This proposed research represents the first step toward the investigators eventual goal of biologically and mechanistically based modeling of a cell. Thus, the immediate goal for this project is to integrate chemical engineering modeling technology and molecular, biochemical, and cellular biology to elucidate the chemical reaction networks of cytochrome P450 2El (CYP2El) and its toxicologically significant chemical substrates. The investigators envision that, following successful completion of this work, they will move on to the """"""""Reaction Network Modeling"""""""" for the entire P450 system, and then progressively to cellular organelles and, finally, to the modeling of a whole cell. They intend to address this objective through the creation and utilization of a novel biochemical reaction network model using BioMOL (Biological application of Molecular Oriented Lumping) coupled with focused biochemical experimentation. The investigators hypothesize that a reaction network model of CYP2El-mediated metabolism will predict a distribution of reaction intermediates and products more accurately than that predicted by single reaction kinetic studies. Furthermore, they hypothesize that a reaction network constructed to accommodate mixtures of chemical species will show complex reaction interdependencies not anticipated through conventional modeling or experimental techniques.
The specific aims of this project are: 1) to create a reaction network model for metabolism of selected toxicologically-relevant chemicals by cytochrome P450 2EI; 2) to use experimentation in vitro on a model set of chemicals to provide necessary kinetic rate constants for establishing the reaction network model; and 3) to use experimentation in vitro to validate predictions made by the reaction network model.
| Lyons, Michael A; Yang, Raymond S H; Mayeno, Arthur N et al. (2008) Computational toxicology of chloroform: reverse dosimetry using Bayesian inference, Markov chain Monte Carlo simulation, and human biomonitoring data. Environ Health Perspect 116:1040-6 |
| Brown, Caitlin M; Reisfeld, Brad; Mayeno, Arthur N (2008) Cytochromes P450: a structure-based summary of biotransformations using representative substrates. Drug Metab Rev 40:1-100 |
| Mayeno, Arthur N; Yang, Raymond S H; Reisfeld, Brad (2005) Biochemical reaction network modeling: predicting metabolism of organic chemical mixtures. Environ Sci Technol 39:5363-71 |
