title: Epoxyalcohols: bioactivation and conjugation required for skin sensitization.
abstract: Allylic alcohols, such as geraniol 1, are easily oxidized by varying mechanisms, including the formation of both 2,3-epoxides and/or aldehydes. These epoxides, aldehydes, and epoxy-aldehydes can be interconverted to each other, and the reactivity of them all must be considered when considering the sensitization potential of the parent allylic alcohol. An in-depth study of the possible metabolites and autoxidation products of allylic alcohols is described, covering the formation, interconversion, reactivity, and sensitizing potential thereof, using a combination of in vivo, in vitro, in chemico, and in silico methods. This multimodal study, using the integration of diverse techniques to investigate the sensitization potential of a molecule, allows the identification of potential candidate(s) for the true culprit(s) in allergic responses to allylic alcohols. Overall, the sensitization potential of the investigated epoxyalcohols and unsaturated alcohols was found to derive from metabolic oxidation to the more potent aldehyde where possible. Where this is less likely, the compound remains weakly or nonsensitizing. Metabolic activation of a double bond to form a nonconjugated, nonterminal epoxide moiety is not enough to turn a nonsensitizing alcohol into a sensitizer, as such epoxides have low reactivity and low sensitizing potency. In addition, even an allylic 2,3-epoxide moiety is not necessarily a potent sensitizer, as shown for 2, where formation of the epoxide weakens the sensitization potential.
authors.affiliation: Department of Chemistry and Molecular Biology, Dermatochemistry and Skin Allergy, University of Gothenburg , SE-412 96 Gothenburg, Sweden.
authors.forename: Tamara
authors.initials: T
authors.lastname: Delaine
authors.forename: David J
authors.initials: DJ
authors.lastname: Ponting
authors.forename: Ida B
authors.initials: IB
authors.lastname: Niklasson
authors.forename: Roger
authors.initials: R
authors.lastname: Emter
authors.forename: Lina
authors.initials: L
authors.lastname: Hagvall
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Norrby
authors.forename: Andreas
authors.initials: A
authors.lastname: Natsch
authors.forename: Kristina
authors.initials: K
authors.lastname: Luthman
authors.forename: Ann-Therese
authors.initials: AT
authors.lastname: Karlberg
mesh_terms: D000080462:Acyclic Monoterpenes; D000447:Aldehydes / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D004852:Epoxy Compounds / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D023441:Local Lymph Node Assay; D008198:Lymph Nodes / Q000187:drug effects; D051379:Mice; D008808:Mice, Inbred CBA; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010455:Peptides / Q000032:analysis / Q000737:chemistry; D020005:Propanols / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D000080462:Acyclic Monoterpenes; D000447:Aldehydes; D004852:Epoxy Compounds; D010455:Peptides; D020005:Propanols; D013729:Terpenes; C006463:allyl alcohol; D006913:Hydroxysteroid Dehydrogenases; C007836:geraniol