title: Carbon- and oxygen-centered radicals are equally important haptens of allylic hydroperoxides in allergic contact dermatitis.
abstract: Limonene is one of the most commonly used fragrance compounds in western countries today. When exposed to air, it autoxidises, forming hydroperoxides that are strong contact allergens. To cause allergic contact dermatitis (ACD), the hydroperoxides are considered to bind covalently to proteins in the skin via a radical pathway. Consequently, the nature and reactions of the radicals formed from the hydroperoxides are important. We have examined the radical formation from, and sensitizing potential of, three allylic hydroperoxides. Two of these are found in the oxidation mixture of limonene, while the third is a synthetic structural analogue. The identity of the radicals formed from these hydroperoxides has been studied in radical trapping experiments. Chemical trapping experiments were performed using 5,10,15,20-tetraphenyl-21 H,23 H-porphine iron(III) chloride [Fe(III)TPPCl 3] as an initiator and 1,1,3,3-tetramethylisoindolin-2-yloxyl as a radical trapper. Electron paramagnetic resonance experiments using photolysis for initiation were performed with and without 5-diethoxy-phosphoryl-5-methyl-1-pyrroline N-oxide. Our results demonstrate the ability of the studied hydroperoxides to form peroxyl, allyloxyl, and oxiranylcarbinyl radicals. These radicals can potentially react with proteins to form immunogenic hapten-protein complexes relevant for ACD. The sensitizing potency of the hydroperoxides was studied in the murine local lymph node assay. All three hydroperoxides were found to be potent sensitizers with some variations, which can be related to the identity and quantity of the radicals formed. The results indicate that both carbon- and oxygen-centered radicals are important intermediates in the formation of hapten-protein complexes and that the sensitizing potency of the hydroperoxides is related to their structures.
authors.affiliation: Department of Chemistry, Dermatochemistry and Skin Allergy, Medicinal Chemistry, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Staffan
authors.initials: S
authors.lastname: Johansson
authors.forename: Elena
authors.initials: E
authors.lastname: Giménez-Arnau
authors.forename: Morten
authors.initials: M
authors.lastname: Grøtli
authors.forename: Ann-Therese
authors.initials: AT
authors.lastname: Karlberg
authors.forename: Anna
authors.initials: A
authors.lastname: Börje
mesh_terms: D000485:Allergens / Q000737:chemistry* / Q000633:toxicity; D000818:Animals; D053138:Cyclohexenes / Q000737:chemistry* / Q000633:toxicity; D017449:Dermatitis, Allergic Contact / Q000209:etiology* / Q000473:pathology; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D005609:Free Radicals / Q000737:chemistry; D006241:Haptens / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000737:chemistry*; D000077222:Limonene; D023441:Local Lymph Node Assay; D008198:Lymph Nodes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D010084:Oxidation-Reduction; D019097:Spin Trapping; D013729:Terpenes / Q000737:chemistry* / Q000633:toxicity; D013936:Thymidine / Q000378:metabolism
chemical_list: D000485:Allergens; D053138:Cyclohexenes; D005609:Free Radicals; D006241:Haptens; D013729:Terpenes; D000077222:Limonene; D006861:Hydrogen Peroxide; D013936:Thymidine