Please use this identifier to cite or link to this item: http://hdl.handle.net/10553/43070
Title: Role of pituitary hormones on 17α-ethinylestradiol-induced cholestasis in rat
Authors: Henríquez-Hernández, L. A. 
Flores-Morales, A. 
Santana-Farré, R.
Axelson, M.
Nilsson, P.
Norstedt, G.
Fernández-Pérez, L. 
Keywords: Small Heterodimer Partner
Growth-Hormone
Gene-Expression
In-Vivo
Cholesterol 7-Alpha-Hydroxylase, et al
Issue Date: 2007
Publisher: 0022-3565
Journal: Journal of Pharmacology and Experimental Therapeutics 
Abstract: Estrogens cause intrahepatic cholestasis in susceptible women during pregnancy, after administration of oral contraceptives, or during postmenopausal hormone replacement therapy. 17 alpha-Ethinylestradiol ( EE) is a synthetic estrogen widely used to cause experimental cholestasis in rodents with the aim of examining molecular mechanisms involved in this disease. EE actions on the liver are thought to be mediated by estrogen receptor alpha ( ER alpha) and pituitary hormones. We tested this hypothesis by analyzing metabolic changes induced by EE in livers from hypophysectomized ( HYPOX) and hypothyroid rats. Microarray studies revealed that the number of genes regulated by EE was increased almost 4-fold in HYPOX rat livers compared with intact males. Little overlap was apparent between the effects of EE in intact and HYPOX rats, demonstrating that pituitary hormones play a critical role in the hepatic effects of EE. Consistently, hypophysectomy protects the liver against induction by EE of serum bilirubin and alkaline phosphatase, two markers of cholestasis and hepatotoxicity and modulates the effects of EE on several genes involved in bile acid homeostasis ( e. g., FXR, SHP, BSEP, and Cyp8b1). Finally, we demonstrate a novel mechanism of action of EE through binding and negative regulation of glucocorticoid receptor-mediated transcription. In summary, pituitary- and ER alpha- independent mechanisms contribute to development of EE-induced changes in liver transcriptome. Such mechanisms may be relevant when this model of EE-induced cholestasis is evaluated. The observation that the pharmacological effects of estrogen in liver differ in the absence or presence of the pituitary could be clinically relevant, because different drugs that block actions of pituitary hormones are now available.
URI: http://hdl.handle.net/10553/43070
ISSN: 0022-3565
DOI: 10.1124/jpet.106.113209
Source: Journal of Pharmacology and Experimental Therapeutics[ISSN 0022-3565],v. 320, p. 695-705
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