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17β-estradiol suppresses carboxylesterases by activating c-Jun/AP-1 pathway in primary human and mouse hepatocytes

Lili Wu1, Muhammad Zubair Hafiz1, Yu Guan1

  • 1Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China.

European Journal of Pharmacology
|November 28, 2017
PubMed

Insights

17β-estradiol suppresses carboxylesterases (CES1 and CES2) by activating the c-Jun/AP-1 pathway. This finding is crucial for optimizing drug therapy safety and efficacy in women.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Endocrinology

Background:

  • Carboxylesterases (CES1 and CES2) play vital roles in drug metabolism.
  • Estrogen levels fluctuate during specific life stages in women, potentially impacting drug efficacy.

Purpose of the Study:

  • To investigate the influence of 17β-estradiol on CES1 and CES2 expression and activity.
  • To elucidate the molecular mechanisms underlying estrogen's effect on carboxylesterases.

Main Methods:

  • Treatment of human and mouse hepatocytes with 17β-estradiol.
  • Quantitative analysis of CES1/CES2 mRNA and protein levels.
  • Measurement of enzyme activity and investigation using AP-1 inhibitor (SP600125).
  • In vivo studies in ovariectomized mice.

Main Results:

  • 17β-estradiol significantly decreased CES1 and CES2 mRNA and protein levels in hepatocytes.
  • Enzyme activity of carboxylesterases was reduced by 17β-estradiol.
  • The effect was mediated through the c-Jun/AP-1 pathway, as shown by inhibitor studies.
  • In vivo, estrogen administration restored CES1/CES2 expression and activity in ovariectomized mice.

Conclusions:

  • 17β-estradiol suppresses carboxylesterase expression and activity via the c-Jun/AP-1 pathway.
  • These findings have implications for pharmacotherapy in women, particularly during pregnancy and menopause.
Keywords:
17β-estradiol17β-estradiol (PubChem CID: 5757)AP-1Actinomycin D (PubChem CID: 44460192)CarboxylesterasesClopidogrel (PubChem CID: 60606)Irinotecan carboxylate sodium salt (PubChem CID: 46781988)Para-nitrophenylacetate (PubChem CID:6931101)SP600125 (PubChem CID: 8515)The primary hepatocytesc-Jun

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