INHIBITION OF RAT-LIVER MICROSOMAL BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE BY URSODEOXYCHOLIC ACID

Ursodeoxycholic acid and its endogenous metabolite tauroursodeoxycholi c acid inhibited in vitro the microsomal bilirubin UDP-glucuronosyltra nsferase from rat liver. The magnitude of the inhibition correlated we ll with the loss of integrity of microsomal vesicles, suggesting that bile salts needed to reach the lumen to exert their inhibitory effects . The endogenous bile acids cholic acid, chenodeoxycholic acid and deo xycholic acid also exhibited inhibitory effects on bilirubin glucuroni dation in digitonin-disrupted microsomes. Ursodeoxycholic acid inhibit ory capacity was similar to that of chenodeoxycholic acid and deoxycho lic acid but greater than that of cholic acid, the major endogenous bi le salt. Kinetic studies, performed in detergent-activated preparation s, showed that the inhibitions produced by ursodeoxycholic and taurour sodeoxycholic acids were competitive toward both bilirubin and UDP-glu curonic acid. The estimated K-i(app) for both substrates did not diffe r statistically between ursodeoxycholic and tauroursodeoxycholic acids . Both bile salts were weak inhibitors toward bilirubin but rather str ong inhibitors toward UDP-glucuronic acid.