Bioactivation of Cinnamic Alcohol Forms Several Strong Skin Sensitizers

Cinnamic
alcohol is a frequent contact allergen, causing allergic
contact dermatitis (ACD) in a substantial number of individuals sensitized
from contacts with fragrances. Hence, cinnamic alcohol is one of the
constituents in fragrance mix I (FM I) used for screening contact
allergy in dermatitis patients. Cinnamic alcohol lacks structural
alerts for protein reactivity and must therefore be activated by either
air oxidation or bioactivation to be able to act as a sensitizer.
In the present study, we explored the bioactivation of cinnamic alcohol
using human liver microsomes (HLM), and the potential pathways for
these reactions were modeled by in silico (DFT) techniques.
Subsequently, the reactivity of cinnamic alcohol and its metabolites
toward a model hexapeptide were investigated. In addition to cinnamic
aldehyde and cinnamic acid, two highly sensitizing epoxides previously
unobserved in studies of bioactivation were detected in the incubations
with HLMs. Formation of epoxy cinnamic aldehyde was shown (both by
the liver microsomal experiments, in which no depletion of epoxy cinnamic
alcohol was observed after initial formation, and by the very high
activation energy found for the oxidation thereof by calculations)
to proceed via cinnamic aldehyde and not epoxy cinnamic alcohol.

肉桂醇（cinnamic alcohol）是一种常见的接触性变应原，可在大量因接触香料而致敏的个体中引发变应性接触性皮炎（allergic contact dermatitis, ACD）。因此，肉桂醇是用于皮炎患者接触性变应原筛查的香料混合物I（fragrance mix I, FM I）的组分之一。肉桂醇缺乏介导蛋白质反应的结构警示基团，因此必须通过空气氧化或生物活化途径才能发挥致敏原的作用。本研究利用人肝微粒体（human liver microsomes, HLM）探究了肉桂醇的生物活化过程，并通过计算机模拟（密度泛函理论，DFT）技术对该反应的潜在路径进行了建模。随后，我们研究了肉桂醇及其代谢产物对模型六肽（hexapeptide）的反应活性。在人肝微粒体孵育体系中，除检测到肉桂醛与肉桂酸外，还发现了两种此前在生物活化研究中未被观测到的高致敏性环氧化物（epoxides）。研究表明，环氧肉桂醛的生成路径为肉桂醛而非环氧肉桂醇，这一结论得到了两项佐证：其一，肝微粒体实验中，环氧肉桂醇在初始生成后未出现消耗现象；其二，计算结果显示环氧肉桂醛氧化过程的活化能极高。