Estradiol induces cytochrome P450 2B6 expression at high concentrations: implication in estrogen-mediated gene regulation in pregnancy

Biochem Pharmacol. 2012 Jul 1;84(1):93-103. doi: 10.1016/j.bcp.2012.03.016. Epub 2012 Mar 30.


Pregnancy alters the rate and extent of drug metabolism, but little is known about the underlying molecular mechanism. We have found that 17β-estradiol (E2) upregulates expression of the major drug-metabolizing enzyme CYP2B6 in primary human hepatocytes. Results from promoter reporter assays in HepG2 cells revealed that E2 activates constitutive androstane receptor (CAR) and enhances promoter activity of CYP2B6, for which high concentrations of E2 reached during pregnancy were required. E2 triggered nuclear translocation of CAR in primary rat hepatocytes that were transiently transfected with human CAR as well as in primary human hepatocytes, further confirming transactivation of CAR by E2. E2-activated estrogen receptor (ER) also enhanced CYP2B6 promoter activity. The DNA-binding domain of ER was not required for the induction of CYP2B6 promoter activity by E2, suggesting involvement of a non-classical mechanism of ER action. Results from deletion and mutation assays as well as electrophorectic mobility shift and supershift assays revealed that two AP-1 binding sites (-1782/-1776 and -1664/-1658 of CYP2B6) are critical for ER-mediated activation of the CYP2B6 promoter by E2. Concurrent activation of both ER and CAR by E2 enhanced CYP2B6 expression in a synergistic manner. Our data demonstrate that at high concentrations reached during pregnancy, E2 activates both CAR and ER that synergistically induce CYP2B6 expression. These results illustrate pharmacological activity of E2 that would likely become prominent during pregnancy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Binding Sites
  • Cell Nucleus / metabolism
  • Chromatin Immunoprecipitation
  • Chromatography, High Pressure Liquid
  • Constitutive Androstane Receptor
  • Cytochrome P-450 CYP2B6
  • Dose-Response Relationship, Drug
  • Electrophoretic Mobility Shift Assay
  • Estradiol / blood
  • Estradiol / pharmacology*
  • Estrogens / blood
  • Estrogens / pharmacology*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Genes, Reporter
  • Hep G2 Cells
  • Hepatocytes / drug effects*
  • Hepatocytes / enzymology
  • Humans
  • Luciferases / genetics
  • Middle Aged
  • Nuclear Proteins / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Oxidoreductases, N-Demethylating / genetics*
  • Oxidoreductases, N-Demethylating / metabolism
  • Pregnancy / blood
  • Pregnancy / genetics*
  • Promoter Regions, Genetic
  • Real-Time Polymerase Chain Reaction
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Tandem Mass Spectrometry
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism
  • Transcriptional Activation


  • Constitutive Androstane Receptor
  • Estrogens
  • Nuclear Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Transcription Factor AP-1
  • Estradiol
  • Luciferases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Oxidoreductases, N-Demethylating