Chronic Effects of Alcohols on Mouse Biomembranes

Abstract

Our recent work has been directed at determining the role of membrane lipids in the chronic effects of ethanol. The hypothesis that alcohols act at hydrophobic sites has been in favor ever since the work of Meyer and Overton, because the aliphatic alcohols fit nicely on plots showing correlation of potency with lipid solubility (1). Much more recently, Seeman (2) has shown that ethanol and its close relatives expand the membranes of red blood cells, with potencies proportional to their lipid solubility in the membrane. Either the lipids or the hydrophobic portions of the proteins could be the site of action of alcohols in biomembranes. If lipid solubility determines potency, it follows that a membrane-acting drug should affect every cell in the body. Any specificity of action of such drugs very likely reflects the relative sensitivity of various cells to perturbations of their membranes. Neurons would be expected to be the most sensitive cells in the body, since their membranes perform all the functions of general transport and in addition must carry out ion transport with a speed and precision that seems beyond the abilities of other cell types. Some specificity may also be due to differential solubility of drugs in lipids of different composition. It now seems likely that there is a good deal of variety of membrane lipid composition, not only between cells but at different regions of the same cell. The subsynaptic membrane is likely to differ from the membrane of an axon. Microscopic inhomogeneities exist in the region of the membrane proteins, many of which are apparently surrounded by a layer of boundary lipid. Thus there are many possibilities for differential actions of a membrane-acting drug on different cells. It is easy to imagine how much more complicated this field of investigation will become when we get past the early exploratory stage and begin to deal with specific actions of drugs on different parts of membranes. But for the moment, it is of interest just to sketch out the outlines of what a drug might do if it acts simply by occupying space in cell membranes and thus disrupting the function of the embedded proteins.