EFFECTS OF ETHANOL ON HEPATIC ORGANIC ANION UPTAKE

肝脏的主要功能之一是摄取低分子量的 重量有机阴离子。其中有三类化合物- 胆汁酸、非胆汁酸嗜胆固醇如胆红素和 磺溴酞（BSP）和长链脂肪酸-有效地 从血浆中提取，尽管白蛋白结合非常紧密， 独立的主动质膜转运系统。虽然色素 胆结石形成和酒精性脂肪肝与慢性 酒精滥用，酒精在其表现中的确切作用尚不清楚。 已经表明，乙醇改变脂肪酸和甘油三酯 在肝脏中的积累，胆汁流量和胆汁的成分，在一个 各种各样的方式，但一直没有系统的研究， 酒精中毒对有机阴离子摄取参数的影响 等离子体因此，本项目的总体目标是审查 急性和慢性酒精摄入对肝脏摄取的影响 以及这三类有机阴离子的细胞内转运， 在分子水平上研究其控制的改变， 乙醇和其他外源性物质对老鼠的影响 为了实现这一目标，将对来自以下国家的肝脏进行研究： 酗酒的老鼠除了研究整个肝脏的匀浆， 将分离并培养肝细胞，质膜和血浆 制备膜囊泡，并分离结合蛋白。利用这些， 将测量载体介导的摄取， 运输蛋白定量。估计将作出的 对胞质结合蛋白摄取变化的贡献 这些有机阴离子在乙醇的存在下。转录和/或 还将评估响应于乙醇的翻译控制变化。 最后，研究了乙醇代谢产物，如乙醛和其他 异生物素如双硫仑、4-甲基吡唑和苯巴比妥将被 在这些系统中进行评估，无论是单独评估，还是与 乙醇 希望获得的关于乙醇对 肝阴离子摄取可外推至人，并将最终证明 可用于治疗酒精性肝的某些表现 疾病

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.