Estrogen-dependent regulation of the expression of hepatic Cyp2b and 3a isoforms: assessment using aromatase-deficient mice

Toxicol Appl Pharmacol. 2002 Apr 1;180(1):1-10. doi: 10.1006/taap.2002.9366.


The role of estrogen in the expression and induction of hepatic Cyp2b and Cyp3a isoforms was studied using mice [Ar (-/-) mice] lacking aromatase, a key enzyme for estrogen biosynthesis. The expression of P450s was determined by reverse transcription-polymerase chain reaction, immunoblotting, and measuring testosterone 6beta- and 16alpha-hydroxylase activity as markers. Basic expression of Cyp3a11 mRNA and protein was seen in both sexes of Ar (+/+) mice. Disruption of the aromatase gene caused an increase in the expression of Cyp3a11 protein, although the mRNA level remained unchanged. Female-specific Cyp3a41 disappeared in Ar (-/-) mice, and this could not be reversed by administration of exogenous beta-estradiol to adult knockout mice. The constitutive expression of female-specific Cyp2b9 also disappeared on disrupting the aromatase gene. However, in clear contrast to Cyp3a41, some individual Ar (-/-) mice exhibited expression of this form following treatment with exogenous beta-estradiol. Disruption of the aromatase gene had no effect on PB-mediated induction of Cyp2b10 or on the noninducible nature of Cyp2b9, Cyp3a11, and Cyp3a41. These results suggest that (1) Cyp3a11 is suppressed by estrogen; (2) the expression of female-specific Cyp3a41 is programmed by neonatal and/or infantile exposure to estrogen; (3) maintenance of the expression of female-specific Cyp2b9 requires estrogen in adults; and (4) endogenous estrogen plays little, if any, role in the mechanism by which PB induces Cyp2b10.

MeSH terms

  • Animals
  • Aromatase / deficiency*
  • Aromatase / genetics
  • Aryl Hydrocarbon Hydroxylases*
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / biosynthesis*
  • Cytochrome P-450 Enzyme System / genetics
  • DNA Primers / chemistry
  • Enzyme Induction
  • Estradiol / pharmacology
  • Estrogens / metabolism*
  • Female
  • Immunoblotting
  • Liver / drug effects
  • Liver / enzymology*
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Organ Size / drug effects
  • Oxidoreductases, N-Demethylating / biosynthesis*
  • Oxidoreductases, N-Demethylating / genetics
  • Protein Isoforms
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sex Factors
  • Steroid 16-alpha-Hydroxylase
  • Uterus / drug effects
  • Uterus / pathology


  • DNA Primers
  • Estrogens
  • Membrane Proteins
  • Protein Isoforms
  • RNA, Messenger
  • Estradiol
  • Cytochrome P-450 Enzyme System
  • Aromatase
  • Aryl Hydrocarbon Hydroxylases
  • Cyp3a11 protein, mouse
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • Steroid 16-alpha-Hydroxylase
  • Oxidoreductases, N-Demethylating