title: Ximelagatran increases membrane fluidity and changes membrane lipid composition in primary human hepatocytes.
abstract: Ximelagatran, the first oral agent in the new class of direct thrombin inhibitors, was withdrawn from the market due to a potential risk of severe liver injury. Increased rates of liver enzyme elevations had been observed during clinical trials of chronic use. Despite intensive preclinical investigations the cellular mechanisms behind the observed hepatic effects remain unknown. The aim of this study was to investigate whether ximelagatran has an effect on the plasma membrane fluidity and the membrane lipid composition which may be important for the cell integrity. After 1h exposure of primary human hepatocytes with 10 or 100 microM ximelagatran, a significant elevation of membrane fluidity was observed. This elevation was maintained at 24h, but diminished at 48 h exposure. As changed membrane lipid composition could influence membrane fluidities, changes in membrane lipid profiles were also studied. After 1h exposure, the phosphatidylcholine/phosphatidylethanolamine molar ratio decreased, whereas the total cholesterol/phospholipid molar ratio decreased after a 48 h exposure. The change in membrane fluidity and lipid composition in human hepatocytes exposed to ximelagatran might indicate changes in plasma membrane properties that in susceptible subjects, could result in loss of membrane integrity and leakage of cellular proteins.
authors.affiliation: UPRES EA SeRAIC, IFR 140, Université Rennes 1, 2 Av Prof Léon Bernard, 35043 Rennes Cedex, France. osergent@univ-rennes1.fr
authors.forename: Odile
authors.initials: O
authors.lastname: Sergent
authors.forename: Kim
authors.initials: K
authors.lastname: Ekroos
authors.forename: Luz
authors.initials: L
authors.lastname: Lefeuvre-Orfila
authors.forename: Mary
authors.initials: M
authors.lastname: Rissel
authors.forename: Gun-Britt
authors.initials: GB
authors.lastname: Forsberg
authors.forename: Jan
authors.initials: J
authors.lastname: Oscarsson
authors.forename: Tommy B
authors.initials: TB
authors.lastname: Andersson
authors.forename: Dominique
authors.initials: D
authors.lastname: Lagadic-Gossmann
mesh_terms: D000925:Anticoagulants / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008560:Membrane Fluidity / Q000187:drug effects*; D008563:Membrane Lipids / Q000737:chemistry* / Q000378:metabolism; D013619:Tacrine / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D008563:Membrane Lipids; C426686:ximelagatran; D013619:Tacrine