Valproic acid induces CYP3A4 and MDR1 gene expression by activation of constitutive androstane receptor and pregnane X receptor pathways
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
17392393
DOI
10.1124/dmd.106.014456
PII: S0090-9556(24)01335-7
Knihovny.cz E-resources
- MeSH
- Transcriptional Activation drug effects MeSH
- Anticonvulsants pharmacology MeSH
- Aryl Hydrocarbon Hydroxylases genetics MeSH
- Cytochrome P-450 CYP3A MeSH
- Cytochrome P-450 CYP2B6 MeSH
- Enzyme Induction MeSH
- Transcription, Genetic drug effects MeSH
- Hepatocytes drug effects enzymology metabolism MeSH
- Hydroxylation MeSH
- Constitutive Androstane Receptor MeSH
- Valproic Acid pharmacology MeSH
- Humans MeSH
- Luciferases MeSH
- RNA, Messenger metabolism MeSH
- Oxidoreductases, N-Demethylating genetics MeSH
- Cell Line, Tumor MeSH
- Oximes pharmacology MeSH
- ATP Binding Cassette Transporter, Subfamily B, Member 1 biosynthesis genetics MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- Pregnane X Receptor MeSH
- Promoter Regions, Genetic drug effects MeSH
- Receptors, Cytoplasmic and Nuclear drug effects metabolism MeSH
- Genes, Reporter MeSH
- Electrophoretic Mobility Shift Assay MeSH
- Retinoid X Receptor alpha drug effects metabolism MeSH
- Rifampin pharmacology MeSH
- Receptors, Steroid drug effects metabolism MeSH
- Drug Synergism MeSH
- Cytochrome P-450 Enzyme System biosynthesis genetics MeSH
- Testosterone metabolism MeSH
- Thiazoles pharmacology MeSH
- Transfection MeSH
- Transcription Factors drug effects metabolism MeSH
- Up-Regulation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime MeSH Browser
- Anticonvulsants MeSH
- Aryl Hydrocarbon Hydroxylases MeSH
- CYP2B6 protein, human MeSH Browser
- CYP3A4 protein, human MeSH Browser
- Cytochrome P-450 CYP3A MeSH
- Cytochrome P-450 CYP2B6 MeSH
- Constitutive Androstane Receptor MeSH
- Valproic Acid MeSH
- Luciferases MeSH
- RNA, Messenger MeSH
- Oxidoreductases, N-Demethylating MeSH
- Oximes MeSH
- ATP Binding Cassette Transporter, Subfamily B, Member 1 MeSH
- Pregnane X Receptor MeSH
- Receptors, Cytoplasmic and Nuclear MeSH
- Retinoid X Receptor alpha MeSH
- Rifampin MeSH
- Receptors, Steroid MeSH
- Cytochrome P-450 Enzyme System MeSH
- Testosterone MeSH
- Thiazoles MeSH
- Transcription Factors MeSH
In our study, we tested the hypothesis whether valproic acid (VPA) in therapeutic concentrations has potential to affect expression of CYP3A4 and MDR1 via constitutive androstane receptor (CAR) and pregnane X receptor (PXR) pathways. Interaction of VPA with CAR and PXR nuclear receptors was studied using luciferase reporter assays, real-time reverse transcriptase polymerase chain reaction (RT-PCR), electrophoretic mobility shift assay (EMSA), and analysis of CYP3A4 catalytic activity. Using transient transfection reporter assays in HepG2 cells, VPA was recognized to activate CYP3A4 promoter via CAR and PXR pathways. By contrast, a significant effect of VPA on MDR1 promoter activation was observed only in CAR-cotransfected HepG2 cells. These data well correlated with up-regulation of CYP3A4 and MDR1 mRNAs analyzed by real-time RT-PCR in cells transfected with expression vectors encoding CAR or PXR and treated with VPA. In addition, VPA significantly up-regulated CYP3A4 mRNA in primary hepatocytes and augmented the effect of rifampicin. EMSA experiments showed VPA-mediated augmentation of CAR/retinoid X receptor alpha heterodimer binding to direct repeat 3 (DR3) and DR4 responsive elements of CYP3A4 and MDR1 genes, respectively. Finally, analysis of specific CYP3A4 catalytic activity revealed its significant increase in VPA-treated LS174T cells transfected with PXR. In conclusion, we provide novel insight into the mechanism by which VPA affects gene expression of CYP3A4 and MDR1 genes. Our results demonstrate that VPA has potential to up-regulate CYP3A4 and MDR1 through direct activation of CAR and/or PXR pathways. Furthermore, we suggest that VPA synergistically augments the effect of rifampicin in transactivation of CYP3A4 in primary human hepatocytes.
References provided by Crossref.org
Metformin suppresses pregnane X receptor (PXR)-regulated transactivation of CYP3A4 gene
