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Research ArticleTOXICOLOGY

Hepatotoxicity of Tacrine: Occurrence of Membrane Fluidity Alterations without Involvement of Lipid Peroxidation

Milagros Galisteo, Mary Rissel, Odile Sergent, Martine Chevanne, Josiane Cillard, André Guillouzo and Dominique Lagadic-Gossmann
Journal of Pharmacology and Experimental Therapeutics July 2000, 294 (1) 160-167;
Milagros Galisteo
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Mary Rissel
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Odile Sergent
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Martine Chevanne
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Josiane Cillard
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André Guillouzo
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Dominique Lagadic-Gossmann
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Abstract

Tacrine (THA), used in the treatment of Alzheimer's disease, is known to induce hepatotoxicity, the mechanisms of which remain to be fully established. We have previously shown that THA reduced intracellular glutathione concentration in rat hepatocytes in primary culture, thus pointing to a possible role for oxidative stress in THA toxicity. To test this, the effects of antioxidant molecules, namely, the flavonoids silibinin, silibinin dihydrogensuccinate, and silymarin, were evaluated on the toxicity of THA in cultured rat hepatocytes. This toxicity was investigated after a 24-h treatment over a concentration range from 0 to 1 mM, in the presence or absence of antioxidant (1 and 10 μM). We found that simultaneous treatment of hepatocytes with any of the antioxidants and THA remained ineffective on the lactate dehydrogenase release induced by THA. Then, the production of lipid-derived radicals (to estimate lipid peroxidation) was measured in THA (0.05–0.50 mM)-treated cells using a spin-trapping technique coupled to electron paramagnetic resonance (EPR) spectroscopy. No increase of the EPR signal was observed over the period of 30 min to 24 h. In contrast, treatment of cells with the spin label 12-doxyl stearic acid followed by EPR spectroscopy showed that THA (0.05 and 0.25 mM) rapidly increased hepatocyte membrane fluidity. Extracellular application of GM1 ganglioside (60 μM) both reversed this increase in fluidity and partially reduced lactate dehydrogenase release on THA exposure. In conclusion, this work indicates that early alterations of membrane fluidity, not resulting from lipid peroxidation, are likely to play an important role in the development of THA toxicity.

Footnotes

  • Send reprint requests to: Dr. Dominique Lagadic-Gossmann, INSERM U456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, 2, avenue du Professeur Léon Bernard, 35043 Rennes cedex, France. E-mail:Dominique.Lagadic{at}rennes.inserm.fr

  • ↵1 This work was supported by the Réseau HEPATOX, the European Union BIOMED 2 research program (Hepatox network project; Contract BMH4-CT96-0658), and by MADAUS A.G. (Cologne, Germany).

  • ↵2 M.G. was a recipient of a postdoctoral fellowship from the Universidad de Granada (Spain).

  • Abbreviations:
    THA
    tacrine
    DSA
    doxyl stearic acid
    EPR
    electron paramagnetic resonance
    LDH
    lactate dehydrogenase
    pHi
    intracellular pH
    POBN
    α-(4-pyridyl 1-oxide)-N-tert-butyl-nitrone
    SDH
    silibinin dihydrogensuccinate
    SNARF-1
    seminaphtorhodafluor-1
    ROS
    reactive oxygen species
    Fe-NTA
    ferric nitriloacetate
    • Received December 7, 1999.
    • Accepted March 24, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 1
1 Jul 2000
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Research ArticleTOXICOLOGY

Hepatotoxicity of Tacrine: Occurrence of Membrane Fluidity Alterations without Involvement of Lipid Peroxidation

Milagros Galisteo, Mary Rissel, Odile Sergent, Martine Chevanne, Josiane Cillard, André Guillouzo and Dominique Lagadic-Gossmann
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 160-167;

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Research ArticleTOXICOLOGY

Hepatotoxicity of Tacrine: Occurrence of Membrane Fluidity Alterations without Involvement of Lipid Peroxidation

Milagros Galisteo, Mary Rissel, Odile Sergent, Martine Chevanne, Josiane Cillard, André Guillouzo and Dominique Lagadic-Gossmann
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 160-167;
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