Epoxyalcohols: Bioactivation and Conjugation Required for Skin Sensitization
Epoxyalcohols: Bioactivation and Conjugation Required for Skin Sensitization
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DOI：
10.1021/tx500297d
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发表时间：
2014-10-01
影响因子：
4.1
通讯作者：
Karlberg, Ann-Therese
中科院分区：
文献类型：
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作者：
Delaine, Tamara;Ponting, David J.;Karlberg, Ann-Therese
烯丙醇，如香叶醇1，很容易被不同的机制氧化，包括2，3-环氧化物和/或醛的形成。这些环氧化物、醛和环氧醛可以相互转化，在考虑母体烯丙醇的敏化潜力时，必须考虑它们的反应性。采用体内、体外、化学和硅胶相结合的方法，对烯丙醇可能的代谢物和自氧化产物进行了深入的研究，包括它们的形成、相互转化、反应活性和敏化潜力。这项多模式研究利用多种技术的集成来研究分子的致敏潜力，从而可以确定对烯丙醇过敏反应的真正罪魁祸首的潜在候选者(S)(S)。总体而言，被研究的环氧醇和不饱和醇的敏化潜力被发现来自于代谢氧化成更有效的醛。在不太可能发生这种情况的地方，化合物仍然是弱的或不敏感的。双键的代谢活化以形成非共轭的非末端环氧化物部分不足以将不敏化的醇转变为增敏剂，因为这种环氧化物具有低反应性和低敏化能力。此外，即使是烯丙基的2，3-环氧化物部分也不一定是有效的增敏剂，如2所示，其中环氧化物的形成削弱了增感潜力。
Allylic alcohols, such as geraniol 1, are easily oxidized by varying mechanisms, including the formation of both 2,3-epoxides and/or aldehydes. These epoxides, aldehydes, and epoxy-aldehydes can be interconverted to each other, and the reactivity of them all must be considered when considering the sensitization potential of the parent allylic alcohol. An in-depth study of the possible metabolites and autoxidation products of allylic alcohols is described, covering the formation, interconversion, reactivity, and sensitizing potential thereof, using a combination of in vivo, in vitro, in chemico, and in silico methods. This multimodal study, using the integration of diverse techniques to investigate the sensitization potential of a molecule, allows the identification of potential candidate(s) for the true culprit(s) in allergic responses to allylic alcohols. Overall, the sensitization potential of the investigated, epoxyalcohols and unsaturated alcohols was found to derive from metabolic oxidation to the more potent aldehyde where possible. Where this is less likely, the compound remains weakly or nonsensitizing. Metabolic activation of a double bond to form a nonconjugated nonterminal epoxide moiety is not enough to turn a nonsensitizing alcohol into a sensitizer, as such epoxides have low reactivity and low sensitizing potency. In addition, even an allylic 2,3-epoxide moiety is not necessarily a potent sensitizer, as shown for 2, where formation of the epoxide weakens the sensitization potential.