydroperoxides, we found that the formation of carbon- and oxygen-centered radicals, as well as the sensitizing capacity, is influenced by the structure of the hydroperoxides. The aim of the present work was to further investigate the connection between structure, radical formation, and sensitizing capacity by studying alkylic analogues of the previously investigated allylic limonene hydroperoxides. The radical formation was studied in radical-trapping experiments employing 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride as an initiator and 1,1,3,3-tetramethylisoindolin-2-yloxyl as a radical trapper. We found that the investigated hydroperoxides initially form carbon- and oxygen-centered radicals that subsequently form alcohols and ketones. Trapped carbon-centered radicals and nonradical products were isolated and identified. Small changes in structure, like the omission of the endocyclic double bond or the addition of a methyl group, resulted in large differences in radical formation. The results indicate that alkoxyl radicals seem to be more important than carbon-centered radicals in the immunogenic complex formation. The sensitizing capacities were studied in the murine local lymph node assay (LLNA), and all hydroperoxides tested were found to be potent sensitizers. For two of the hydroperoxides investigated, the recently suggested thiol-ene reaction is a possible mechanism for the formation of immunogenic complexes. For the third investigated, fully saturated, hydroperoxide, the thiol-ene mechanism is not possible for immunogenic complex formation. This strongly indicates that several radical reaction pathways for immunogenic complex formation of limonene hydroperoxides are active in parallel.
authors.affiliation: Dermatochemistry and Skin Allergy and Medicinal Chemistry, Department of Chemistry, University of Gothenburg, SE-412 96 Gothenburg, Sweden.
authors.forename: Staffan G H
authors.initials: SG
authors.lastname: Johansson
authors.forename: Katarina
authors.initials: K
authors.lastname: Emilsson
authors.forename: Morten
authors.initials: M
authors.lastname: Grøtli
authors.forename: Anna
authors.initials: A
authors.lastname: Börje
mesh_terms: D000485:Allergens / Q000737:chemistry* / Q000276:immunology*; D000818:Animals; D053138:Cyclohexenes / Q000737:chemistry* / Q000276:immunology*; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy; D006241:Haptens / Q000737:chemistry / Q000276:immunology; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry* / Q000276:immunology*; D000077222:Limonene; D051379:Mice; D013729:Terpenes / Q000737:chemistry* / Q000276:immunology*
chemical_list: D000485:Allergens; D053138:Cyclohexenes; D006241:Haptens; D013729:Terpenes; D000077222:Limonene; D006861:Hydrogen Peroxide