Different protective effects of tauroursodeoxycholate, ursodeoxycholate, and 23-methyl-ursodeoxycholate against taurolithocholate-induced cholestasis

Abstract

The coinfusion of tauroursodeoxycholate (TUDC) prevents taurolithocholate (TLC) -induced cholestasis. 23-Methyl-ursodeoxycholate (MUDC) is a side-chain derivative of ursodeoxycholate (UDC). If conjugation with taurine is important for the protective effect of UDC, the MUDC may not be as able as TUDC to prevent TLC-induced cholestasis since it is poorly amidated by the liver. To answer this question, isolated livers of adult Sprague-Dawley rats were coinfused with MUDC (UDC, TUDC) and TLC. After 15 min, inflow rates of the bile acids were doubled. In further experiments taurine in excess was added to the coinfused bile acids. The uptake of bile acids was >90% in all groups, irrespective of whether they were perfused alone or in combination. Single perfusion of TLC caused a rapid decrease in bile flow. UDC and MUDC were hypercholeretic; TUDC moderately choleretic. During coinfusion experiments, TUDC not only completely abolished cholestasis but in addition increased bile flow and biliary bile acid secretion. UDC did prevent TLC cholestasis at the lower inflow rates. At high inflow rates, bile flow decreased significantly. Addition of taurine to this bile acid combination did not significantly improve the anticholestatic effect of UDC. At low and high infusion rates of MUDC, cholestasis induced by TLC was reduced very little. Cumulative bile flow over 30 min fell by approximately 70% as compared to that of singly perfused MUDC. Addition of taurine to the coinfused MUDC/TLC slightly, but less significantly, improved the anticholestatic effect of MUDC. Since MUDC is by far less protective than UDC (and TUDC) despite similar physiochemical properties, it is concluded that taurine conjugation of UDC seems to be a prerequisite to prevent TLC-induced cholestasis. The results imply that treatment of cholestatic liver diseases with taurine-conjugated UDC might be more appropriate than with unconjugated UDC in cases where taurine conjugation is defective or where taurine depletion has occurred.