A Conjugated Diene Identified as a Prohapten: Contact Allergenic Activity and Chemical Reactivity of Proposed Epoxide Metabolites

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• 作者：Anna-Malin Nilsson ; Moa Andresen Bergströ ; m ; Kristina Luthman ; J. Lars G. Nilsson ; and Ann-Therese Karlberg
• 刊名：Chemical Research in Toxicology
• 出版年：2005
• 出版时间：February 2005
• 年：2005
• 卷：18
• 期：2
• 页码：308 - 316
• 全文大小：144K
• 年卷期：v.18,no.2(February 2005)
• ISSN：1520-5010

文摘

A hapten causing allergic contact dermatitis binds covalently to macromolecules via nucleophilic-electrophilic reactions or radical couplings. A prohapten can be seen as a chemicallyinert compound without electrophilic or radical forming properties. To exert its activity, theprohapten is activated, for example, metabolically, to the hapten. We have investigated thecontact 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 activityis likely to be exerted via epoxide metabolites. Thus, two potential metabolites of theinvestigated 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 toanimal tests. Both epoxides were sensitizers. They also elicited significant reactions when testedin 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. Thechemical 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 cysteineand proline residues. Since it is possible to relate the sensitizing capacity of a compound to itskey physicochemical properties, knowledge-based expert systems have been developed to predictthe toxicity of novel compounds by comparing the structure with activity data stored in thecomputer database. A diene related to 1 found in the knowledge-based expert system DEREKwas considered as a nonsensitizer by this system. Our study indicates that conjugated dienescan be metabolized to contact allergens in the skin. Thus, when constructing predictive testmethods based on SARs, it is important to analyze not only the virtual chemical structure ofa compound but also its ability to act as a prohapten.