Substituent effects on the reactivity of benzoquinone derivatives with thiols

Details

• Personal Author:
  Chipinda I ; Mbiya W ; Mhike M ; Siegel, Paul D. ; Simoyi RH
• Description:
  Benzoquinone (BQ) is an extremely potent electrophilic contact allergen that haptenates endogenous proteins through Michael addition (MA). It is also hypothesized that BQ may haptenate proteins via free radical formation. The objective of this study was to assess the inductive effects (activating and deactivating) of substituents on BQ reactivity and the mechanistic pathway of covalent binding to a nucleophilic thiol. The BQ binding of Cys34 on human serum albumin was studied, and for reactivity studies, nitrobenzenethiol (NBT) was used as a surrogate for protein binding of the BQ and benzoquinone derivatives (BQD). Stopped flow techniques were used to determine pseudofirst order rate constants (k) of methyl-, t-butyl-, and chlorine-substituted BQD reactions with NBT, whereas electron pair resonance (EPR) studies were performed to investigate the presence of the free radical mediated binding mechanism of BQD. Characterization of adducts was performed using mass spectrometry and nuclear magnetic resonance spectroscopy (NMR). The rate constant values demonstrated the chlorine-substituted (activated) BQD to be more reactive toward NBT than the methyl and t-butyl-substituted (deactivated) BQD, and this correlated with the respective EPR intensities. The EPR signal, however, was quenched in the presence of NBT suggesting MA as the dominant reaction pathway. MS and NMR results confirmed adduct formation to be a result of MA onto the BQ ring with vinylic substitution also occurring for chlorine-substituted derivatives. The binding positions on BQ and NBT/BQ(D) stoichiometric ratios were affected by whether the inductive effects of the substituents on the ring were positive or negative. The reactivity of BQ and BQD is discussed in terms of the potential relationship to potential allergenic potency. [Description provided by NIOSH]
• Subjects:
  Benzene Chemistry Chemistry, Analytic Dermatitis Free Radicals Hypersensitivity Mass Spectrometry Nitrogen Compounds Occupational Health Safety Skin Skin Diseases Solvents Spectrum Analysis Sulfhydryl Compounds

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• Keywords:
  Allergens Allergic-dermatitis Allergic-reactions Analytical-chemistry Analytical-instruments Benzenes Bioactivation Chemical-analysis Chemical-binding Chemical-hypersensitivity Chemical-reactions Contact-dermatitis Free-radical-generation Free-radicals Mass-spectrometry Nitro-compounds Protein-chemistry Proteins Skin-irritants Skin-sensitivity Spectrographic-analysis Spectroscopes Thiols

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• ISSN:
  0893-228X
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Oregon ; OSHA Region 10 ; OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  112-123
• Volume:
  26
• Issue:
  1
• NIOSHTIC Number:
  nn:20042204
• Citation:
  Chem Res Toxicol 2013 Jan; 26(1):112-123
• Contact Point Address:
  Itai Chipinda, Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505-2888, USA
• Email:
  Itai.Chipinda@p66.com
• CAS Registry Number:
  Hydroquinone (CAS RN 123-31-9) ; Quinone (CAS RN 106-51-4)
• Federal Fiscal Year:
  2013
• NORA Priority Area:
  Healthcare and Social Assistance
• Peer Reviewed:
  True
• Source Full Name:
  Chemical Research in Toxicology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:308261cfac9fa7a256fdc0f3b6891f8909021b156aa3fc2068bcc4278032a54bfe7de233e75528111451ce50496b033f30ac5dfd5c9b04fe1f285028240f0123
• Download URL:
  https://stacks.cdc.gov/view/cdc/194504/cdc_194504_DS1.pdf
• File Type:
  [PDF - 519.89 KB ]