CARRIER-MEDIATED TRANSPORT OF XENOBIOTICS IN LIVER CELLS

肝细胞中载体介导的异生物质转运

• 批准号: 3250674
• 负责人: David L Eaton
• 金额: $ 7.87万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-09-28 至 1987-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3250674
• 关键词: aminoacid transport; cations; dioxins; drug metabolism; environmental toxicology; fresh water environment; hexoses; ion transport; liver cells; liver metabolism; ouabain; procainamide; steroids; toxin metabolism

Previous studies have demonstrated that the liver possesses a variety of active, carrier-mediated transport systems which are responsible for the hepatic uptake and elimination of a variety of foreign chemicals (xenobiotics) as well as endogenous compounds (steroids amino acids and bile acids). The long-term objectives of this proposal are to characterize the structural specificities, and the nature and significance of chemical modification of these transport systems. Specific aims of this proposal are to: 1) determine if transport of ouabain and/or procaine amide ethobromide (PAEB), prototype substrates for "neutral" and "organic cation" transport systems, respectively, is related to the transport of endogenous substances such as inorganic cations, amino acids or hexoses, 2) characterize the hepatocellular efflux processes for ouabain and PAEB, 3) define the relationship between the hepatocyte carrier-mediated transport system for ouabain and those for bile acids, 4) determine if such transport systems are functional in species other than the laboratory rat, 5) determine if such transport systems can be induced by prior exposure to transport-system substrates and 6) further examine the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on these transport systems in isolated hepatocytes. Isolated hepatic parenchymal cells in suspension are utilized to examine the rate of accumulation and efflux of radiolabeled ouabain, taurocholic acid and PAEB, each of which is transported by different carrier-systems. Kinetic analysis of the initial rates of uptake of various concentrations of these substrates in the presence of other potential substrates, or from isolated hepatocytes obtained from TCDD-treated animals, should provide information on the structural specificities and redundancies of these carrier-mediated transport systems. Preparation of isolated hepatocytes from trout, mice, guinea pig and macaque should provide information on the phylogenetic preservation of these transport systems, and an evaluation of their significance in species other than the rat. Results of these studies will be of significance in 1) defining potential rate-limiting steps for the hepatic elimination of various drugs and toxicants, and 2) understanding and/or predicting potential chemical interactions that might occur through competitive interaction or chemical modification of these hepatic transport systems upon exposure to various drugs and/or environmental hepatotoxic chemicals.

以前的研究表明，肝脏拥有多种不同的 主动的、承运商中介的运输系统，负责 肝脏对多种外来化学物质的摄取和排出 (外来生物)以及内源化合物(类固醇、氨基酸和 胆汁酸)。这项提案的长期目标是 化学物质的结构特性、性质和意义 这些运输系统的改装。这项提案的具体目标 目的是：1)确定哇巴因和/或普鲁卡因酰胺的运输 乙溴胺(PAEB)，“中性”和“有机阳离子”的原型底物 运输系统，分别与内源性的运输有关 无机阳离子、氨基酸或己糖等物质，2) 哇巴因和PAEB的肝细胞外排过程的特征，3) 明确肝细胞载体介导的转运之间的关系 哇巴因系统和胆汁酸系统，4)确定这种转运 系统在实验鼠以外的物种中是正常的，5) 确定这样的运输系统是否可以通过事先接触到 运输系统基质和6)进一步检查 2，3，7，8-四氯二苯并对二恶英 肝细胞。利用悬液中分离的肝实质细胞 为了检查放射性标记哇巴因的累积和外流速度， 牛磺胆酸和PAEB，每一种都是由不同的 航母系统。硝酸甘油初始吸收速率的动力学分析 在其他物质存在的情况下这些底物的不同浓度 潜在的底物，或来自从 经TCDD处理的动物，应提供有关结构的信息 这些承运人中介运输的特殊性和冗余性 系统。鲑鱼、小鼠、豚鼠肝细胞的分离制备 猕猴应该提供有关物种系统发育保存的信息 这些运输系统，以及它们在物种中的意义的评估 除了那只老鼠。这些研究的结果将在1)中具有重要意义 确定潜在的限速步骤以消除肝脏中的 各种药物和毒物，以及2)了解和/或预测 可能通过竞争发生的潜在化学相互作用 这些肝脏转运系统的相互作用或化学修饰 在接触各种药物和/或环境中的肝毒性化学品时。