title: Comparison of the ligand binding site of CYP2C8 with CYP26A1 and CYP26B1: a structural basis for the identification of new inhibitors of the retinoic acid hydroxylases.
abstract: The CYP26s are responsible for metabolizing retinoic acid and play an important role in maintaining homeostatic levels of retinoic acid. Given the ability of CYP2C8 to metabolize retinoic acid, we evaluated the potential for CYP2C8 inhibitors to also inhibit CYP26. In vitro assays were used to evaluate the inhibition potencies of CYP2C8 inhibitors against CYP26A1 and CYP26B1. Using tazarotenic acid as a substrate for CYP26, IC50values for 17 inhibitors of CYP2C8 were determined for CYP26A1 and CYP26B1, ranging from ∼20 nM to 100 μM, with a positive correlation observed between IC50s for CYP2C8 and CYP26A1. An evaluation of IC50's versus in vivo Cmaxvalues suggests that inhibitors such as clotrimazole or fluconazole may interact with CYP26 at clinically relevant concentrations and may alter levels of retinoic acid. These findings provide insight into drug interactions resulting in elevated retinoic acid concentrations and expand upon the pharmacophore of CYP26 inhibition.
authors.affiliation: a Amgen Pharmacokinetics and Drug Metabolism , Cambridge , MA , USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Foti
authors.affiliation: b Department of Biomedical and Pharmaceutical Sciences , Core Laboratory for Neuromolecular Production, University of Montana , Missoula , MT , USA.|c Dermaxon , Missoula , MT , USA , and.
authors.forename: Philippe
authors.initials: P
authors.lastname: Diaz
authors.affiliation: d CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, Université Nice Sophia Antipolis , Valbonne , France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Douguet
mesh_terms: D001665:Binding Sites; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D000072516:Retinoic Acid 4-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D008024:Ligands; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase
keywords: CYP26; CYP2C8; homology model; retinoic acid; tazarotenic acid