(HEPATOLOGY 2010;52:1758-1768) Chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are characterized by impaired biliary secretion of bile acids

and other potentially harmful cholephiles. Intrahepatic accumulation of endogenous hydrophobic bile acids, together with cytokine- and chemokine-mediated inflammatory bile ductular and liver parenchymal BMS 354825 injury, may contribute to development of fibrosis and cirrhosis in chronic cholestatic disorders. The ratio of toxic to less toxic bile acids correlates with severity of liver injury.1 The hydrophilic C24 bile acid, ursodeoxycholic acid (UDCA) improves biochemical and histological features in PBC, halts progression to cirrhosis in the majority of patients with PBC, Silmitasertib ic50 normalizes life expectancy in two-thirds of patients with PBC2-5 and currently represents the only approved therapy for PBC.6 In PSC, its therapeutic long-term benefit remains so far unclear although serum liver tests and surrogate markers of long-term prognosis improved during UDCA treatment in pilot trials.6 Mechanisms of action of UDCA in cholestatic disorders have not yet been fully resolved.7 Stimulation of impaired hepatocellular secretion by mainly

posttranscriptional mechanisms, detoxification of bile, antiapoptotic effects in hepatocytes and cholangiocytes, and stimulation of cholangiocyte HCO secretion may contribute to the beneficial effect observed during UDCA treatment in cholestatic disorders.7 NorUDCA is a C23 homolog of UDCA. C23 bile acids are found only in trace amounts in human bile.8 They are poorly conjugated with taurine and glycine in liver, and their pharmacokinetic properties differ from their naturally occurring C24 homologs.8NorUDCA has recently been shown to exert therapeutic effects superior to those of UDCA in

multidrug resistance protein 2 (Mdr2)/ATP-binding cassette b4 (Abcb4) knockout mice, a murine model of nonsuppurative, sclerosing cholangitis.9, 10 The mechanisms of action of norUDCA Selleckchem Ibrutinib in Mdr2−/− mice remain obscure.10NorUDCA is a potent (hyper-)choleretic bile acid as a result of cholehepatic shunting.8, 10 Whether this property may explain, at least in part, the anticholestatic, anti-inflammatory, and antifibrotic effects of norUDCA in Mdr2−/− mice9, 10 still remains unresolved. Most importantly, it is unclear whether norUDCA, like UDCA, may exert anticholestatic effects at the level of the hepatocyte.7, 11 Lithocholic acid conjugates are the most potent cholestatic agents among the major human bile acids.12 Taurolithocholic acid (TLCA)-induced cholestasis is an established experimental model of hepatocellular cholestasis.