title: Reactivity measurement in estimation of benzoquinone and benzoquinone derivatives' allergenicity.
abstract: Benzoquinone (BQ) and benzoquinone derivatives (BQD) are used in the production of dyes and cosmetics. While BQ, an extreme skin sensitizer, is an electrophile known to covalently modify proteins via Michael Addition (MA) reaction whilst halogen substituted BQD undergo nucleophilic vinylic substitution (SNV) mechanism onto amine and thiol moieties on proteins, the allergenic effects of adding substituents on BQ have not been reported. The effects of inserting substituents on the BQ ring has not been studied in animal assays. However, mandated reduction/elimination of animals used in cosmetics testing in Europe has led to an increased need for alternatives for the prediction of skin sensitization potential. Electron withdrawing and electron donating substituents on BQ were assessed for effects on BQ reactivity toward nitrobenzene thiol (NBT). The NBT binding studies demonstrated that addition of EWG to BQ as exemplified by the chlorine substituted BQDs increased reactivity while addition of EDG as in the methyl substituted BQDs reduced reactivity. BQ and BQD skin allerginicity was evaluated in the murine local lymph node assay (LLNA). BQD with electron withdrawing groups had the highest chemical potency followed by unsubstituted BQ and the least potent were the BQD with electron donating groups. The BQD results demonstrate the impact of inductive effects on both BQ reactivity and allergenicity, and suggest the potential utility of chemical reactivity data for electrophilic allergen identification and potency ranking.
authors.affiliation: Department of Chemistry, Portland State University, Portland, OR 97207-0751, United States. Electronic address: wilbesm@gmail.com.
authors.forename: Wilbes
authors.initials: W
authors.lastname: Mbiya
authors.affiliation: Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505-2888, United States.
authors.forename: Itai
authors.initials: I
authors.lastname: Chipinda
authors.affiliation: Department of Chemistry, Portland State University, Portland, OR 97207-0751, United States.
authors.forename: Reuben H
authors.initials: RH
authors.lastname: Simoyi
authors.affiliation: Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505-2888, United States.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Siegel
mesh_terms: D000465:Algorithms; D000485:Allergens / Q000633:toxicity*; D000826:Animal Testing Alternatives; D000818:Animals; D016227:Benzoquinones / Q000633:toxicity*; D017449:Dermatitis, Allergic Contact / Q000473:pathology; D005260:Female; D023441:Local Lymph Node Assay; D008745:Methylation; D051379:Mice; D008807:Mice, Inbred BALB C; D021281:Quantitative Structure-Activity Relationship; D012867:Skin / Q000473:pathology; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D014753:Vinyl Compounds / Q000737:chemistry
chemical_list: D000485:Allergens; D016227:Benzoquinones; D013438:Sulfhydryl Compounds; D014753:Vinyl Compounds; C014712:4-nitrothiophenolate
keywords: Allergic contact dermatitis; Benzoquinone; Local lymph node assay; Michael addition; Nucleophilic vinylic substitution; SNV; Stimulation index