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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 11, 2005; DOI: 10.1124/jpet.104.079665

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*Compound via MeSH
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Medline Plus Health Information
*Bile Duct Diseases


Received for publication October 26, 2004.
Revised January 7, 2005.
Accepted for publication January 7, 2005.

Protective Effects of 6-Ethyl Chenodeoxycholic Acid, A Farnesoid X receptor (FXR) Ligand, In Estrogen Induced Cholestasis

Stefano Fiorucci 1*, Carlo Clerici 1, Eliabetta Antonelli 1, Stefano Orlandi 1, Bryan Goodwin 2, Bahman Sadeghpour 1, Giuseppe Sabatino 1, Giuseppe Russo 1, Danilo Castellani 1, Timothy M. Willson 2, Roberto Pellicciari 1, Antonio Morelli 1

1 University of Perugia 2 GlaxoSmithKline, NC

* Address correspondence to: E-mail: fiorucci{at}unipg.it

Abstract

The farnesoid X receptor (FXR), an endogenous sensor for bile acids, regulates a program of genes involved in bile acid biosynthesis, conjugation, and transport. Cholestatic liver diseases are a group of immunologically and genetically mediated disorders in which accumulation of endogenous bile acids play a role in the disease progression and symptoms. Here we describe the effect of 6-ethyl chenodexyxholic acid (6-ECDCA) a semi-synthetic bile acid derivative and potent FXR ligand in a model of cholestasis induced by 5-day administration of 17 {alpha}-ethynylestradiol (E217 {alpha}) to rats. The exposure of rat hepatocytes to 1 µM 6-ECDCA caused a 3-5 fold induction of small heterodimer partner (Shp) and bile salt export pump (bsep) mRNA and 70-80% reduction of cyp7a1 (cholesterol 7{alpha}-hydroxylase), cyp8b1 (oxysterol 12{beta}-hydroxylase) and ntcp (Na+/taurocholate cotransporting peptide). In vivo administration of 6-ECDCA protects against cholestasis induced by E217{alpha}. Thus, 6-ECDCA, reverted bile flow impairment induced by E217 {alpha}, reduced secretion of cholic acid and deoxycholic acid, but increased muricholic acid and CDCA secretion. In vivo administration of 6-ECDCA increased liver expression of Shp, bsep, mrp2 and mdr2 while reduce cyp7a1 and cyp8b1 and ntcp mRNA. These changes were reproduced by GW4064, a synthetic FXR ligand. In conclusion, by demonstrating that 6-ECDCA protects against E217 {alpha} cholestasis, our data support the notion that development of potent FXR ligands might represent a new approach for the treatment of cholestastic disorders.


Key words: Bile acids, Cholestasis, Estrogen, FXR, Hepatocytes, Nuclear receptors


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