Chemical biology approaches to understand interindividual variability in carboxylesterase activity

PROJECT SUMMARY – Michael W. Beck, Eastern Illinois University
Before an orally delivered drug can reach its target in the body it must first be absorbed by the digestive system
and pass through the liver via the hepatic portal system. During this process, the drug is metabolized by enzymes
in these tissues. This metabolism controls the bioavailability of oral drugs; thus the activity and expression levels
of these enzymes is important. Human carboxylesterases (CESs) are highly expressed in the intestines and the
liver and therefore play a key role in controlling the metabolism of many drugs. The overall activity of CESs,
however, can be drastically different from person to person. This interindividual variability has been shown to
influence the metabolism and, in some cases, clinical outcomes of patients treated with drugs that are substrates
for carboxylesterase 1 (CES1). The factors that contribute to CES1 activity variation have not been fully
uncovered, despite the established importance of CES1 in drug metabolism. We believe this lack of knowledge
is due to the scarcity and limitations of currently available approaches to study CES1 activity in live samples. To
address these challenges, this proposal aims to develop and optimize fluorogenic probes that can specifically
report on CES1 activity in live samples. These probes will be deployed to generate chemical biology-based
approaches that can rapidly evaluate small molecules for their potential to interfere with CES1 activity and
determine the influence of CES1 genetic polymorphisms on CES1 activity. The probes and methods created in
this proposal will enable rapid analysis of CES1 activity under different conditions in live cells. The application of
these approaches to study factors that influence CES1-mediated drug metabolism will reveal new risk factors for
ineffective treatment with CES1-substrate drugs. Overall, the studies proposed here uncover factors that
modulate CES1 activity resulting in safer and more effective treatments with CES1-substrate drugs while
providing an excellent training platform for undergraduate students in modern biomedical research.

Grant Number: 1R15GM152890-01
NIH Institute/Center: NIH
Principal Investigator: Michael Beck