title: Mechanistic proposal for the formation of specific immunogenic complexes via a radical pathway: a key step in allergic contact dermatitis to olefinic hydroperoxides.
abstract: The widespread use of scented products causes an increase of allergic contact dermatitis to fragrance compounds in Western countries today. Many fragrance compounds are prone to autoxidation, forming hydroperoxides as their primary oxidation products. Hydroperoxides are known to be strong allergens and to form specific immunogenic complexes. However, the mechanisms for the formation of the immunogenic complexes are largely unknown. We have investigated this mechanism for (5R)-5-isopropenyl-2-methyl-2-cyclohexene-1-hydroperoxide (Lim-2-OOH) by studying the formation of adducts in the reaction between this hydroperoxide and 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride (Fe(III)TPPCl) in the presence of protected cysteine (NAc-Cys-OMe) or glutathione (GSH). Isolated adducts originate from the addition of the thiol group of NAc-Cys-OMe over the carbon-carbon double bonds of carvone. Furthermore, adducts between NAc-Cys-OMe and carveol as well as between GSH and carvone have been identified. The formation of these adducts most likely proceeds via the radical thiol-ene mechanism. The addition of a terpene moiety to cysteine offers an explanation of the specificity of the immune response to structurally different hydroperoxides. These results also explain the lack of cross-reactivity between carvone and Lim-2-OOH. In conclusion, we propose that immunogenic complexes of olefinic hydroperoxides can be formed via the radical thiol-ene mechanism. These complexes will be specific for the individual olefinic hydroperoxides due to the inclusion of a terpene moiety derived from the hydroperoxide.
authors.affiliation: Department of Chemistry, Dermatochemistry and Skin Allergy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Staffan
authors.initials: S
authors.lastname: Johansson
authors.forename: Theres
authors.initials: T
authors.lastname: Redeby
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Altamore
authors.forename: Ulrika
authors.initials: U
authors.lastname: Nilsson
authors.forename: Anna
authors.initials: A
authors.lastname: Börje
mesh_terms: D002851:Chromatography, High Pressure Liquid; D000081005:Cyclohexane Monoterpenes; D003545:Cysteine / Q000737:chemistry; D017449:Dermatitis, Allergic Contact / Q000209:etiology*; D005978:Glutathione / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000276:immunology*; D007501:Iron / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D039821:Monoterpenes / Q000737:chemistry; D011166:Porphyrins / Q000737:chemistry
chemical_list: C509964:5,10,15,20-tetraphenylporphyrin; D000081005:Cyclohexane Monoterpenes; D039821:Monoterpenes; D011166:Porphyrins; C006923:carvone; C075856:carveol; D006861:Hydrogen Peroxide; D007501:Iron; D005978:Glutathione; D003545:Cysteine