Lewis D F, Ioannides C, Parke D V
Molecular Toxicology Group, School of Biological Sciences, University of Surrey, Guildford, UK.
Hum Exp Toxicol. 1998 Oct;17(10):577-86. doi: 10.1177/096032719801701009.
The COMPACT approach for defining structural criteria for substrates and inducers of cytochrome P450 (CYP) enzymes which mediate the formation of reactive intermediates is discussed in the context of prediction of potential carcinogenicity. This is broadened to encompass structural studies on mammalian P450s, including those relevant to genetic polymorphism in man. The use of the COMPACT system, in parallel with the structure alert program HazardExpert (now incorporated into the Pallas system), for evaluating human carcinogenicity data is reported, as an example of the possible employment of a battery of short-term test procedures for safety evaluation. In particular, the importance of using the log P value (as a measure of compound lipophilicity) to assess the likelihood of a potentially toxic compound reaching the site of activation, is emphasized by the finding that most procarcinogens requiring metabolic activation by P450s are lipophilic in nature.
在预测潜在致癌性的背景下，讨论了用于定义介导反应性中间体形成的细胞色素P450（CYP）酶底物和诱导剂结构标准的COMPACT方法。这一方法得到扩展，涵盖了对哺乳动物P450的结构研究，包括与人类基因多态性相关的研究。报告了将COMPACT系统与结构警报程序HazardExpert（现已纳入Pallas系统）并行使用以评估人类致癌性数据的情况，作为使用一系列短期测试程序进行安全性评估的一个可能示例。特别是，发现大多数需要由P450进行代谢激活的前致癌物本质上是亲脂性的，这一发现强调了使用log P值（作为化合物亲脂性的度量）来评估潜在有毒化合物到达激活位点可能性的重要性。
