NERDG 2026
Poster 12 Abstract
Structural and Functional Basis of Drug Binding to Human Cytochrome P450 2C8
Roshni Chavan, Manish B. Shah
Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, 106 New Scotland Ave, Albany, NY 12208
Presenting Author: Roshni Chavan
Corresponding Author: Manish B. Shah, [email protected]
Abstract
Cytochrome P450 (CYP) enzymes are heme-containing monooxygenases responsible for the oxidative metabolism of xenobiotics and numerous endogenous compounds. The CYP1, CYP2, and CYP3 families account for most of the Phase I drug biotransformation, converting lipophilic chemicals into more water-soluble metabolites suitable for elimination. Among these, CYP2C8 is a key drug-metabolizing enzyme involved in the disposition of several therapeutically important substrates, including diclofenac, paclitaxel, amodiaquine, and pioglitazone. Its activity is influenced by genetic variation, environmental inducers or inhibitors, and tissue-specific expression patterns, all of which contribute to interindividual variability in drug response. Our laboratory has established robust systems for recombinant expression and purification of CYP2C8 in Escherichia coli, enabling high-quality of protein production for biochemical and structural analyses. Using these approaches, CYP2C8 was crystallized in the absence and presence of the drug substrate diclofenac, and diffraction data were collected at the Stanford Synchrotron Radiation Light source. CYP2C8 and CYP2C9 are the two major enzymes that contribute to the metabolism of diclofenac. Isothermal titration calorimetry studies and enzymatic assays are in progress to determine and compare the binding affinity and activity of diclofenac with CYP2C8 and CYP2C9. Using a multitude of techniques that include structural, biophysical, and functional methods, the goal of this research is to elucidate the molecular determinants of diclofenac binding to CYP2C8, thereby improving our understanding of xenobiotic biotransformation and therapeutic outcomes.
Keywords
Cytochrome P450, CYP2C8, Diclofenac, Drug metabolism, X-ray crystallography, Isothermal titration calorimetry, Enzymatic assays, Pharmacogenetic variability
Poster 12 Abstract
Structural and Functional Basis of Drug Binding to Human Cytochrome P450 2C8
Roshni Chavan, Manish B. Shah
Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, 106 New Scotland Ave, Albany, NY 12208
Presenting Author: Roshni Chavan
Corresponding Author: Manish B. Shah, [email protected]
Abstract
Cytochrome P450 (CYP) enzymes are heme-containing monooxygenases responsible for the oxidative metabolism of xenobiotics and numerous endogenous compounds. The CYP1, CYP2, and CYP3 families account for most of the Phase I drug biotransformation, converting lipophilic chemicals into more water-soluble metabolites suitable for elimination. Among these, CYP2C8 is a key drug-metabolizing enzyme involved in the disposition of several therapeutically important substrates, including diclofenac, paclitaxel, amodiaquine, and pioglitazone. Its activity is influenced by genetic variation, environmental inducers or inhibitors, and tissue-specific expression patterns, all of which contribute to interindividual variability in drug response. Our laboratory has established robust systems for recombinant expression and purification of CYP2C8 in Escherichia coli, enabling high-quality of protein production for biochemical and structural analyses. Using these approaches, CYP2C8 was crystallized in the absence and presence of the drug substrate diclofenac, and diffraction data were collected at the Stanford Synchrotron Radiation Light source. CYP2C8 and CYP2C9 are the two major enzymes that contribute to the metabolism of diclofenac. Isothermal titration calorimetry studies and enzymatic assays are in progress to determine and compare the binding affinity and activity of diclofenac with CYP2C8 and CYP2C9. Using a multitude of techniques that include structural, biophysical, and functional methods, the goal of this research is to elucidate the molecular determinants of diclofenac binding to CYP2C8, thereby improving our understanding of xenobiotic biotransformation and therapeutic outcomes.
Keywords
Cytochrome P450, CYP2C8, Diclofenac, Drug metabolism, X-ray crystallography, Isothermal titration calorimetry, Enzymatic assays, Pharmacogenetic variability
