Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole

Oncogene. 2007 Jan 11;26(2):258-68. doi: 10.1038/sj.onc.1209788. Epub 2006 Jul 3.


Individual variation in drug metabolism is a major cause of unpredictable side effects during therapy. Drug metabolism is controlled by a class of orphan nuclear receptors (NRs), which regulate expression of genes such as CYP (cytochrome)3A4 and MDR-1 (multi-drug resistance-1), that are involved in this process. We have found that xenobiotic-mediated induction of CYP3A4 and MDR-1 gene transcription was inhibited by ketoconazole, a commonly used antifungal drug. Ketoconazole mediated its effect by inhibiting the activation of NRs, human pregnenolone X receptor and constitutive androstene receptor, involved in regulation of CYP3A4 and MDR-1. The effect of ketoconazole was specific to the group of NRs that control xenobiotic metabolism. Ketoconazole disrupted the interaction of the xenobiotic receptor PXR with the co-activator steroid receptor co-activator-1. Ketoconazole treatment resulted in delayed metabolism of tribromoethanol anesthetic in mice, which was correlated to the inhibition of PXR activation and downmodulation of cyp3a11 and mdr-1 genes and proteins. These studies demonstrate for the first time that ketoconazole represses the coordinated activation of genes involved in drug metabolism, by blocking activation of a specific subset of NRs. Our results suggest that ketoconazole can be used as a pan-antagonist of NRs involved in xenobiotic metabolism in vivo, which may lead to novel strategies that improve drug effect and tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Antifungal Agents / pharmacology*
  • Blotting, Western
  • Constitutive Androstane Receptor
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors
  • Ethanol / analogs & derivatives
  • Ethanol / metabolism
  • Female
  • Gene Expression Regulation / drug effects*
  • Hepatocytes / metabolism
  • Histone Acetyltransferases / antagonists & inhibitors
  • Humans
  • Ketoconazole / pharmacology*
  • Liver X Receptors
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Coactivator 1
  • Orphan Nuclear Receptors
  • Pregnane X Receptor
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Steroid / antagonists & inhibitors
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / antagonists & inhibitors
  • Tumor Cells, Cultured


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antifungal Agents
  • Constitutive Androstane Receptor
  • DNA-Binding Proteins
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Pregnane X Receptor
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Transcription Factors
  • tribromoethanol
  • Ethanol
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Histone Acetyltransferases
  • NCOA1 protein, human
  • Ncoa1 protein, mouse
  • Nuclear Receptor Coactivator 1
  • Ketoconazole