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

Br J Pharmacol. 2008 Feb;153(4):805-19. doi: 10.1038/sj.bjp.0707601. Epub 2007 Nov 26.


Background and purpose: 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.

Experimental approach: 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.

Key results: 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.

Conclusions and implications: 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
  • ATP-Binding Cassette Transporters / biosynthesis*
  • ATP-Binding Cassette Transporters / genetics
  • Aryl Hydrocarbon Hydroxylases / biosynthesis
  • Caco-2 Cells
  • Cell Culture Techniques
  • Cells, Cultured
  • Chenodeoxycholic Acid / pharmacology
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A / biosynthesis
  • Cytochrome P-450 Enzyme System / biosynthesis*
  • Cytochrome P-450 Enzyme System / genetics
  • DNA-Binding Proteins / agonists
  • Dexamethasone / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Induction
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Humans
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / metabolism
  • Membrane Transport Proteins / biosynthesis
  • Multidrug Resistance-Associated Proteins / biosynthesis
  • Oxidoreductases, N-Demethylating / biosynthesis
  • Phenobarbital / pharmacology
  • Pregnane X Receptor
  • Pregnenolone Carbonitrile / pharmacology
  • RNA, Messenger / biosynthesis
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / biosynthesis
  • Receptors, Steroid / agonists
  • Research Design
  • Rifampin / pharmacology
  • Transcription Factors / agonists
  • Up-Regulation


  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • DNA-Binding Proteins
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • Pregnane X Receptor
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Transcription Factors
  • farnesoid X-activated receptor
  • Chenodeoxycholic Acid
  • Pregnenolone Carbonitrile
  • constitutive androstane receptor
  • multidrug resistance-associated protein 2
  • Dexamethasone
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Oxidoreductases, N-Demethylating
  • Rifampin
  • multidrug resistance-associated protein 1
  • Phenobarbital