title: Cytochrome P450-mediated activation of the fragrance compound geraniol forms potent contact allergens.
abstract: Contact sensitization is caused by low molecular weight compounds which penetrate the skin and bind to protein. In many cases, these compounds are activated to reactive species, either by autoxidation on exposure to air or by metabolic activation in the skin. Geraniol, a widely used fragrance chemical, is considered to be a weak allergen, although its chemical structure does not indicate it to be a contact sensitizer. We have shown that geraniol autoxidizes and forms allergenic oxidation products. In the literature, it is suggested but not shown that geraniol could be metabolically activated to geranial. Previously, a skin-like CYP cocktail consisting of cutaneous CYP isoenzymes, was developed as a model system to study cutaneous metabolism. In the present study, we used this system to investigate CYP-mediated activation of geraniol. In incubations with the skin-like CYP cocktail, geranial, neral, 2,3-epoxygeraniol, 6,7-epoxygeraniol and 6,7-epoxygeranial were identified. Geranial was the main metabolite formed followed by 6,7-epoxygeraniol. The allergenic activities of the identified metabolites were determined in the murine local lymph node assay (LLNA). Geranial, neral and 6,7-epoxygeraniol were shown to be moderate sensitizers, and 6,7-epoxygeranial a strong sensitizer. Of the isoenzymes studied, CYP2B6, CYP1A1 and CYP3A5 showed high activities. It is likely that CYP1A1 and CYP3A5 are mainly responsible for the metabolic activation of geraniol in the skin, as they are expressed constitutively at significantly higher levels than CYP2B6. Thus, geraniol is activated through both autoxidation and metabolism. The allergens geranial and neral are formed via both oxidation mechanisms, thereby playing a large role in the sensitization to geraniol.
authors.affiliation: Department of Chemistry, Dermatochemistry and Skin Allergy, University of Gothenburg, SE-412 96 Gothenburg, Sweden.
authors.forename: Lina
authors.initials: L
authors.lastname: Hagvall
authors.forename: Jens Malte
authors.initials: JM
authors.lastname: Baron
authors.forename: Anna
authors.initials: A
authors.lastname: Börje
authors.forename: Lars
authors.initials: L
authors.lastname: Weidolf
authors.forename: Hans
authors.initials: H
authors.lastname: Merk
authors.forename: Ann-Therese
authors.initials: AT
authors.lastname: Karlberg
mesh_terms: D000080462:Acyclic Monoterpenes; D000485:Allergens / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D017449:Dermatitis, Allergic Contact / Q000209:etiology*; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D023441:Local Lymph Node Assay; D051379:Mice; D039821:Monoterpenes / Q000378:metabolism / Q000633:toxicity; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010476:Perfume / Q000737:chemistry / Q000633:toxicity*; D013729:Terpenes / Q000378:metabolism / Q000633:toxicity*
chemical_list: D000080462:Acyclic Monoterpenes; D000485:Allergens; D004852:Epoxy Compounds; D039821:Monoterpenes; D010476:Perfume; D013729:Terpenes; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C510164:CYP3A5 protein, human; D019363:Cytochrome P-450 CYP1A1; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; C007836:geraniol; C007076:citral