title: Pathogenesis of lithocholate-induced intrahepatic cholestasis: role of glucuronidation and hydroxylation of lithocholate.
abstract: It has been shown that lithocholic glucuronide is more cholestatic than lithocholic acid (LCA), as well as its taurine and glycine conjugates. Furthermore, LCA hydroxylation is thought to be a major detoxifying mechanism. Therefore, the role of LCA glucuronidation and hydroxylation was investigated during the development of LCA-induced cholestasis and recovery from it. Male rats received a bolus intravenous injection of [14C]LCA (12 mumol/100 g body weight) and bile samples were collected every 30 min for 5 h. Bile flow (BF) was reduced immediately after LCA injection, dropping to 40% of basal BF at 60 min. It then started to increase, reaching normal bile flow values at 3.5 h. Morphologically, canalicular lesions were dominant at 60 min and virtually absent at 2 h. At 60 min (maximal cholestasis), 30% of the LCA injected was secreted in bile, 20% was found in plasma while the other 50% was recovered in the liver and distributed mainly in plasma membranes, microsomes and cytosol. At the end of the experiment (normal BF), 20% of the LCA injected was still in the liver but was present mainly in the cytosol. In bile, within 30 min after injection, 46% of the LCA secreted was lithocholic glucuronide, 24% was conjugated with taurine and glycine, and 21% was in the form of hydroxylated bile acids. During the recovery period, lithocholic glucuronide secretion decreased to 18-25%. Taurine and glycine conjugate secretion increased to a maximum of 43% at 60 min, after which it was reduced to 21-28%. In contrast, hydroxylated metabolites were elevated during the recovery periods, reaching a maximum (45%) at 120 min and remaining constant thereafter. These results suggest that: (i) LCA binding to plasma membranes and microsomes appeared to correlate with the development of cholestasis; (ii) LCA glucuronidation may initiate and/or contribute to LCA-induced cholestasis; and (iii) hydroxylation predominates during recovery from cholestasis.
authors.affiliation: Department of Pharmacology, University of Montreal, Canada.
authors.forename: D D
authors.initials: DD
authors.lastname: Vu
authors.forename: B
authors.initials: B
authors.lastname: Tuchweber
authors.forename: G L
authors.initials: GL
authors.lastname: Plaa
authors.forename: I M
authors.initials: IM
authors.lastname: Yousef
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D002779:Cholestasis / Q000209:etiology*; D002784:Cholesterol / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism; D006900:Hydroxylation; D008095:Lithocholic Acid / Q000008:administration & dosage / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D001647:Bile Acids and Salts; D010743:Phospholipids; D008095:Lithocholic Acid; D002784:Cholesterol; D005966:Glucuronidase