Linked Life Data

12181452

Source:http://linkedlifedata.com/resource/pubmed/id/12181452

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2002-8-15
pubmed:abstractText
The CYP2C subfamily metabolizes many clinically important drugs. These genes respond to prototypical inducers such as phenobarbital and rifampicin, yet little has been reported on the mechanisms of induction. This report examines the regulation of CYP2C9 with respect to two specific receptors thought to be involved in phenobarbital (PB) induction, the constitutive androstane receptor (CAR) and pregnane X receptor (PXR). Transfection of either mouse CAR (mCAR) or human CAR (hCAR) into HepG2 cells results in increased CYP2C9 mRNA content. Inducers further increased this response in CAR transfected cells. mCAR but not hCAR conferred drug inducibility to the proximal -2145 bp of the CYP2C9 promoter in luciferase assays. Further examination of a -2925-bp promoter construct revealed that hCAR cotransfection increased activity 20-fold. Gel shift assays confirmed the presence of a distal PB-responsive enhancer module-like enhancer module, CAR-responsive enhancer (CAR-RE), between -2900 and -2841 bp consisting of two DR-5 nuclear receptor binding motifs capable of binding hCAR, mCAR, and, to a lesser extent, human PXR. The majority of binding and hCAR activation is derived from the NR1 portion of the CAR-RE. PB treatment did not further increase the hCAR activation in any of the constructs. In summary, a new CAR/PXR binding site was identified in the CYP2C9 promoter, and this site seems to constitutively regulate transcription via a CAR-dependent mechanism; however, it could not be shown to account for PB inducibility of the gene.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0026-895X
pubmed:author
pubmed:issnType
Print
pubmed:volume
62
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
737-46
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:12181452-Aryl Hydrocarbon Hydroxylases, pubmed-meshheading:12181452-Base Sequence, pubmed-meshheading:12181452-Binding Sites, pubmed-meshheading:12181452-Cytochrome P-450 Enzyme System, pubmed-meshheading:12181452-DNA, pubmed-meshheading:12181452-Electrophoretic Mobility Shift Assay, pubmed-meshheading:12181452-Gene Expression Regulation, Enzymologic, pubmed-meshheading:12181452-Genes, Reporter, pubmed-meshheading:12181452-Humans, pubmed-meshheading:12181452-Molecular Sequence Data, pubmed-meshheading:12181452-Mutation, pubmed-meshheading:12181452-Promoter Regions, Genetic, pubmed-meshheading:12181452-Receptors, Cytoplasmic and Nuclear, pubmed-meshheading:12181452-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:12181452-Steroid 16-alpha-Hydroxylase, pubmed-meshheading:12181452-Steroid Hydroxylases, pubmed-meshheading:12181452-Transcription Factors, pubmed-meshheading:12181452-Transfection, pubmed-meshheading:12181452-Tumor Cells, Cultured
pubmed:year
2002
pubmed:articleTitle
Regulation of human CYP2C9 by the constitutive androstane receptor: discovery of a new distal binding site.
pubmed:affiliation
Laboratory of Pharmacology & Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
pubmed:publicationType
Journal Article