Ioannides C, Lewis D F, Parke D V
Molecular Toxicology Group, School of Biological Sciences, University of Surrey, GuildFord, UK.
Eur J Drug Metab Pharmacokinet. 1994 Jul-Sep;19(3):225-33. doi: 10.1007/BF03188925.
The toxicity and carcinogenicity of drugs and other chemicals is, in most cases, mediated by highly reactive intermediates which are generated following metabolism catalysed by the enzymic apparatus of the exposed organisms. These reactive intermediates readily interact covalently with vital cellular components to provoke toxicity and carcinogenicity. The ubiquitous cytochrome P450-dependent mixed-function oxidases are the most important enzyme system in the activation of chemicals. This enzyme system comprises a number of families, each of which contains one or more subfamilies. The CYPIA and CYP2E subfamilies are the most closely associated with the production of reactive intermediates and, consequently, the manifestation of toxicity and carcinogenicity. A computer based molecular structure procedure (COMPACT) has been developed which, via a calculation of the molecular and electronic structure of the chemical, determines whether the chemical will interact with either of these two cytochrome P450 subfamilies and hence be metabolised to form reactive intermediates that manifest toxicity. As the basal levels of these two subfamilies are generally low, the ability of a chemical to induce them selectively, on repeated administration, is an important determinant of its toxic and carcinogenic potential. This inductive capability may be determined in short-term studies (ENACT) using only a small number of animals. Thus the combination of COMPACT and ENACT provides a rapid and inexpensive means for the preliminary screening of chemicals for toxicity and carcinogenicity before undertaking the long-term and expensive rodent lifetime bioassays.
在大多数情况下，药物和其他化学物质的毒性及致癌性是由高反应性中间体介导的，这些中间体是在暴露生物体的酶系统催化的代谢过程中产生的。这些反应性中间体很容易与重要的细胞成分发生共价相互作用，从而引发毒性和致癌性。普遍存在的细胞色素P450依赖性混合功能氧化酶是化学物质活化过程中最重要的酶系统。该酶系统由多个家族组成，每个家族包含一个或多个亚家族。CYPIA和CYP2E亚家族与反应性中间体的产生以及毒性和致癌性的表现最为密切相关。已经开发了一种基于计算机的分子结构程序（COMPACT），通过计算化学物质的分子和电子结构，确定该化学物质是否会与这两个细胞色素P450亚家族中的任何一个相互作用，从而被代谢形成具有毒性的反应性中间体。由于这两个亚家族的基础水平通常较低，一种化学物质在反复给药时选择性诱导它们的能力是其毒性和致癌潜力的重要决定因素。这种诱导能力可以在仅使用少量动物的短期研究（ENACT）中确定。因此，COMPACT和ENACT的结合为在进行长期且昂贵的啮齿动物终生生物测定之前对化学物质进行毒性和致癌性的初步筛选提供了一种快速且廉价的方法。
