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Comparison of the induction profile for drug disposition proteins by typical nuclear receptor activators in human hepatic and intestinal cells.
- Source :
-
British Journal of Pharmacology . Feb2008, Vol. 153 Issue 4, p805-819. 15p. 1 Chart, 7 Graphs. - Publication Year :
- 2008
-
Abstract
- <bold>Background and Purpose: </bold>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.<bold>Experimental Approach: </bold>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.<bold>Key Results: </bold>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.<bold>Conclusions and Implications: </bold>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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *NUCLEAR receptors (Biochemistry)
*PROTEINS
*LIVER cells
*CYTOCHROMES
*ENZYMES
*BIOCHEMISTRY
*CARRIER proteins
*CELL culture
*CELL receptors
*COMPARATIVE studies
*DOSE-effect relationship in pharmacology
*EPITHELIAL cells
*EXPERIMENTAL design
*GENES
*GLYCOPROTEINS
*HEMOPROTEINS
*INTESTINAL mucosa
*PHENOMENOLOGY
*RESEARCH methodology
*MEDICAL cooperation
*OXIDOREDUCTASES
*RESEARCH
*RIFAMPIN
*RNA
*TRANSCRIPTION factors
*DNA-binding proteins
*EVALUATION research
*DEXAMETHASONE
*PHENOBARBITAL
*MEMBRANE transport proteins
*PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 00071188
- Volume :
- 153
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- British Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 30000946
- Full Text :
- https://doi.org/10.1038/sj.bjp.0707601