Stereoselective interactions of warfarin enantiomers with the pregnane X nuclear receptor in gene regulation of major drug-metabolizing cytochrome P450 enzymes
Language English Country England, Great Britain Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
20735727
DOI
10.1111/j.1538-7836.2010.04036.x
PII: S1538-7836(22)06630-2
Knihovny.cz E-resources
- MeSH
- Transcriptional Activation MeSH
- Anticoagulants chemistry pharmacology MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- Pregnane X Receptor MeSH
- Gene Expression Regulation, Enzymologic drug effects MeSH
- Genes, Reporter MeSH
- Fluorescence Resonance Energy Transfer MeSH
- Stereoisomerism MeSH
- Receptors, Steroid drug effects MeSH
- Cytochrome P-450 Enzyme System genetics MeSH
- Two-Hybrid System Techniques MeSH
- Up-Regulation drug effects MeSH
- Warfarin chemistry pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Anticoagulants MeSH
- Pregnane X Receptor MeSH
- Receptors, Steroid MeSH
- Cytochrome P-450 Enzyme System MeSH
- Warfarin MeSH
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 K₂ 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. Up-regulation of PXR-target gene mRNAs by warfarin enantiomers was studied using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) in primary human hepatocytes. RESULTS: We found that R-warfarin interacts with the PXR nuclear receptor. Consistently, R-warfarin significantly induced CYP3A4 and CYP2C9 mRNAs in cultures of primary human hepatocytes or in LS174T intestinal cells. On the other hand, S-warfarin is a less potent inducer of PXR-target genes in human hepatocytes and activates PXR only at supraphysiological concentrations. In addition, we showed that racemic 10- and 4'-hydroxywarfarins are also highly potent PXR ligands and inducers of CYP3A4 and CYP2C9 mRNA in human hepatocytes. CONCLUSION: We showed that R-warfarin can significantly up-regulate major drug-metabolizing enzymes CYP3A4 and CYP2C9 in the liver and thus may cause drug-drug interactions (DDI) with co-administered drugs. The results warrant reconsideration of racemic warfarin usage in clinics.
References provided by Crossref.org
