Lipid perturbation hypothesis

Following Overton s early observation of the direct relationship between the efficacy of an alcohol and oil/water partition coefficient of that alcohol, most research concerning the mechanism of action of ethanol and similar anesthetics has focused on the interior of neuronal membranes and model membrane systems. The lipid perturbation hypothesis simply states that the effects of alcohols result from changes in the fluidity of the interior of the membrane. The observed changes in membrane order, however, are usually small or occur at nonphysiological concentrations of alcohol. ... 

Membrane conformational changes are observed on exposure to anesthetics, further supporting the importance of physical interactions that lead to perturbation of membrane macromolecules. For example, exposure of membranes to clinically relevant concentrations of anesthetics causes membranes to expand beyond a critical volume (critical volume hypothesis) associated with normal cellular function. Additionally, membrane structure becomes disorganized, so that the insertion of anesthetic molecules into the lipid membrane causes an increase in the mobility of the fatty acid chains in the phospholipid bilayer (membrane fluidization theory) or prevent the interconversion of membrane lipids from a gel to a liquid form, a process that is assumed necessary for normal neuronal function (lateral phase separation hypothesis). 

The perturbation of the incorporation of linoleic add metabolites into mammary gland lipids by CLA metabolism may lead to the hypothesis that CLA is able to create a mild arachidonic acid deficiency condition, in particular in the mammary tissue which is composed mainly of neutral lipids. In fact, because CLA and some of its metabolites are preferentially incorporated into neutral lipids (15), unlike linoleic acid, which is instead incorporated mainly into phospholipids, the preponderance of neutral lipids in the mammary tissue renders the competition between these two fatty acids more favorable toward CLA. It has been demonstrated that mammary tumorigenesis requires essential fatty acids, and eicosanoid inhibitors are able to reduce tumor incidence in experimental models (22). CLA, likely by decreasing the supply of arachidonic acid and inhibiting eicosanoid formation through its metabolites, may counteract arachidonic acid-derived eicosanoid action. Because the decrease of arachidonic acid, CLA metabolite incorporation, TEB density, and tumor incidence correlated with the (XA dietary intake, we can speculate that TEB density could also be modulated by eicosanoids. More data are required, however, to substantiate this hypothesis and to identify which eicosanoid(s) may be responsible for such effects. 

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