Development of FXR, PXR and CAR Agonists and Antagonists for Treatment of Liver Disorders

Stefano      Fiorucci; Angela      Zampella; Eleonora      Distrutti

Abstract

The farnesoid-x-receptor (FXR), the constitute-androstane-receptor (CAR) and the pregnane-x-receptor (PXR) are ligand regulated nuclear receptors highly expressed in the liver and intestine supervising essential steps in the metabolism of xeno and endo-biotics in entero-hepatic tissues. Primary and secondary bile acids function as receptor agonists/ activators for these receptors. Activation of FXR by steroidal and non steroidal ligands promotes bile acids secretion by activating bile acids transporters in the apical membrane of hepatocytes. These effects are coordinated with a reduction in bile acids uptake at the basolateral membrane. However, FXR agonists interfere with the regulatory activity of CAR on hepatocytes basolateral transporters. Because these effects might worsen liver injury in a subset of patients with obstructive cholestasis, development of FXR antagonists might be of clinical relevance. Structure-activity relationship studies have shown that available FXR antagonists are poorly specific for FXR, however specific FXR antagonists that are currently used in pre-clinical models of liver injury have been identified from marine organisms. PXR agonists are endowed with a wide array of biological activities but their effects on the expression/activity of phase I and II metabolizing enzymes is likely to limit their pharmacological development. Nevertheless a combination between FXR agonists and CAR and PXR agonists might hold utility in treating subset of patients with liver disorders. In addition, development of tissue specific FXR antagonists is an attractive opportunity to target subsets of genes in the intestine and liver avoiding sideeffects linked to FXR activation.

Keywords: Bile acids, cholestasis, constitute-androstane-receptor, farnesoid-x-receptor, hepatocytes, pregnane-x-receptor, constitute-androstane-receptor (CAR), bile acids secretion, hepatocyte's basolateral transporters, obstructivecholestasis, antagonists, liver disorders