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Computer modelling in predicting carcinogenicity
C Ioannides1, D F Lewis, D V Parke
1Division of Toxicology, School of Biological Sciences, University of Surrey, Guildford, UK.
Abstract:
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.
Insights
Cytochrome P450 enzymes (CYP) activate chemicals into toxic intermediates. COMPACT and ENACT methods rapidly screen chemicals for toxicity and carcinogenicity, reducing the need for lengthy rodent bioassays.
Area of Science:
- Biochemistry
- Toxicology
- Computational Chemistry
Background:
- Cytochrome P450 (CYP) enzymes are crucial for metabolizing xenobiotics.
- CYP1A and CYP2E families activate planar and small molecular weight compounds, respectively, into toxic intermediates.
- Chemicals interacting with cellular components can cause toxicity and carcinogenicity.
Purpose of the Study:
- To develop and evaluate a computational method (COMPACT) for predicting chemical interaction with CYP1A and CYP2E.
- To assess the utility of short-term animal studies (ENACT) for determining chemical induction of CYP enzymes.
- To establish a rapid and cost-effective preliminary screening strategy for chemical carcinogenicity.
Main Methods:
- Development of the COMPACT (Computergraphic Prediction of Chemical-CYP Interaction) procedure.
- COMPACT analyzes molecular shape and electronic structure to predict CYP1A/CYP2E interaction.
- ENACT (Enzyme Induction Assay) utilizes short-term animal experiments to assess inductive capability.
Main Results:
- COMPACT predicts whether a chemical will interact with CYP1A or CYP2E families.
- The ability of a chemical to induce CYP enzyme levels is a key factor in its carcinogenic potential.
- ENACT provides a method to determine inductive capability using fewer animals.
Conclusions:
- The combination of COMPACT and ENACT offers a rapid, inexpensive preliminary screening for chemical carcinogenicity.
- This approach can help prioritize chemicals for further, more extensive testing.
- Reduces reliance on long-term, costly rodent bioassays for initial assessment.