Estrogen Receptor α Mediates 17α-Ethynylestradiol Causing Hepatotoxicity*

@article{Yamamoto2006EstrogenR,
  title={Estrogen Receptor $\alpha$ Mediates 17$\alpha$-Ethynylestradiol Causing Hepatotoxicity*},
  author={Yukio Yamamoto and Rick Moore and Holly A Hess and Grace L. Guo and Frank J. Gonzalez and Kenneth S. Korach and Robert R. Maronpot and Masahiko Negishi},
  journal={Journal of Biological Chemistry},
  year={2006},
  volume={281},
  pages={16625 - 16631}
}
Estrogens are known to cause hepatotoxicity such as intrahepatic cholestasis in susceptible women during pregnancy, after administration of oral contraceptives, or during postmenopausal replacement therapy. Enterohepatic nuclear receptors including farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive active/androstane receptor (CAR) are important in maintaining bile acid homeostasis and protecting the liver from bile acid toxicity. However, no nuclear receptor has been… 
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134 Citations

Role of Pituitary Hormones on 17α-Ethinylestradiol-Induced Cholestasis in Rat
TLDR
Analysis of metabolic changes induced by EE in livers from hypophysectomized (HYPOX) and hypothyroid rats shows that pituitary hormones play a critical role in the hepatic effects of EE, and demonstrates a novel mechanism of action of EE through binding and negative regulation of glucocorticoid receptor-mediated transcription.
Role of pituitary hormones on 17alpha-ethinylestradiol-induced cholestasis in rat.
TLDR
Analysis of metabolic changes induced by EE in livers from hypophysectomized (HYPOX) and hypothyroid rats shows that pituitary hormones play a critical role in the hepatic effects of EE, and demonstrates a novel mechanism of action of EE through binding and negative regulation of glucocorticoid receptor-mediated transcription.
Molecular mechanism of 17α-ethinylestradiol cytotoxicity in isolated rat hepatocytes.
TLDR
Accelerated cytotoxicity mechanism screening techniques using isolated rat hepatocytes showed that CYP1A inhibitors decreased cytot toxicity, whereas tyrosinase increased toxicity; this suggests that the toxic mechanism involved is the oxidation of 17-EE.
Role of AMP-activated protein kinase α1 in 17α-ethinylestradiol-induced cholestasis in rats
TLDR
Results revealed that activation of cAMP-ERK-LKB1-AMPKα1 signaling pathway plays a critical role in EE-mediated dysregulation of the expression of FXR and bile acid transporters and may represent an important therapeutic target for estrogen-induced cholestasis.
Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries.
Induction of Hepatic Multidrug Resistance-Associated Protein 3 by Ethynylestradiol Is Independent of Cholestasis and Mediated by Estrogen Receptor
TLDR
EE increased the expression of hepatic Mrp3 transcriptionally and independently of any cholestatic manifestation and required participation of an ER, most likely ER-α through its phosphorylation, implicating ER as a key mediator.
Baicalin Protects Against 17α-Ethinylestradiol-Induced Cholestasis via the Sirtuin 1/Hepatic Nuclear Receptor-1α/Farnesoid X Receptor Pathway
Estrogen-induced cholestasis (EIC) is characterized by impairment of bile flow and accumulated bile acids (BAs) in the liver, always along with the liver damage. Baicalin is a major flavonoid…
Metformin impairs bile acid homeostasis in ethinylestradiol-induced cholestasis in mice.
The Pathological Mechanisms of Estrogen-Induced Cholestasis: Current Perspectives
TLDR
The role of estrogens in intrahepatic cholestasis is reviewed, the mechanisms of EIC are outlined, providing a greater understanding of this disease, and impaired cell membrane fluidity, inflammatory responses and change of hepatocyte tight junctions are also involved in the pathogenesis of Eic.
Hepatotoxicity induced by neonatal exposure to diethylstilbestrol is maintained throughout adulthood via the nuclear receptor SHP
TLDR
It is demonstrated that neonatal DES exposure alters adult hepatic physiology in an SHP-dependent manner, and the molecular mechanisms by which neonatal exposure persist to affect the adult liver physiology remain to be defined.
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