The REU 2011 group consisted of four undergraduates, myself, and two mentors from the US EPA (Dr. Marina Evans and Christopher Eklund). We worked on modeling an alternate metabolic pathway for bromochloromethane (BCM) using physiologically-based pharmacokinetic (PBPK) modeling.
The undergraduates were:
The following project description was taken from the NCSU 2011 REU site:
Title: Application of physiologically based pharmacokinetic (PBPK) modeling to discriminate between different metabolic pathways for the water disinfection by-product bromochloromethane.
Description: The application of mathematical models that take into account physiological and chemical information is now well established as a risk assessment tool, especially for extrapolation across species and different exposure scenarios. These PBPK models are usually calibrated using data collected in rodents and used to predict internal dose to humans. Many volatile compounds are transformed into carcinogens after metabolism by a liver enzyme known as CYP2E1. This enzyme is known to metabolize volatiles, which are small molecules, as well as intermediate and large molecules, such as fatty acids. The molecular structure of the human CYP2E1 has been recently deciphered, allowing for the application of modeling tools to help predict biological effects. The purpose of this project is to use inhalation data designed to measure metabolism in rats an apply different mechanistic ideas to explain how CYP2E1 metabolizes bromochloromethane, a by-product of water chlorination. The current null hypothesis states that this compound is probably metabolized by two distinct liver enzymes. Recent information about the ability of CYP2E1's active to adapt to larger molecules opens the possibility to the idea that CYP2E1 alone could perform all metabolism. In short, the students will make use of different enzymatic models to determine which one describes the inhalation data optimally. The students involved in this project will make use of mathematics to test different hypotheses using scientific principles, apply their mathematical background to a real world problem, and learn basic kinetics and biology in the process.
Our paper describing this work was published in the Journal of Toxicology and can be found here.
Cuello, W.S., Janes, T.A.T, Jessee, J.M., Venecek, M.A., Sawyer, M.E., Eklund, C.R., Evans, M.V., (2012). Physiologically based pharmacokinetic (PBPK) modeling of metabolic pathways of bromochloromethane in rats. Journal of Toxicology, vol. 2012, Article ID 629781. DOI:10.1155/2012/629781
The abstract is as follows:
Bromochloromethane (BCM) is a volatile compound and a by-product of disinfection of water by chlorination. Physiologically based pharmacokinetic (PBPK) models are used in risk assessment applications. An updated PBPK model for BCM is generated and applied to hypotheses testing calibrated using vapor uptake data. The two different metabolic hypotheses examined are (1) a two-pathway model using both CYP2E1 and glutathione transferase enzymes and (2) a two-binding site model where metabolism can occur on one enzyme, CYP2E1. Our computer simulations show that both hypotheses describe the experimental data in a similar manner. The two pathway results were comparable to previously reported values (Vmax = 3.8 mg/hour, Km = 0.35 mg/liter, and kGST = 4.7 /hour). The two binding site results were Vmax1 = 3.7 mg/hour, Km1 = 0.3 mg/hour, CL2 = 0.047 liter/hour. In addition, we explore the sensitivity of different parameters for each model using our obtained optimized values.
This project contributed to work awarded the US Environmental Protection Agency 2013 Level III Scientific and Technological Achievement Awards (STAA). The citation it received was Testing of a Mechanistic Hypothesis for Volatile Methanes Using Computational Modeling and Sensitivity Analyses.
This project has been taken to several conferences, including the Joint Meetings in Mathematics and the Third International Conference on Mathematics and Modeling, in the form of talks and posters.