title: Conjugates of ursodeoxycholate protect against cholestasis and hepatocellular necrosis caused by more hydrophobic bile salts. In vivo studies in the rat.
abstract: The protective effect of ursodeoxycholate conjugates against bile salt hepatotoxicity was studied in chronic bile fistula rats. Taurochenodeoxycholate or taurodeoxycholate, infused intraduodenally at 24 or 16 mumols/100 g rat per hour, respectively, caused cholestasis and severe hepatocellular necrosis within 8 hours. In contrast, tauroursodeoxycholate or taurocholate at 48 mumols/100 g rat per hour were choleretic. Tauroursodeoxycholate was not hepatotoxic, whereas taurocholate produced moderate hepatocellular necrosis. Simultaneous infusion of tauroursodeoxycholate to rats receiving taurochenoxycholate or taurodeoxycholate preserved bile flow and ameliorated hepatic injury in a dose-dependent manner. Tauroursodeoxycholate protected equally by intravenous and intraduodenal routes. Intravenous glycoursodeoxycholate also was protective. The hydrophobicity index of infused bile salts correlated well with their toxicity. Concurrent administration of ursodeoxycholate conjugates did not reduce biliary recovery of intraduodenally infused [24-14C]-taurocholate. Biliary alkaline phosphatase secretion was stimulated by infusion of taurocholate, taurodeoxycholate, or taurochenodeoxycholate; simultaneous infusion of ursodeoxycholate conjugates failed to prevent this increase. We conclude that ursodeoxycholate counteracts hepatoxicity of more hydrophobic bile salts via a direct effect at the level of the liver.
authors.affiliation: Department of Medicine, Medical College of Virginia, Richmond.
authors.forename: D M
authors.initials: DM
authors.lastname: Heuman
authors.forename: A S
authors.initials: AS
authors.lastname: Mills
authors.forename: J
authors.initials: J
authors.lastname: McCall
authors.forename: P B
authors.initials: PB
authors.lastname: Hylemon
authors.forename: W M
authors.initials: WM
authors.lastname: Pandak
authors.forename: Z R
authors.initials: ZR
authors.lastname: Vlahcevic
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000037:antagonists & inhibitors; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D008107:Liver Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009336:Necrosis / Q000188:drug therapy; D051381:Rats; D011919:Rats, Inbred Strains; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*
chemical_list: D001647:Bile Acids and Salts; D014580:Ursodeoxycholic Acid