title: Conjugated dienes as prohaptens in contact allergy: in vivo and in vitro studies of structure-activity relationships, sensitizing capacity, and metabolic activation.
abstract: There is a great interest in developing in vitro/in silico methods for the prediction of contact allergenic activity. However, many proposed methods do not take the activation of prohaptens to sensitizers by skin metabolism into account. As a consequence, consumer products containing potent sensitizers could be marketed. To identify prohaptens, studies regarding their structure-activity relationships and the mechanisms of their activation must be conducted. In the present investigation, we have studied the structure-activity relationships for alkene prohaptens. A series of seven alkenes (1-7), all of the same basic structure but with variation in the number and position(s) of the double bond(s), were designed and screened for sensitizing capacity using the murine local lymph node assay. Compounds 1-7 were also incubated with liver microsomes in the presence of glutathione to trap and identify reactive metabolites. The metabolic conversion of three alkenes (9-11) to epoxides (12-15) was also studied along with comparison of their sensitizing capacity. Our results show that conjugated dienes in or in conjunction with a six-membered ring are prohaptens that can be metabolically activated to epoxides and conjugated with GSH. Related alkenes containing isolated double bonds and an acyclic conjugated diene were shown to be weak or nonsensitizers. For the first time, the naturally occurring monoterpenes alpha-phellandrene, beta-phellandrene, and alpha-terpinene were demonstrated to be prohaptens able to induce contact allergy. The difference in sensitizing capacity of conjugated dienes as compared to alkenes with isolated double bonds was found to be due to the high reactivity and sensitizing capacity of the allylic epoxides metabolically formed from conjugated dienes. We recommend that these structure-activity relationship rules are incorporated into in silico predictive databases and propose that the prediction of contact allergenic activity of suspected prohaptens is based on assessment of susceptibility to metabolic activation and chemical reactivity of potential metabolites.
authors.affiliation: Department of Chemistry, Dermatochemistry and Skin Allergy and Department of Chemistry, Medicinal Chemistry, Göteborg University, Sweden.
authors.forename: Moa Andresen
authors.initials: MA
authors.lastname: Bergström
authors.forename: Kristina
authors.initials: K
authors.lastname: Luthman
authors.forename: J Lars G
authors.initials: JL
authors.lastname: Nilsson
authors.forename: Ann-Therese
authors.initials: AT
authors.lastname: Karlberg
mesh_terms: D000818:Animals; D017449:Dermatitis, Allergic Contact / Q000276:immunology* / Q000378:metabolism*; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry; D006241:Haptens / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008861:Microsomes / Q000187:drug effects; D015394:Molecular Structure; D008970:Molecular Weight; D010955:Plasmalogens / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004852:Epoxy Compounds; D006241:Haptens; D010955:Plasmalogens; D005978:Glutathione