Comprehensive study of the effects of rifampicin and ursodeoxycholic acid on genes and proteins involved in regulation, transport and detoxification of biliary compounds in gallstone patients

摘要

Ursodeoxycholic acid (UDCA) improves clinical and biochemical indices in a variety of cholestatic liver diseases1. UDCA is nowadays considered as the first-line treatment option for patients with primary biliary cirrhosis (PBC), since the results from the combined analysis of the three largest randomized clinical trials of UDCA in PBC indicate that UDCA improves survival free of liver transplantation2. However, the efficacy of UDCA treatment has been debated, and the mechanism(s) of action are still not defined.Before the era of UDCA there were small trials with rifampicin (RIFA) in cholestatic liver disease that all showed a marked improvement of pruritus . In PBC, three trials administered RIFA for 2 weeks. Two studies followed patients for 8 and 2-24 months, respectively, on open-label RIFA. Significant decreases of transaminases, gamma-glutamyltransferase, alkaline phosphatase and total bile salt levels were observed. A suggested molecular mechanism of action of RIFA-induced relief of pruritus is the formation of hydroxylated, less toxic bile acids by stimulation of CYP3A expression via activation of the nuclear receptor SXR/PXR. In rodents decreased expression of the key enzyme of bile acid synthesis, Cyp7al, was also observed.