EFFECTS OF ETHANOL ON HEPATIC ORGANIC ANION UPTAKE

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One of the major functions of the liver is the uptake of low molecular weight organic anions. Three classes of these compounds in particular - bile acids, nonbile acid cholephils such as bilirubin and sulfobromophthalein (BSP), and long-chain fatty acids - are efficiently extracted from the plasma, despite extremely tight albumin binding, by independent active plasma membrane transport systems. Although pigment gallstone formation and alcoholic fatty liver are associated with chronic alcohol abuse, the exact role of alcohol in their manifestation is unknown. It has been shown that ethanol alters fatty acid and triglyceride accumulation in the liver, bile flow and the constituents of bile, in a variety of ways, but there has been no systematic study of the effects of alcohol intoxication on the uptake parameters of organic anions from the plasma. It is therefore the overall aim of this project to examine the effects of acute and chronic alcohol administration on the hepatic uptake and intracellular transport of these three classes of organic anions and to investigate the alterations to their control at the molecular level induced by ethanol and other xenobiotics in rats. In order to achieve this, studies will be carried out on livers from alcoholic rats. As well as studying homogenates from whole livers, hepatocytes will be isolated and cultured, plasma membranes and plasma membrane vesicles prepared, and the binding proteins isolated. Using these, carrier mediated uptake will be measured and changes in the plasma membrane transport proteins quantitated. Estimations will be made of the contributions to changes in uptake made by the cytosolic binding proteins for these organic anions in the presence of ethanol. Transcriptional and/or translational control changes in response to ethanol will also be assessed. Finally, the effects of ethanol metabolites, such as acetaldehyde and other xenobiotics such as disulfiram, 4-methyl pyrazole and phenobarbital will be evaluated in these systems, either individually, or in conjunction with ethanol. It is hoped that the information gained on the effects of ethanol on hepatic anion uptake can be extrapolated to man and will eventually prove useful in the treatment of some of the manifestations of alcoholic liver disease.