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Published on: November 10, 2017
Ximelagatran increases membrane fluidity and changes membrane lipid composition in primary human hepatocytes
Odile Sergent1, Kim Ekroos, Luz Lefeuvre-Orfila
1UPRES EA SeRAIC, IFR 140, Université Rennes 1, 2 Av Prof Léon Bernard, 35043 Rennes Cedex, France. osergent@univ-rennes1.fr
Summary
Ximelagatran, a direct thrombin inhibitor, altered human liver cell membrane fluidity and lipid composition, potentially explaining its liver injury risk. This study investigated ximelagatran
Area of Science:
- Hepatology
- Pharmacology
- Biochemistry
Background:
- Ximelagatran, an oral direct thrombin inhibitor, was withdrawn due to liver injury risks.
- Observed liver enzyme elevations in clinical trials lacked a clear cellular mechanism.
- Preclinical studies did not elucidate the hepatic effects of ximelagatran.
Purpose of the Study:
- To investigate ximelagatran's effects on primary human hepatocyte plasma membrane fluidity.
- To determine if ximelagatran alters the membrane lipid composition of hepatocytes.
- To explore the link between membrane changes and potential liver injury.
Main Methods:
- Primary human hepatocytes were exposed to ximelagatran (10 or 100 microM) for 1, 24, and 48 hours.
- Plasma membrane fluidity was measured using established techniques.
- Membrane lipid profiles, including phosphatidylcholine, phosphatidylethanolamine, cholesterol, and phospholipid ratios, were analyzed.
Main Results:
- Ximelagatran significantly increased hepatocyte membrane fluidity after 1-hour exposure, sustained at 24 hours but reduced at 48 hours.
- The phosphatidylcholine/phosphatidylethanolamine molar ratio decreased after 1-hour exposure.
- The total cholesterol/phospholipid molar ratio decreased after 48-hour exposure.
Conclusions:
- Ximelagatran alters plasma membrane fluidity and lipid composition in human hepatocytes.
- These changes suggest potential alterations in cell membrane properties.
- This may contribute to membrane integrity loss and cellular leakage in susceptible individuals, explaining ximelagatran's hepatotoxicity.
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