Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis.

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 plays a role in the disease progression and symptoms. Here, we describe the effect of 6-ethyl chenodeoxycholic acid (6-ECDCA or INT-747), a semisynthetic bile acid derivative and potent FXR ligand, in a model of cholestasis induced by 5-day administration of 17alpha-ethynylestradiol (E(2)17alpha) to rats. The exposure of rat hepatocytes to 1 microM 6-ECDCA caused a 3- to 5-fold induction of small heterodimer partner (Shp) and bile salt export pump (bsep) mRNA and 70 to 80% reduction of cholesterol 7alpha-hydroxylase (cyp7a1), oxysterol 12beta-hydroxylase (cyp8b1), and Na(+)/taurocholate cotransporting peptide (ntcp). In vivo administration of 6-ECDCA protects against cholestasis induced by E(2)17alpha. Thus, 6-ECDCA reverted bile flow impairment induced by E(2)17alpha, reduced secretion of cholic acid and deoxycholic acid, but increased muricholic acid and chenodeoxycholic acid secretion. In vivo administration of 6-ECDCA increased liver expression of Shp, bsep, multidrug resistance-associated protein-2, and multidrug resistance protein-2, whereas it reduced 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 E(2)17alpha cholestasis, our data support the notion that development of potent FXR ligands might represent a new approach for the treatment of cholestatic disorders.

• Authors: Stefano Fiorucci, Carlo Clerici, Elisabetta Antonelli, Stefano Orlandi, Bryan Goodwin, Bahman M Sadeghpour, Giuseppe Sabatino, Giuseppe Russo, Danilo Castellani, Timothy M Willson, Mark Pruzanski, Roberto Pellicciari, Antonio Morelli
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 313 Issue 2 Pg. 604-12 (May 2005) ISSN: 0022-3565 [Print] United States
• PMID: 15644430 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Estrogens
• Ligands
• Receptors, Cytoplasmic and Nuclear
• Transcription Factors
• obeticholic acid
• farnesoid X-activated receptor
• Chenodeoxycholic Acid

Topics

• Animals
• Chenodeoxycholic Acid (analogs & derivatives, metabolism, pharmacology, therapeutic use)
• Cholestasis (chemically induced, physiopathology, prevention & control)
• DNA-Binding Proteins (agonists, metabolism, physiology)
• Dose-Response Relationship, Drug
• Estrogens (toxicity)
• Hepatocytes (drug effects, physiology)
• Ligands
• Male
• Rats
• Rats, Wistar
• Receptors, Cytoplasmic and Nuclear
• Transcription Factors (agonists, metabolism, physiology)