Chan Katie, O'Brien Peter J
University of Toronto, Faculty of Pharmacy, Toronto, ON, Canada.
J Appl Toxicol. 2008 Nov;28(8):1004-15. doi: 10.1002/jat.1366.
Covalent binding of reactive electrophiles to cellular targets is a molecular interaction that has the potential to initiate severe adverse biological effects. Therefore, electrophile reactivity towards biological nucleophiles could serve as an important correlate for toxic effects such as hepatocyte death. To determine if reactivity correlates with rat hepatotoxicity, alpha,beta-unsaturated esters, consisting of acrylates and methacrylates, that are inherently electrophilic and exhibit widely varying degrees of reactivity were investigated. Reactivity was measured using simple assays with glutathione and butylamine as surrogates for soft thiol and hard amino biological nucleophile targets. A linear relationship was observed between hepatotoxicity and thiol reactivity only, while no amine reactivity was observed. Structure-activity relationships were also investigated, with results showing toxicity was well modeled by electronic parameters E(LUMO) and partial charge of the carbon atoms in the reactive center. No relationship was observed between toxicity and logP. These results suggest that differences in hepatocyte toxicity of acrylates and methacrylates can be related to their electrophilic reactivity which corresponds to their ability to deplete GSH and protein thiols.
活性亲电试剂与细胞靶点的共价结合是一种分子相互作用，有可能引发严重的不良生物学效应。因此，亲电试剂对生物亲核试剂的反应性可作为肝细胞死亡等毒性效应的重要关联指标。为了确定反应性是否与大鼠肝毒性相关，研究了由丙烯酸酯和甲基丙烯酸酯组成的α,β-不饱和酯，它们本质上是亲电试剂，且表现出广泛不同程度的反应性。使用以谷胱甘肽和丁胺作为软硫醇和硬氨基生物亲核试剂靶点替代物的简单测定法来测量反应性。仅观察到肝毒性与硫醇反应性之间存在线性关系，而未观察到胺反应性。还研究了构效关系，结果表明毒性可以通过电子参数E(LUMO)和反应中心碳原子的部分电荷很好地模拟。未观察到毒性与logP之间的关系。这些结果表明，丙烯酸酯和甲基丙烯酸酯的肝细胞毒性差异可能与其亲电反应性有关，而亲电反应性与其消耗谷胱甘肽和蛋白质硫醇的能力相对应。
