Regulation of CYP3A4 and CYP2B6 expression by liver X receptor agonists

Biochem Pharmacol. 2007 Nov 15;74(10):1535-40. doi: 10.1016/j.bcp.2007.07.040. Epub 2007 Aug 3.


The liver X receptor (LXR) agonists, 24(S),25-epoxycholesterol and T0901317, were previously shown to be capable of inducing CYP3A expression in primary cultured rodent hepatocytes through activation of the pregnane X receptor (PXR). In this study, the abilities of these two LXR agonists to regulate CYP3A4 and CYP2B6 mRNA expression in primary cultures of human hepatocytes were evaluated. Treatment with 10 or 30 microM of the endogenous oxysterol, 24(S),25-epoxycholesterol, had no effect on CYP3A4 mRNA content in five preparations of primary cultured human hepatocytes, while 30 microM 24(S),25-epoxycholesterol treatment increased CYP2B6 mRNA content by approximately two-fold. By comparison, treatment with the synthetic LXR agonist, T0901317, potently increased CYP3A4 and CYP2B6 mRNA levels in the human hepatocyte cultures, producing multi-fold increases at 10nM. Using a HepG2-based transactivation assay, T0901317 activated human PXR with an EC(50) approximately 20nM, which was more than 10-fold lower than that of the potent PXR ligand, SR-12813, while treatment with 24(S),25-epoxycholesterol failed to induce reporter expression in this assay. Therefore, while 24(S),25-epoxycholesterol-mediated PXR activation and CYP3A induction does not appear to be conserved from rodent to human, T0901317 is among the most potent known activators of human PXR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged, 80 and over
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Cell Line
  • Cells, Cultured
  • Cholesterol / analogs & derivatives
  • Cholesterol / pharmacology
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics*
  • DNA-Binding Proteins / agonists*
  • Female
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Hepatocytes / enzymology
  • Humans
  • Hydrocarbons, Fluorinated
  • Infant
  • Liver X Receptors
  • Male
  • Middle Aged
  • Orphan Nuclear Receptors
  • Oxidoreductases, N-Demethylating / genetics*
  • Pregnane X Receptor
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Steroid / agonists*
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism
  • Sulfonamides / pharmacology*
  • Transfection


  • DNA-Binding Proteins
  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Pregnane X Receptor
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Sulfonamides
  • TO-901317
  • 24,25-epoxycholesterol
  • Cytochrome P-450 Enzyme System
  • Cholesterol
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Oxidoreductases, N-Demethylating