BILE ACID METABOLISM IN HEALTH AND DISEASE

健康和疾病中的胆汁酸代谢

基本信息

批准号：
3151382
负责人：
ALAN F HOFMANN
金额：
$ 29.79万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-04-01 至 1988-03-31
项目状态：
已结题

项目摘要

Experiments are described with two overall aims. The first is to define the relationship between bile acid (BA) structure, hepatic transport of BA, BA bio-transformation and enterohepatic cycling. The second is to define the influence of BA structure on biliary secretion, i.e. bile volume and secretion of biliary lipids and biliary CA++. To do this, novel BA will be synthesized (C23-nor and C22-bis-nor; amino-alkyl-sulfonate conjugates; and "epimeric" BA, i.e. BA with 7BetaOH and 12BetaOH groups), such as ursocholic acid. The following physicochemical properties of these BA will be characterized: a) critical micellar concentration (CMC) using surface tension; b) CMC in systems to which a phosphatidyl choline analogue (PCA) has been added; c) solubilizing capacity of novel BA for PCA; d) CMC and solubilizing capacity of selected novel BA for phosphatidyl choline (PC); e) solubilizing capacity of BA-PCA and BA-PC systems for cholesterol. Osmotic activity of these systems will be measured, and the interaction of CA++ with conjugated BA will be defined. Physiological experiments will be carried out using the isolated perfused liver or appropriate animal models to define hepatic transport, biotransformation, and enterohepatic cycling of these novel BA. The enterohepatic circulation of C23 nor and C22 bisnor BA will be defined in experimental animals to show that BA which are not amidated during hepatic transport display prolonged retention in the enterohepatic circulation. Physiological experiments will determine the effects of these novel BA on induced bile flow, biliary lipid secretion, and CA++ secretion in the isolated perfused liver and biliary fistula animal. If successful, these experiments should provide "principles" of hepatic BA transformation and induced biliary lipid secretion which are applicable to man. They should provide further insight into the mechanism of biliary lipid secretion, and they should aid in the identification of BA structures of potential therapeutic value in man. The long term aim of these studies is the prevention of calculous biliary disease.

实验以两个总体目的描述。首先是定义胆汁酸（BA）结构，Ba的肝运输之间的关系， BA生物转化和肠肝循环。第二个是定义 BA结构对胆道分泌的影响，即胆汁量和胆道脂质和胆道Ca ++的分泌。为此，新颖的ba将是合成（C23-NOR和C22-BIS-NOR；氨基烷基磺酸盐偶联物；和 “ epiperic” ba，即带有7betaoh和12betaoh组的ba），例如 ursocholic酸。这些BA的以下理化特性将为表征：a）使用表面的临界胶束浓度（CMC）紧张; b）磷脂酰胆碱类似物（PCA）的系统中的CMC 已添加； c）PCA新型BA的溶解能力； d）CMC和磷脂酰胆碱（PC）选定的新型BA的溶解能力； e）胆固醇BA-PCA和BA-PC系统的溶解能力。将测量这些系统的渗透活性，并相互作用将定义具有共轭BA的Ca ++。生理实验将是使用孤立的灌注肝或合适的动物模型进行定义肝运输，生物转化和肠肝循环这些新颖的ba。 C23 NOR和C22 Bisnor的肠肝循环 BA将在实验动物中定义，以表明不是在肝运输显示期间陷入障碍肠肝循环。生理实验将确定这些新型BA对诱导的胆汁流，胆道脂质分泌的影响，和孤立的灌注肝脏和胆道瘘中的Ca ++分泌动物。如果成功，这些实验应提供肝BA转化和诱导胆道脂质分泌适用于人。他们应该进一步了解机制胆道脂质的分泌，它们应有助于识别BA 人类潜在治疗价值的结构。长期目标这些研究是预防胆汁胆道疾病。