Stereoselective interactions of warfarin enantiomers with the pregnane X nuclear receptor in gene regulation of major drug-metabolizing cytochrome P450 enzymes

0355208 - ÚMG 2011 RIV GB eng J - Journal Article
Rulcová, A. - Prokopová, I. - Krausová, L. - Bitman, M. - Vrzal, R. - Dvořák, Z. - Blahoš, Jaroslav - Pávek, P.
Stereoselective interactions of warfarin enantiomers with the pregnane X nuclear receptor in gene regulation of major drug-metabolizing cytochrome P450 enzymes.
Journal of Thrombosis and Haemostasis. Roč. 8, č. 12 (2010), s. 2708-2717. ISSN 1538-7933. E-ISSN 1538-7836
R&D Projects: GA MŠMT(CZ) LC06063
Institutional research plan: CEZ:AV0Z50520514
Keywords : CYP3A4 * gene regulation * warfarin
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 5.439, year: 2010

Background: Warfarin, an antagonist of vitamin K, is an oral coumarin anticoagulant widely used to control and prevent thromboembolic disorders. Warfarin is clinically available as a racemic mixture of R- and S-warfarin. The S-enantiomer has three to five times greater anticoagulation potency than its optical congener. Recently, vitamin K-2 function has been proposed via the pregnane X receptor (PXR) in osteocytes. PXR acts as a xenobiotic sensor that controls expression of many genes involved in drug/xenobiotic metabolic clearance. Objective: The aim was to examine whether enantiomers of warfarin stereoselectively interact with PXR to up-regulate main drug/ xenobiotic-metabolizing enzymes of the cytochrome P450 superfamily. Methods: Interactions of warfarin enantiomers with PXR were tested by gene reporter assays and time-resolved fluorescence resonance energy transfer technology (TR-FRET) ligand binding assay.
Permanent Link: http://hdl.handle.net/11104/0194033