Dermatochemistry and Skin Allergy and Medicinal Chemistry, Department of Chemistry, University of Gothenburg, SE-412 96 Gothenburg, Sweden.
Chem Res Toxicol. 2010 Mar 15;23(3):677-88. doi: 10.1021/tx900433n.
Hydroperoxides are known to be strong contact allergens and a common cause of contact allergy. They are easily formed by the autoxidation of, for example, fragrance terpenes, compounds that are common in perfumes, cosmetics, and household products. A requirement of the immunological mechanisms of contact allergy is the formation of an immunogenic hapten-protein complex. For hydroperoxides, a radical mechanism is postulated for this formation. In our previous investigations of allylic limonene hydroperoxides, we found that the formation of carbon- and oxygen-centered radicals, as well as the sensitizing capacity, is influenced by the structure of the hydroperoxides. The aim of the present work was to further investigate the connection between structure, radical formation, and sensitizing capacity by studying alkylic analogues of the previously investigated allylic limonene hydroperoxides. The radical formation was studied in radical-trapping experiments employing 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride as an initiator and 1,1,3,3-tetramethylisoindolin-2-yloxyl as a radical trapper. We found that the investigated hydroperoxides initially form carbon- and oxygen-centered radicals that subsequently form alcohols and ketones. Trapped carbon-centered radicals and nonradical products were isolated and identified. Small changes in structure, like the omission of the endocyclic double bond or the addition of a methyl group, resulted in large differences in radical formation. The results indicate that alkoxyl radicals seem to be more important than carbon-centered radicals in the immunogenic complex formation. The sensitizing capacities were studied in the murine local lymph node assay (LLNA), and all hydroperoxides tested were found to be potent sensitizers. For two of the hydroperoxides investigated, the recently suggested thiol-ene reaction is a possible mechanism for the formation of immunogenic complexes. For the third investigated, fully saturated, hydroperoxide, the thiol-ene mechanism is not possible for immunogenic complex formation. This strongly indicates that several radical reaction pathways for immunogenic complex formation of limonene hydroperoxides are active in parallel.
氢过氧化物已知是强接触过敏原，也是接触过敏的常见原因。它们很容易通过例如，香料萜烯的自动氧化形成，这些化合物在香水、化妆品和家用产品中很常见。接触过敏的免疫机制要求形成免疫原性半抗原-蛋白质复合物。对于氢过氧化物，自由基机制被假定用于这种形成。在我们之前对烯丙基柠檬烯氢过氧化物的研究中，我们发现碳和氧中心自由基的形成以及致敏能力受到氢过氧化物结构的影响。本工作的目的是通过研究先前研究过的烯丙基柠檬烯氢过氧化物的烷基类似物，进一步研究结构、自由基形成和致敏能力之间的联系。自由基形成通过使用 5,10,15,20-四苯基-21H,23H-卟啉三氯化铁作为引发剂和 1,1,3,3-四甲基异吲哚啉-2-基氧自由基作为自由基捕获剂的自由基捕获实验进行研究。我们发现，所研究的氢过氧化物最初形成碳和氧中心自由基，随后形成醇和酮。捕获的碳中心自由基和非自由基产物被分离和鉴定。结构的微小变化，如环内双键的省略或甲基的添加，导致自由基形成的巨大差异。结果表明，烷氧基自由基似乎比免疫复合物形成中的碳中心自由基更重要。致敏能力在小鼠局部淋巴结测定（LLNA）中进行研究，所有测试的氢过氧化物都被发现是有效的致敏剂。对于研究的两种氢过氧化物，最近提出的硫醇-烯反应可能是形成免疫原性复合物的机制。对于第三种研究的完全饱和的氢过氧化物，硫醇-烯反应对于免疫原性复合物的形成是不可能的。这强烈表明，几种自由基反应途径对于柠檬烯氢过氧化物的免疫原性复合物形成是活跃的。
