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The effect of activating and deactivating substituents on the allergenicity of benzoquinone and benzoquinone derivatives.
Mbiya-W; Chipinda-I; Simoyi-RH; Siegel-PD
Toxicologist 2012 Mar; 126(Suppl 1):161
Benzoquinone (BQ) is an electrophilic contact allergen whose extreme skin sensitization (SS) potency is known to be mediated through Michael Addition (MA). It is also hypothesized that BQ will haptenate proteins via free radical formation. The reactivity and subsequent SS potency of BQ derivatives (BQD) is, however, unknown. The objective of this study was to assess the negative inductive effects (activating) and positive inductive effects (deactivating) of substituents on BQ reactivity to a nucleophilic thiol and utilize this in chemico assay to predict the allergenicity of BQD. Reactivity of BQ and BQD to nitrobenzenethiol (NBT) was used as a surrogate for protein binding of the electrophiles. Pseudo-first order rate constants (k) of chlorine, methyl and t-butyl substituted BQD reactions to NBT were determined at pH 7.4 and 5.5. Electron paramagnetic resonance (EPR) studies to probe a potential free radical mediated binding mechanism of BQD to nucleophiles were also performed. The k values demonstrated the chlorine substituted (activated) BQD to be more reactive than the methyl and t-butyl substituted (deactivated) BQD, correlating with the respective EPR intensities. The results suggest that binding of BQD to proteins may also occur via free radical mechanism which is pH dependent, in addition to the predominant MA mechanism. Local lymph node assays (LLNA) for BQ and BQD were conducted in BALB/c mice. The LLNA EC3 values for the BQD were of the order; chlorine < methyl < t-butyl substituted BQD, consistent with that predicted by reactivity data. Results of the present study suggest potential utility of employing chemical reactivity data for electrophilic allergen identification and potency ranking.
Allergens; Skin-irritants; Sensitization; Free-radical-generation; Chemical-hypersensitivity; Chemical-reactions; Thiols; Proteins; Allergic-reactions; Nitro-compounds; Bioassays; Free-radicals; Lymph-nodes
Healthcare and Social Assistance; Services
The Toxicologist. Society of Toxicology 51st Annual Meeting and ToxExpo, March 11-15, 2012, San Francisco, California
OR; WV; CA