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

Abstract

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.

Protective Effects of Alisol B 23-Acetate Via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Estrogen-Induced Cholestatic Liver Injury in Mice

“…2). Particularly worth mentioning is that EE-induced cholestatic liver injury has been shown to be related with the decreases in bile acid efflux in hepatocytes which leads to decreases in bile flow and biliary bile acid output (4,24). Therefore, in the present study, we focused on the effects of AB23A on bile acid transport, as well as bile acid synthesis and metabolism (or detoxification).…”

“…Decreases in bile flow and bile acid synthesis induced by EE, have been demonstrated to be related with the changes in transporters and enzymes involved in bile acid homeostasis (4). Therefore, appropriate regulation of hepatobiliary transporters and enzymes has provided a novel strategy to treat cholestatic disorders.…”

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

“…Our data may provide an alternative explanation for this observation: the protective role of TER may arise from its inhibition of NTCP function, which leads to less bile acid accumulation in hepatocytes and less apoptosis. However, from another perspective, down-regulation of NTCP and disturbance of bile acid circulation may lead to liver toxicity over the long term [32][33][34] . In fact, the elimination half-life of TER is approximately 2 weeks, which is thought to result from a combination of extremely low hepatic clearance and enterohepatic recycling [27,35] .…”

Searching for novel molecular targets of chronic rejection in an orthotopic experimental lung transplantation model

“…18 We examined the expression of claudin 5 (Cldn5), heat shock protein 1 (Hsp27), endothelial PAS domain protein 1 (Epas1), transforming growth factor-beta 1 (Tgfb1), selenoprotein P (Selp1), vascular endothelial growth factor (Vegf), insulin-like growth factor 1 (Igf1) and polymerase II polypeptide A (Porl2a). For qPCR, 1 g of total RNA was treated with RNase-free DNase I (Promega) to remove genomic DNA and was reverse-transcribed using an reverse transcriptase kit (iScript; Bio-Rad Laboratories).…”

“…Image analysis was performed using GENEPIX PRO, version 6.0 (Axon Instruments, Union City, CA), as described elsewhere. 18 The locally weighted scatterplot smoother (LOWESS) method in the Statistics for Microarray (SMA) 19 software program (www.bioconductor.org) was used to normalize raw data. The probe sets not present in at least two of the three chips were considered meaningless and, therefore, were eliminated to reduce data complexity.…”