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.
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