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Updated: Oct 1, 2026
A Hyperandrogenic Mouse Model to Study Polycystic Ovary Syndrome
Published on: October 2, 2018
Estrogen-dependent regulation of the expression of hepatic Cyp2b and 3a isoforms: assessment using
Hideyuki Yamada1, Noriko Gohyama, Shin-ichiro Honda
1Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Abstract:
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.
Insights
Estrogen suppresses Cyp3a11 and requires adult exposure for Cyp2b9 maintenance. Aromatase gene disruption impacts female-specific Cyp3a41 expression, suggesting developmental programming by estrogen.
Area of Science:
- Biochemistry
- Pharmacology
- Endocrinology
Background:
- Estrogen plays a crucial role in regulating gene expression, including drug-metabolizing enzymes in the liver.
- Cytochrome P450 (CYP) enzymes, such as Cyp2b and Cyp3a isoforms, are vital for xenobiotic metabolism and are known to be influenced by hormonal factors.
Purpose of the Study:
- To investigate the role of endogenous estrogen, synthesized by aromatase, in the expression and induction of hepatic Cyp2b and Cyp3a isoforms.
- To elucidate the specific effects of aromatase deficiency on the regulation of these key drug-metabolizing enzymes.
Main Methods:
- Utilized aromatase knockout (Ar-/-) mice to study estrogen biosynthesis disruption.
- Assessed P450 expression via reverse transcription-polymerase chain reaction (RT-PCR), immunoblotting, and enzyme activity assays (testosterone 6beta- and 16alpha-hydroxylase).
Main Results:
- Aromatase gene disruption increased Cyp3a11 protein but not mRNA, indicating post-transcriptional suppression by estrogen.
- Female-specific Cyp3a41 disappeared in Ar-/- mice, suggesting developmental estrogen programming, and was not reversible by adult estradiol administration.
- Constitutive expression of female-specific Cyp2b9 was lost in Ar-/- mice but could be restored by exogenous estradiol in adults, indicating a requirement for ongoing estrogen.
- Aromatase deficiency did not affect phenobarbital (PB)-mediated induction of Cyp2b10 or the non-inducible nature of other isoforms.
Conclusions:
- Estrogen suppresses Cyp3a11 expression.
- Estrogen exposure during neonatal/infantile periods programs the expression of female-specific Cyp3a41.
- Adult estrogen is necessary for maintaining the expression of female-specific Cyp2b9.
- Endogenous estrogen has a minimal role in phenobarbital-induced Cyp2b10 expression.
