Comparison of the induction profile for drug disposition proteins by typical nuclear receptor activators in human hepatic and intestinal cells

Autor: P, Martin, R, Riley, D J, Back, A, Owen
Rok vydání: 2007
Předmět:
Pregnenolone Carbonitrile
Receptors
Steroid
ATP Binding Cassette Transporter
Subfamily B
Cell Culture Techniques
Receptors
Cytoplasmic and Nuclear
Chenodeoxycholic Acid
Dexamethasone
Cytochrome P-450 Enzyme System
Cytochrome P-450 CYP3A
Humans
ATP Binding Cassette Transporter
Subfamily B
Member 1
RNA
Messenger
Intestinal Mucosa
Cells
Cultured
Constitutive Androstane Receptor
Dose-Response Relationship
Drug
Pregnane X Receptor
Membrane Transport Proteins
Epithelial Cells
Oxidoreductases
N-Demethylating
Research Papers
Multidrug Resistance-Associated Protein 2
Up-Regulation
DNA-Binding Proteins
Cytochrome P-450 CYP2B6
Research Design
Enzyme Induction
Phenobarbital
Hepatocytes
ATP-Binding Cassette Transporters
Aryl Hydrocarbon Hydroxylases
Caco-2 Cells
Multidrug Resistance-Associated Proteins
Rifampin
Transcription Factors
Zdroj: British journal of pharmacology. 153(4)
ISSN: 0007-1188
Popis: Certain nuclear receptors (NRs) such as the constitutive androstane receptor (CAR), pregnane X receptor (PXR) and farnesoid X receptor (FXR) mediate induction of some cytochrome P450 enzymes and ABC transporters but conflicting reports exist. The purpose of this study was to assess the reasons for these discrepancies and use a standardized approach to compare activators of NRs.Dexamethasone, pregnenolone 16alpha-carbonitrile, rifampicin, phenobarbital and chenodeoxycholic acid were incubated with HepG2, Caco-2 and cryopreserved human hepatocytes prior to analysis of mRNA and protein for CYP2B6, CYP3A4, CYP3A5, ABCB1, ABCC1, ABCC2, PXR, CAR and FXR.Dexamethasone significantly up-regulated PXR, CYP3A4 and ABCB1 expression in HepG2 and Caco-2 cells. As a result, including dexamethasone as a media supplement masked the induction of these genes by pregnenolone 16alpha-carbonitrile, which may explain discrepancies between previous reports. In the absence of dexamethasone, significant activator-dependent induction was observed in all cell types. Significant correlations were observed between the fold increase in mRNA and in protein, which were, for most instances, logarithmic. Changes in mRNA expression were greater in cell lines than primary cells but for most transcripts correlations were observed between fold increases in HepG2 and hepatocytes.Clearly, no in vitro system can imitate the physiology of a hepatocyte or intestinal cell within an intact organ in vivo, but these data explain some of the discrepancies reported between laboratories and have important implications for study design.
Databáze: OpenAIRE
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