Computer modelling in predicting carcinogenicity.

The cytochrome P450-dependent mixed-function oxidases are the most important enzyme system in the oxidation of chemicals to their reactive intermediates which then interact with cellular components to provoke toxicity and carcinogenicity. These enzymes comprise a multifamily of proteins, two families of which, namely CYP1A and CYP2E, activate planar and small molecular weight compounds, respectively. A computer graphic procedure (COMPACT) has been developed which, based on the molecular shape and electronic structure of the chemical, determines whether the chemical will interact with these two particular cytochrome P450 families and thus be metabolized to toxic and carcinogenic intermediates. As the basal levels of these enzyme families are low, the ability of the chemical to induce them selectively, on repeated administration, is an important determinant of its carcinogenic potential. Inductive capability may be determined in short-term experiments (ENACT) utilizing a small number of animals. Thus the combination of COMPACT and ENACT provides a rapid and inexpensive means for the preliminary screening of chemicals, before the long term and expensive rodent lifetime bioassays are undertaken.