Lewis D F, Ioannides C, Parke D V
Molecular Toxicology Group, School of Biological Sciences, University of Surrey, Guildford, UK.
Mutat Res. 1993 Feb;291(1):61-77. doi: 10.1016/0165-1161(93)90018-u.
The molecular dimensions and electronic structures of 100 chemicals of structural diversity have been determined from molecular orbital calculations and molecular mechanics. From these parameters of molecular structure, those chemicals that are likely substrates of cytochromes P4501 and P4502E have been identified by the computer-optimized molecular parametric analysis of chemical toxicity (COMPACT) programme, and their potential toxicity, mutagenicity and carcinogenicity evaluated. The degree of correlation between COMPACT prediction of toxicity and rodent two species life-span carcinogenicity data is estimated to be 92%, and between COMPACT and Salmonella mutagenicity (Ames test) data is 64%. Anomalous rodent carcinogens are rationalized on the basis of biochemical mechanisms of metabolism, genotoxicity and carcinogenicity. Correlation of the Ames test data with rodent carcinogenicity data was 64%, but correlation of COMPACT plus Ames data versus rodent carcinogenicity data provided the highest correlation of 94%.
通过分子轨道计算和分子力学确定了100种结构多样的化学物质的分子尺寸和电子结构。根据这些分子结构参数，通过计算机优化的化学毒性分子参数分析（COMPACT）程序识别出可能是细胞色素P4501和P4502E底物的那些化学物质，并评估了它们的潜在毒性、致突变性和致癌性。COMPACT毒性预测与啮齿动物两种物种终生致癌性数据之间的相关程度估计为92%，COMPACT与沙门氏菌致突变性（艾姆斯试验）数据之间的相关程度为64%。异常啮齿动物致癌物可根据代谢、遗传毒性和致癌性的生化机制进行合理分析。艾姆斯试验数据与啮齿动物致癌性数据的相关性为64%，但COMPACT加艾姆斯数据与啮齿动物致癌性数据的相关性最高，为94%。
