title: Understanding P450-mediated Bio-transformations into Epoxide and Phenolic Metabolites.
abstract: Adverse drug reactions are commonly the result of cytochrome P450 enzymes (CYPs) converting the drugs into reactive metabolites. Thus, information about the CYP bioactivation of drugs would not only provide insight into metabolic stability, but also into the potential toxicity. For example, oxidation of phenyl rings may lead to either toxic epoxides or safer phenols. Herein, we demonstrate that the potential to form reactive metabolites is encoded primarily in the properties of the molecule to be oxidized. While the enzyme positions the molecule inside the binding pocket (selects the site of metabolism), the subsequent reaction is only dependent on the substrate itself. To test this hypothesis, we used this observation as a predictor of drug inherent toxicity. This approach was used to successfully identify the formation of reactive metabolites in over 100 drug molecules. These results provide a new perspective on the impact of functional groups on aromatic oxidation of drugs and their effects on toxicity.
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, H3A 0B8 (Canada).
authors.forename: Anna
authors.initials: A
authors.lastname: Tomberg
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, H3A 0B8 (Canada).
authors.forename: Joshua
authors.initials: J
authors.lastname: Pottel
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, H3A 0B8 (Canada).
authors.forename: Zhaomin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Chemical Computing Group Inc., 1010 Sherbrooke Street West, Montreal, QC, H3A 2R7 (Canada).
authors.forename: Paul
authors.initials: P
authors.lastname: Labute
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, H3A 0B8 (Canada). nicolas.moitessier@mcgill.ca.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Moitessier
mesh_terms: D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010636:Phenols / Q000737:chemistry / Q000378:metabolism*; D011789:Quantum Theory
chemical_list: D004852:Epoxy Compounds; D010636:Phenols; D003577:Cytochrome P-450 Enzyme System
keywords: computational chemistry; cytochromes; frontier-orbital model; metabolism; toxicology