Differences in transactivation between rat CYP3A1 and human CYP3A4 genes by human pregnane X receptor

Drug Metab Pharmacokinet. 2004 Apr;19(2):103-13. doi: 10.2133/dmpk.19.103.


In an assay system using a human CYP3A4 reporter constructed with the promoter (+11 nt to -362 nt) and enhancer (-7.2 knt to -7.8 knt) regions including everted repeat separated by six nucleotides (ER-6) and direct repeat separated by three nucleotides (DR-3) motifs, the CYP3A4 transactivation was detected without overexpression of any nuclear receptors in rifampicin-treated HepG2 cells. Overexpression of human pregnane X receptor (hPXR) enhanced the transactivation. Rat CYP3A1 reporter constructed with the promoter region (+31 nt to -171 nt) including both DR-3 and ER-6 motifs was, however, not transactivated in rifampicin-treated cells, even after overexpression of hPXR. Although overexpression of retinoid X receptor alpha (RXRalpha) had no clear effect for both CYP3A reporters, co-expression of apolipoprotein AI regulatory protein-1 (ARP-1) with hPXR resulted in the rifampicin-induced transactivation of the CYP3A1 reporter. A truncated CYP3A4 reporter retaining the both motifs showed the rifampicin-induced transactivation by overexpression of hPXR and ARP-1, while the transactivation in hPXR-overexpressed cells was not observed. These results support the idea that a nuclear receptor other than RXRalpha may play a role in the CYP3A transactivation together with hPXR. The present study also suggests the involvement of a novel cis-element in the hPXR-mediated CYP3A4 transactivation.

Publication types

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

MeSH terms

  • Amino Acid Motifs / genetics
  • Animals
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Cell Line, Tumor
  • Cells, Cultured
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics*
  • Electrophoretic Mobility Shift Assay
  • Enhancer Elements, Genetic / genetics
  • Gene Deletion
  • Gene Expression Regulation, Enzymologic / genetics
  • Genes, Reporter / genetics
  • Humans
  • Pregnane X Receptor
  • Rats
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Steroid / genetics*
  • Species Specificity
  • Transcriptional Activation / genetics*
  • Transfection


  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • CYP3A protein, human
  • Cyp3a23-3a1 protein, rat
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human