Nilsson Anna-Malin, Bergström Moa Andresen, Luthman Kristina, Nilsson J Lars G, Karlberg Ann-Therese
Department of Chemistry, Dermatochemistry and Skin Allergy, Göteborg University, SE-412 96 Göteborg, Sweden.
Chem Res Toxicol. 2005 Feb;18(2):308-16. doi: 10.1021/tx049758c.
A hapten causing allergic contact dermatitis binds covalently to macromolecules via nucleophilic-electrophilic reactions or radical couplings. A prohapten can be seen as a chemically inert compound without electrophilic or radical forming properties. To exert its activity, the prohapten is activated, for example, metabolically, to the hapten. We have investigated the contact allergenic properties of a diene, (5R)-5-isopropenyl-2-methyl-1-methylene-2-cyclohexene (1), as a potential prohapten, and we found it to be a sensitizer in animal studies. The activity is likely to be exerted via epoxide metabolites. Thus, two potential metabolites of the investigated diene, (4S)-1,2-epoxy-4-isopropenyl-1-methyl-6-methylene-cyclohexane (3) and (7R)-7-isopropenyl-4-methyl-1-oxa-spiro[2.5]oct-4-ene (4), were synthesized and subjected to animal tests. Both epoxides were sensitizers. They also elicited significant reactions when tested in animals induced with 1, which indicates that they are formed from the diene in the skin. Furthermore, incubation of 1 with human liver microsomes produced both epoxides. The chemical reactivity of 1, 3, and 4 was investigated in relation to a hexapeptide, H-Pro-His-Cys-Lys-Arg-Met-OH. No adducts were obtained from reactions between the peptide and 1. However, epoxide 3 bound covalently to the cysteine residue and epoxide 4 to both the cysteine and proline residues. Since it is possible to relate the sensitizing capacity of a compound to its key physicochemical properties, knowledge-based expert systems have been developed to predict the toxicity of novel compounds by comparing the structure with activity data stored in the computer database. A diene related to 1 found in the knowledge-based expert system DEREK was considered as a nonsensitizer by this system. Our study indicates that conjugated dienes can be metabolized to contact allergens in the skin. Thus, when constructing predictive test methods based on SARs, it is important to analyze not only the virtual chemical structure of a compound but also its ability to act as a prohapten.
引起变应性接触性皮炎的半抗原通过亲核-亲电反应或自由基偶联与大分子共价结合。前半抗原可视为一种没有亲电或形成自由基性质的化学惰性化合物。为发挥其活性，前半抗原例如通过代谢被激活为半抗原。我们研究了一种二烯（(5R)-5-异丙烯基-2-甲基-1-亚甲基-2-环己烯(1)）作为潜在前半抗原的接触致敏特性，并且我们发现在动物研究中它是一种致敏剂。其活性可能通过环氧化物代谢物发挥。因此，合成了所研究二烯的两种潜在代谢物（(4S)-1,2-环氧-4-异丙烯基-1-甲基-6-亚甲基-环己烷(3)和(7R)-7-异丙烯基-4-甲基-1-氧杂-螺[2.5]辛-4-烯(4)）并进行动物试验。两种环氧化物都是致敏剂。当在由1诱导的动物中进行测试时，它们也引发了显著反应，这表明它们是在皮肤中由二烯形成的。此外，1与人肝微粒体一起温育产生了两种环氧化物。研究了1、3和4与六肽H-Pro-His-Cys-Lys-Arg-Met-OH相关的化学反应性。在肽与1之间的反应中未获得加合物。然而，环氧化物3与半胱氨酸残基共价结合，环氧化物4与半胱氨酸和脯氨酸残基都结合。由于可以将化合物的致敏能力与其关键物理化学性质相关联，因此已经开发了基于知识的专家系统，通过将结构与存储在计算机数据库中的活性数据进行比较来预测新化合物 的毒性。在基于知识的专家系统DEREK中发现的与1相关的一种二烯被该系统视为非致敏剂。我们的研究表明共轭二烯在皮肤中可代谢为接触性变应原。因此，在构建基于构效关系的预测测试方法时，不仅分析化合物的虚拟化学结构而且分析其作为前半抗原的能力很重要。
