Sex steroid hormones regulate constitutive expression of Cyp2e1 in female mouse liver

Am J Physiol Endocrinol Metab. 2013 May 15;304(10):E1118-28. doi: 10.1152/ajpendo.00585.2012. Epub 2013 Apr 2.


CYP2E1 is of paramount toxicological significance because it metabolically activates a large number of low-molecular-weight toxicants and carcinogens. In this context, factors that interfere with Cyp2e1 regulation may critically affect xenobiotic toxicity and carcinogenicity. The aim of this study was to investigate the role of female steroid hormones in the regulation of CYP2E1, as estrogens and progesterone are the bases of contraceptives and hormonal replacement therapy in menopausal women. Interestingly, a fluctuation in the hepatic expression pattern of Cyp2e1 was revealed in the different phases of the estrous cycle of female mice, with higher Cyp2e1 expression at estrus (E) and lower at methestrus (ME), highly correlated with that in plasma gonadal hormone levels. Depletion of sex steroids by ovariectomy repressed Cyp2e1 expression to levels similar to those detected in males and cyclic females at ME. Hormonal supplementation brought Cyp2e1 expression back to levels detected at E. The role of progesterone appeared to be more prominent than that of 17β-estradiol. Progesterone-induced Cyp2e1 upregulation could be attributed to inactivation of the insulin/PI3K/Akt/FOXO1 signaling pathway. Tamoxifen, an anti-estrogen, repressed Cyp2e1 expression potentially via activation of the PI3K/Akt/FOXO1 and GH/STAT5b-linked pathways. The sex steroid hormone-related changes in hepatic Cyp2e1 expression were highly correlated with those observed in Hnf-1α, β-catenin, and Srebp-1c. In conclusion, female steroid hormones are clearly involved in the regulation of CYP2E1, thus affecting the metabolism of a plethora of toxicants and carcinogenic agents, conditions that may trigger several pathologies or exacerbate the outcomes of various pathophysiological states.

Keywords: 17β-estradiol; Cyp2e1; estrous cycle; mice; progesterone.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • Cytochrome P-450 CYP2E1 / biosynthesis*
  • Cytochrome P-450 CYP2E1 / genetics
  • Cytochrome P-450 CYP2E1 / metabolism
  • Estradiol / pharmacology*
  • Estrogen Antagonists / pharmacology
  • Estrous Cycle
  • Female
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism
  • Liver / enzymology*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phosphatidylinositol 3-Kinases / metabolism
  • Progesterone / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA / chemistry
  • RNA / genetics
  • Real-Time Polymerase Chain Reaction
  • STAT5 Transcription Factor / metabolism
  • Tamoxifen / pharmacology


  • Estrogen Antagonists
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • STAT5 Transcription Factor
  • Tamoxifen
  • Progesterone
  • Estradiol
  • RNA
  • Cytochrome P-450 CYP2E1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt