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TOXICOLOGY

Role of Pituitary Hormones on 17-Ethinylestradiol-Induced Cholestasis in Rat

Molecular Endocrinology Group, Department of Clinical Sciences, University of Las Palmas of Gran Canaria–Canary Institute for Cancer Research, Spain (L.A.H.-H., R.S.-F., L.F.-P.); Molecular Endocrinology Group, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden (A.F-M., G.N.); Department of Clinical Chemistry, Karolinska Hospital, Stockholm, Sweden (M.A.); and Department of Biotechnology, Kungliga Tekniska Högskolan (Royal Institute of Technology), AlbaNova University Center, Stockholm, Sweden (P.N.)

Estrogens cause intrahepatic cholestasis in susceptible women during pregnancy, after administration of oral contraceptives, or during postmenopausal hormone replacement therapy. 17-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 (ER) 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-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.

Address correspondence to: Dr. Leandro Fernández-Pérez, Molecular Endocrinology Group, University of Las Palmas of G.C., Faculty of Health Sciences, Department of Clinical Sciences, Dr. Pasteur s/n, 35016–Las Palmas of G.C., Canary Islands, Spain. E-mail: lfernandez{at}dcc.ulpgc.es