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TOXICOLOGY
Groupe de Recherche en Thérapeutique Anticancéreuse, Unité Propre de Recherche et de l'Enseignement Supérieur 6027 (O.S., M.P., C.B., M.C.), and Institut National de la Santé et de la Recherche Médicale U620, Université de Rennes 1 (L.H., D.L.-G.), Rennes Cedex, France
The relationship between bulk membrane fluidizing effect of ethanol and its toxicity due to oxidative stress is still unknown. To elucidate this issue, membrane fluidity of primary rat hepatocytes was studied by measuring order parameter after inhibition of ethanol-induced oxidative stress. We showed that pretreating cells with either 4-methyl-pyrazole (to inhibit ethanol metabolism), thiourea [a reactive oxygen species (ROS) scavenger], or vitamin E (a free radical chain-breaking antioxidant) prevented the ethanol-induced increase in membrane fluidity, thus suggesting that ethanol metabolism and ROS formation were involved in this elevation. The effects of membrane stabilizing agents (ursodeoxycholic acid or ganglioside GM1), shown to prevent fluidification, next pointed to a role for this increase in membrane fluidity in the development of ethanol-induced oxidative stress. Indeed, ROS production, lipid peroxidation, and cell death were all inhibited by these agents. In contrast, the fluidizing compounds Tween 20 or 2-(2-methoxyethoxy) ethyl 8-(cis-2-n-octylcyclopropyl) octanoate, which increased the membrane fluidizing effect of ethanol, enhanced the related oxidative stress. Using electron paramagnetic resonance to determine low molecular weight iron, we finally demonstrated that membrane fluidity influence proceeded through an increase in low molecular weight iron to enhance oxidative stress. In conclusion, the present findings clearly highlight the pivotal role of membrane fluidity in ethanol-induced oxidative stress and the potential therapeutic effect of membrane stabilizing compounds.
Address correspondence to: Dr. Odile Sergent, Laboratoire de Biologie Cellulaire et Végétale, Faculté de Pharmacie, 2, av. Pr. Léon Bernard, 35043 Rennes Cedex, France. E-mail: osergent{at}univ-rennes1.fr
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