What Happens After Activation of Ascaridole? Reactive Compounds and Their Implications for Skin Sensitization

Chem Res Toxicol. 2016 Sep 19;29(9):1488-92. doi: 10.1021/acs.chemrestox.6b00157. Epub 2016 Aug 24.

Abstract

To replace animal testing and improve the prediction of skin sensitization, significant attention has been directed to the use of alternative methods. The direct peptide reactivity assay (DPRA), the regulatory agencies' approved alternative in chemico method, has been applied for understanding the sensitization capacity of activated ascaridole. Ascaridole, the oxidative metabolite of α-terpinene, is considered to be one of the components responsible for the contact allergy associated with essential oils derived from Chenopodium and Melaleuca species. The recently developed high-throughput screening based on the dansyl cysteamine (HTS-DCYA) method was applied to understand the reported enhanced reactivity of activated ascaridole and possibly to identify the resulting elusive radical or other reactive species. For the first time, a substituted cyclohexenone was identified as a potential electrophilic intermediate resulting in higher depletion of nucleophilic DCYA, along with several nonreactive byproducts of ascaridole via a radical degradation mechanism. Formation of electrophilic species via radical degradation is one of the possible pathways should be considered for the peptide reactivity of in aged tea tree oil or oils rich in terpinenes along with commonly believed reactants, allylic-epoxides and allylic-peroxides.

MeSH terms

  • Animals
  • Cyclohexane Monoterpenes
  • Cyclohexanones / chemistry
  • Dermatitis, Allergic Contact*
  • Humans
  • Molecular Structure
  • Monoterpenes / chemistry*
  • Monoterpenes / metabolism
  • Monoterpenes / toxicity*
  • Peroxides / chemistry*
  • Peroxides / metabolism
  • Peroxides / toxicity*
  • Skin / drug effects*
  • Skin / immunology*

Substances

  • Cyclohexane Monoterpenes
  • Cyclohexanones
  • Monoterpenes
  • Peroxides
  • ascaridole
  • cyclohexanone