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Received for publication March 25, 2005.
Revised May 26, 2005.
Accepted for publication June 1, 2005.
Abstract
Cytochrome P450 (CYP) enzymes play important roles in the metabolism of endogenous and xenobiotic substrates in humans. CYP2C8 is an important member of the CYP2C subfamily which metabolizes both endogenous compounds (i.e. arachidonic acids and retinoic acid) and xenobiotics (e.g. paclitaxel). Induction of CYP enzymes by drugs can result in tolerance as well as drug-drug interactions. CYP2C8 is the most strongly inducible member of the CYP2C subfamily in human hepatocytes, but the mechanism of induction by xenobiotics has not been delineated. To determine the mechanisms controlling the regulation of this important CYP, we cloned the 5'-flanking region of CYP2C8 and investigated its transcriptional regulation by nuclear factors such as the pregnane X receptor (PXR), constitutive androstane receptor (CAR), glucocorticoid receptor (GR) and hepatic nuclear factor 4 (HNF4
) that are known to be involved in the induction of other CYP enzymes using both cell lines and primary hepatocyte models. First, we identified a distal PXR/CAR binding site in the CYP2C8 promoter that confers inducibility of CYP2C8 via the PXR agonist/ligand rifampicin, and the CAR agonist/ligand CITCO. A glucocorticoid responsive element was identified that mediates dexamethasone induction via the GR. Finally, we identify an HNF4 binding site within the CYP2C8 basal promoter region that is cis-activated by cotransfected HNF4. In summary, the present studies show that CAR, PXR, GR, and HNF4 can regulate CYP2C8 expression and identify specific cis-elements within the promoter that control these regulatory pathways.
Key words:
DNA binding sites, Promoter analysis, Regulation of gene expression, Cytochrome P450, Regulation - transcriptional, Regulation - xenobiotic
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