Ethanol-induced injury and adaptation in biological membranes.
Ethanol intoxication, both acute and chronic, exerts profound effects on the protein and lipid constituents of biological membranes, which reflect damage and adaptation. Changes in mitochondrial structure are accompanied by specific decreases in components of the electron transport chain, an effect probably related to decreased mitochondrial protein synthesis. Ethanol in vitro reduces the transition temperatures of membrane-bound enzyme activities and decreases the order parameter, as measured by electron paramagnetic resonance. By contrast, both are increased after chronic ethanol administration, and membranes from rats chronically treated with ethanol are highly resistant to disordering by ethanol. This adaptation to the acute fluidizing effect of ethanol may be attributed to an increased saturation of mitochondrial phospholipids, particularly cardiolipin. The increased rigidity of mitochondrial and synaptosomal membranes leads to conspicuously reduced binding of ethanol and of the general anesthetic halothane in preparations from chronically treated animals, a finding that may explain tolerance to ethanol and cross-tolerance to anesthetics. Ethanol also affects the plasma membrane, as demonstrated by a decrease in amino acid transport by hepatocytes. Moreover, the addition of physiological concentrations of ethanol to nonlethal concentrations of membrane-active hepatotoxins produces necrosis of hepatocytes, apparently by augmenting the permeability of the plasma membrane to calcium. Inasmuch as the human liver es exposed to numerous membrane-active agents, e.g., viruses, products of intestinal bacteria, and xenobiotics, this finding may explain the sudden onset of hepatic necrosis in individuals who have abused alcohol for many years. The data suggest that initially ethanol increases the fluidity of all biological membranes. This effect, if continued chronically, is balanced by a change in the lipid composition of the membranes, which increases their rigidity and makes them resistant to disordering by ethanol (homeoviscous adaptation). The increased rigidity reduces the binding of ethanol and other compounds, but also impairs a variety of membrane-bound functions. The combination of ethanol and membrane-active toxins can lead to cell necrosis, a mechanism that may explain cell death not only in the liver, but also in organs that do not metabolize ethanol, such as the heart, pancreas, and brain.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000437:Alcoholism / Q000503:physiopathology; D000818:Animals; D002308:Cardiolipins / Q000378:metabolism; D002478:Cells, Cultured; D004347:Drug Interactions; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D006221:Halothane / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000187:drug effects; D008560:Membrane Fluidity / Q000187:drug effects; D008563:Membrane Lipids / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008566:Membranes / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013574:Synaptosomes / Q000187:drug effects; D014118:Toxins, Biological / Q000494:pharmacology
D002308:Cardiolipins; D008563:Membrane Lipids; D008565:Membrane Proteins; D014118:Toxins, Biological; D000431:Ethanol; D000255:Adenosine Triphosphate; D006221:Halothane