DIFFERENT PROTECTIVE EFFECTS OF TAUROURSODEOXYCHOLATE, URSODEOXYCHOLATE, AND 23-METHYL-URSODEOXYCHOLATE AGAINST TAUROLITHOCHOLATE-INDUCED CHOLESTASIS

The coinfusion of tauroursodeoxycholate (TUDC) prevents taurolithochol ate (TLC)-induced cholestasis. 23-Methyl-ursodeoxycholate (MUDC) is a side-chain derivative of ursodeoxycholate (UDC). If conjugation with t aurine is important for the protective effect of UDC, then MUDC may no t be as able as TUDC to prevent TLC-induced cholestasis since it is po orly amidated by the liver. To answer this question, isolated livers o f adult Sprague-Dawley rats were coinfused with MUDC (UDC, TUDC) and T LC. After 15 min, inflow rates of the bile acids were doubled, In furt her experiments taurine in excess was added to the coinfused bile acid s. The uptake of bile acids was >90% in all groups, irrespective of wh ether they were perfused alone or in combination. Single perfusion of TLC caused a rapid decrease in bile flow, UDC and MUDC were hyperchole retic; TUDC moderately choleretic. During coinfusion experiments, TUDC not only completely abolished cholestasis but in addition increased b ile flow and biliary bile acid secretion. UDC did prevent TLC cholesta sis at the lower inflow rates. At high inflow rates, bile flow decreas ed significantly. Addition of taurine to this bile acid combination di d not significantly improve the anticholestatic effect of UDC. At low and high infusion rates of MUDC, cholestasis induced by TLC was reduce d very little. Cumulative bile flow over 30 min fell by approximate to 70% as compared to that of singly perfused MUDC. Addition of taurine to the coinfused MUDC/TLC slightly, but significantly, improved the an ticholestatic effect of MUDC. Since MUDC is by far less protective tha n UDC (and TUDC) despite similar physicochemical properties, it is con cluded that taurine conjugation of UDC seems to be a prerequisite to p revent TLC-induced cholestasis, The results imply that treatment of ch olestatic liver diseases with taurine-conjugated UDC might be more app ropriate than with unconjugated UDC in cases where taurine conjugation is defective or where taurine depletion has occurred.