BILE ACID METABOLISM IN HEALTH AND DISEASE

健康和疾病中的胆汁酸代谢

• 批准号: 2137581
• 负责人: ALAN F HOFMANN
• 金额: $ 29.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-04-01 至 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2137581
• 关键词: biliary tract disorder chemotherapy; biliary tract pharmacology; biochemical evolution; biotransformation; chemical conjugate; chemical structure function; cholanate compound; cholestasis; disease /disorder model; drug design /synthesis /production; fluorescent dye /probe; gastrointestinal absorption /transport; guinea pigs; hamsters; high performance liquid chromatography; human subject; human therapy evaluation; hypercholesterolemia; laboratory rabbit; laboratory rat; lipid structure; lipid transport; malabsorption; membrane transport proteins; molecular cloning; nonhuman therapy evaluation; sarcosine; steroid analog; steroid metabolism; ursodeoxycholate

The overall aims of this multidisciplinary research program are: 1) to develop principles of bile acid evolution; 2) to eludicate structure-activity-metabolism relationships of natural and synthetic bile acids; and 3) to use these principles to develop new therapeutic approaches to hepatobiliary and digestive disease based on bile acid agonists or antagonists. Experiments to be performed may be grouped as follows. Evolution of bile acids and bile alcohols: The chemical structure of bile acids and bile alcohols in a spectrum of vertebrates will be determined using modern chemical techniques in order to develop principles of bile acid evolution as well as define the value of such analyses for tracing evolutionary relationships. Bile acid pharmacology-toxicology: The influence of side chain structure on bile acid biotransformation will be examined using the C22 (dinor) homologues of natural bile acids to test the hypothesis that these compounds will be poorly amidated, glucuronidated, and hypercholeretic. The biotransformation and chronic toxicity of novel monohydroxy- bile acids (7alphaOH,7betaOH,12alphaOH,l2betaOH) will also be defined to provide information on their potential therapeutic utility as inhibitors of ileal transport. Bile acid physiology: The physiological properties of cholylfluorescein and other bile acid fluorescein conjugates will be defined. Biliary lipid composition (phospholipid and cholesterol) will examined in a spectrum of vertebrates to define the biology of bile acid induced biliary lipid secretion. Efforts to clone the apical Na+/conjugated bile acid cotransporter present in the ileal enterocyte will continue; if unsuccessful, the chromatographic isolation of this membrane-bound protein will be attempted. Bile acid therapeutics: Cholylsarcosine will be tested as a bile acid replacement for bile acid deficiency states in patients with severe bile acid malabsorption because of ileal resection. The efficacy of intravenous bile acids in a rabbit model of TPN-induced cholestasis will be tested. Inhibitors of the ileal transport system for conjugated bile acids will be synthesized and tested. Such compounds should be useful for the treatment of cholestatic liver disease or hypercholesterolemia. Biliary bile acid composition in patients with cholestatic liver disease before and during ursodiol therapy, as well as in patients after liver transplantation, will be analyzed by HPLC. If successful, these experiments will provide new physiological insights and new therapeutic approaches to hepatobiliary and digestive disease.

该多学科研究计划的总体目的是：1） 发展胆汁酸进化的原理； 2）令人难以置信 自然和合成胆汁的结构活性代谢关系 酸； 3）使用这些原理来开发新的治疗性 基于胆汁酸的肝胆和消化疾病的方法 激动剂或对手。 要进行的实验可以分为 跟随。 胆汁酸和胆汁醇的进化：化学物质 一系列脊椎动物中胆汁酸和胆汁醇的结构 将使用现代化学技术来确定以开发 胆汁酸进化的原理，并定义了这种价值 追踪进化关系的分析。 胆汁酸 药理学毒理学：侧链结构对胆汁的影响 将使用C22（Dinor）同源物检查酸生物转化 天然胆汁酸的测试假设是这些化合物将是 肿瘤较差，葡萄糖醛酸苷且胆固醇过度。 这 新型单羟基胆汁酸的生物转化和慢性毒性 （7alphaoh，7betaoh，12alphaoh，l2betaoh）也将被定义为提供 有关其潜在的治疗效用的信息 运输。 胆汁酸生理：生理特性 胆囊荧光素和其他胆汁酸荧光素结合物将是 定义。 胆道脂质成分（磷脂和胆固醇）将 在一系列脊椎动物中检查以定义胆汁酸的生物学 诱导胆道脂质分泌。 努力克隆顶端 Na+/共轭胆汁酸共转移蛋白存在于肠肠肠细胞中 将继续；如果不成功，它的色谱隔离 将尝试膜结合的蛋白。 胆汁酸治疗学： 胆囊果碱将作为胆汁酸的胆汁酸测试 严重胆汁酸吸收不良的患者的缺乏状态，因为 回肠切除。 静脉胆汁酸在兔子中的功效 将测试TPN诱导的胆汁淤积的模型。 回肠的抑制剂 共轭胆汁酸的运输系统将合成，并 测试。 这样的化合物应该对胆汁淤积的治疗有用 肝病或高胆固醇血症。 胆汁胆酸组成 乌索二醇之前和期间患有胆固性肝病的患者 肝移植后的治疗以及患者将是 由HPLC分析。 如果成功，这些实验将提供新的生理见解 以及针对肝疾病和消化系统疾病的新治疗方法。