Pregnane X receptor-dependent and -independent effects of 2-acetylaminofluorene on cytochrome P450 3A23 expression and liver cell proliferation

Biochem Biophys Res Commun. 2003 Jan 10;300(2):278-84. doi: 10.1016/s0006-291x(02)02847-4.


The arylamide 2-acetylaminofluorene (AAF) is a powerful carcinogen displaying a marked promoting activity, also known to regulate expression of liver detoxifying proteins. In this study we identified CYP3A23, a major inducible cytochrome P-450 (CYP) isoform, as an AAF target in hepatocytes. Indeed, exposure to AAF of primary rat hepatocytes resulted in a marked up-regulation of CYP3A23 expression at both mRNA and protein levels. Using CYP3A23 reporter gene constructs, we further demonstrated that AAF activated the CYP3A23 Direct Repeat 3 (DR3) promoter element interacting with the nuclear pregnane X receptor (PXR). Moreover, the PXR antagonist ecteinascidin-743 fully suppressed AAF-related CYP3A23 induction. Low doses of AAF inhibiting DNA synthesis in hepatocytes however failed to trigger PXR-related CYP3A23 induction and PXR-negative epithelial liver cells remained sensitive to the mito-inhibitory effects of AAF. Such data indicate that AAF up-regulates CYP3A23 through PXR activation but does not require PXR for exerting its carcinogenic promoting properties based on inhibition of cell growth.

MeSH terms

  • 2-Acetylaminofluorene / pharmacology*
  • Animals
  • Aryl Hydrocarbon Hydroxylases / biosynthesis
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Carcinogens / pharmacology*
  • Cell Division
  • Cells, Cultured
  • Cytochrome P-450 CYP3A
  • DNA / biosynthesis
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Liver / cytology
  • Male
  • Pregnane X Receptor
  • Promoter Regions, Genetic
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Steroid / physiology*
  • Transcriptional Activation
  • Up-Regulation


  • Carcinogens
  • Pregnane X Receptor
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • DNA
  • 2-Acetylaminofluorene
  • Aryl Hydrocarbon Hydroxylases
  • Cyp3a23-3a1 protein, rat
  • Cytochrome P-450 CYP3A