Abstract
Understanding the molecular mechanism of bile formation and the different pathways and pathogenesis of drug induced cholestasis provide different possibilities for treatment. This review summarizes the role of transport proteins in hepatic drug clearance and toxicity, the involvement of inflammatory mediators in cholestasis and the role of nuclear receptors in bile acid metabolism. Understanding nuclear receptor function can help in the development of nuclear receptor ligands for treatment of cholestasis.
Highlights
Understanding the molecular mechanism of bile formation and the different pathways and pathogenesis of drug induced cholestasis provide different possibilities for treatment
Bile acids pool consists of primary bile acids (cholic acid (CA), chenodeoxycholic acid (CDCA)) and secondary bile acids (deoxycholic acid (DCA), and lithocholic acid (LCA)) (Russell and Setchell, 1992)
A recent potent and selective agonist of Farnesoid X receptor (FXR) was detected known as 6a-ethylchenodeoxycholic acid or obeticholic acid (OCA)
Summary
One of the main NRs that regulate bile acid formation, transportation and metabolism is the FXR. It should be a target for treating cholestatic diseases. A recent potent and selective agonist of FXR was detected known as 6a-ethylchenodeoxycholic acid or obeticholic acid (OCA). It is a modified bile acid and FXR agonist that is derived from primary human bile acid chenodeoxycholic acid (being an endogenous ligand of FXR). A phase 3, double-blind, placebo-controlled trial and long term extension OCA in patients with PBC has been published (Kowdley et al, 2018). OCA has been approved in May 2016 by food and drug administration for patients not responding or intolerant to UDCA and the European Commission granted a marketing authorization valid throughout the European Union for OCA in December 2016 (Floreani and Mangini, 2018)
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