sodium-taurodeoxycholate and Cholestasis--Intrahepatic

To clarify the preventive effect of taurohyodeoxycholic acid on liver cholestasis induced by toxic bile acids in rats, we evaluated whether modulation of cytochrome P4503A-linked oxidases is involved in the hepatic bile acid retention and secretion mechanism. We investigated whether the safe or the toxic taurochenodeoxycholic acid, administered singly or together, affects cytochrome P450-catalyzed drug metabolism or biliary parameters. We also considered whether the inhibition of the P-glycoprotein export pump by vinblastine might be related to cytochrome P4503A overexpression.. Hydroxylation of testosterone and N-demethylation of aminopyrine were studied in subcellular rat liver preparations after intravenous infusion of hepatoprotective and toxic bile acids administered singly or together. Bile flow, calcium secretion, biliary enzymes activity, and secretion rates of the endogenous and administrated bile acids were determined. CYP3A-dependent monooxygenases were also measured in the same coinfusion model in the presence of vinblastine.. Although wide modulation of the activities of different P450 subfamily of isoenzymes was seen, P4503A-associated monooxygenases showed similar patterns in the various situations, i.e., induction by taurohyodeoxycholic acid, reduction by taurochenodeoxycholic acid, and protection (intermediate induction) in the coinfusion experiments. This correlates well with biliary parameters demonstrating the hepatoprotective ability of taurohyodeoxycholic acid. Coadministration of bile acids and vinblastine significantly modifies CYP3A-linked activities.. Bile acid structure seems to be linked with hepatotoxicity/hepatoprotection and P4503A modulation. Taurohyodeoxycholic acid could be therapeutic in cholestatic liver disease by inducing P4503A; we can hypothesize that an associated P-glycoprotein expression might facilitate biliary excretion of toxic taurochenodeoxycholic acid accumulated in the liver during cholestasis.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Bile; Calcium; Cholestasis, Intrahepatic; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Male; Oxidoreductases, N-Demethylating; Rats; Rats, Sprague-Dawley; Taurochenodeoxycholic Acid; Taurodeoxycholic Acid; Vinblastine

Bile acid processing in the long-term, bile duct obstructed rat liver was studied ex vivo. Twenty four and 72 h, respectively, after bile duct obstruction the isolated liver was perfused with taurodeoxycholate (16 nmol/min per g liver) the bile duct still being closed. Uptake, metabolism and regurgitation profile were traced by bolus injection of tritium-labeled bile acid; in addition, concurrent histological changes were examined by light- and electron microscopy. Ligation caused dilatation of the intrahepatic ductular branches and increased the serum bile acid concentration to 740 +/- 75 microM (controls: 16 +/- 2.12), reaching its maximum within 24 h. At 16 nmol/min per g liver uptake rate was > 96% in controls and in bile duct obstructed rats. Maximal uptake rates (assessed separately) differed between controls and bile duct obstructed rats (700 nmol/min per g liver vs. 460). Controls excreted more than 80% of labeled bile acid in bile within 10 min after bolus injection. Biliary recovery of label was virtually completed after 30 min. In bile duct obstructed rats excretion of label back to the perfusate effluent (regurgitation) started quantitatively 5 min after bolus application and peaked between 10 and 40 min; after 80 min, effluent recovery was incomplete (about 60% of bolus injected). Biliary bile acids of controls consisted of about 20% taurodeoxycholate-metabolites; bile acids in the perfusate effluent of bile duct obstructed rats of about 55%. The major metabolite in all animal groups was taurocholate; minor metabolites were tauroursocholate, tauro-3 alpha,7 = 0,12 alpha-cholanoic acid and 3-sulfo-taurodeoxycholate. Histologically, inflammation and periportal edema were present after 1 day of bile duct obstruction. After 3 days, marked proliferation of bile ductules was the dominant histological feature. It is concluded that during initial bile duct obstruction, bile acid processing is not altered, although ultrastructural alterations occur early.

Topics: Animals; Bile; Bile Acids and Salts; Bile Reflux; Cholestasis, Intrahepatic; In Vitro Techniques; Liver; Male; Perfusion; Rats; Rats, Sprague-Dawley; Taurodeoxycholic Acid

A direct assay system for conjugated bile acids using an enzymatic procedure and high-performance liquid chromatography was used for the analysis of urinary bile acid profiles in young infants with intrahepatic cholestasis (idiopathic neonatal hepatitis syndrome) or extra-hepatic biliary atresia. The major urinary bile acids were cholate and chenodeoxycholate conjugates, but a small amount of deoxycholate and 3 beta-hydroxy-5-cholenate conjugates were detected. Although there was no significant difference in total bile acid excretion between patients with intrahepatic cholestasis and extrahepatic biliary atresia, mean ratios of cholate to chenodeoxycholate and sulfated to total urinary bile acids were different between the two groups examined (5.63 +/- 2.83 vs. 2.50 +/- 1.25, p less than 0.05, 15.8 +/- 9.9 vs. 34.5 +/- 9.9%, p less than 0.005). The proportion of taurine-conjugated chenodeoxycholate in the sulfate fraction to the total bile acid was lower in intrahepatic cholestasis, compared with that in biliary atresia (7.7 +/- 7.5 vs 22.7% +/- 7.8%, p less than 0.005). The greater ratio of cholate to chenodeoxycholate and the reduced excretion of sulfated urinary bile acids in intrahepatic cholestasis was due to decreased taurine-conjugated chenodeoxycholate sulfate excretion.

Topics: Bile Acids and Salts; Bile Ducts; Cholestasis, Intrahepatic; Chromatography, High Pressure Liquid; Glycochenodeoxycholic Acid; Glycocholic Acid; Glycodeoxycholic Acid; Humans; Infant; Infant, Newborn; Taurochenodeoxycholic Acid; Taurocholic Acid; Taurodeoxycholic Acid