PT - JOURNAL ARTICLE AU - Milagros Galisteo AU - Mary Rissel AU - Odile Sergent AU - Martine Chevanne AU - Josiane Cillard AU - André Guillouzo AU - Dominique Lagadic-Gossmann TI - Hepatotoxicity of Tacrine: Occurrence of Membrane Fluidity Alterations without Involvement of Lipid Peroxidation DP - 2000 Jul 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 160--167 VI - 294 IP - 1 4099 - http://jpet.aspetjournals.org/content/294/1/160.short 4100 - http://jpet.aspetjournals.org/content/294/1/160.full SO - J Pharmacol Exp Ther2000 Jul 01; 294 AB - 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. The American Society for Pharmacology and Experimental Therapeutics