Use of the HSAB principle in quantitative structure-activity relationships in toxicological research: Application to the genotoxicity of chlorinated hydrocarbons
Use of the HSAB principle in quantitative structure-activity relationships in toxicological research: Application to the genotoxicity of chlorinated hydrocarbons
复制标题
DOI：
10.1002/(sici)1097-461x(1999)74:3
复制
发表时间：
1999-08-15
影响因子：
2.2
通讯作者：
Geerlings, P
中科院分区：
文献类型：
--
作者：
Baeten, A;Tafazoli, M;Geerlings, P
在基因毒理学领域，常用定量构效关系（quantitative structure-activity relationship， QSAR）来研究有毒化学物质的结构与其生物活性之间的关系。目前，通常使用量子化学方法来获得化合物性质的相关描述符，然后用它们来建立QSAR方程。然而，研究通常局限于化学物质本身，而不考虑形成的代谢物，而代谢物在大多数情况下才是真正的有毒物质。本文提出的工作是我们先前对约10种氯化碳氢化合物的遗传毒性进行的qsar研究的续作。可见化学物质的遗传毒性与其LUMO轨道的能量之间存在一定的关系，证实了文献中提出的这些化学物质通过谷胱甘肽s -转移酶的还原性活化代谢。在这里，我们考虑了通过这一反应途径产生的异磺代谢物。它们与dna基鸟嘌呤的相互作用能是用基于硬、软酸碱方法的密度泛函理论计算的。结果表明，该相互作用能可以解释实验得到的遗传毒性序列。(C) 1999 John Wiley & Sons, Inc
In the field of genotoxicology, quantitative structure-activity relationships (QSAR) are frequently used to study the relationship between the structure of a toxic chemical and its biological activity. Nowadays, quantum chemical methods are often used to obtain relevant descriptors for the compound properties which are used in their turn to set up the QSAR equations. However, studies usually are restricted to the chemicals themselves and do not consider the metabolites formed, which in most cases are the real toxic agents. The work proposed here is a sequel to a QSAR-study on the genotoxicity of some 10 chlorinated hydrocarbons performed by us earlier. It was seen that there existed a relationship between the genotoxicity of the chemicals and the energy of their LUMO orbital, confirming the reductive activation metabolism by glutathione S-transferase for these chemicals suggested in the Literature. Here, the episulfonium metabolites formed through this reaction path were considered. Their interaction energy with the DNA-base guanine was calculated using a density functional theory based hard and soft acids and bases approach. It was found that this interaction energy could explain the genotoxicity sequence, which had been experimentally obtained. (C) 1999 John Wiley & Sons, Inc.