An integrated multidisciplinary research program is proposed whose aim is to develop general principles of hepatic and intestinal transport of bile acids (BA), bile acid biotransformation during hepatic and intestinal transport as well as principles and mechanisms of bile acid dependent bile flow and biliary lipid secretion. To this end, natural and novel BA will be purchased or synthesized and their physiological properties defined. Biotransformation during hepatic transport and enterohepatic cycling in mammals including man will be quantified using chromatographic and spectroscopic methods. The effect of these bile acids on bile flow and biliary lipid secretion will be measured using biliary fistula animals (including man) as well as the isolated perfused liver. Experiments will be continued to validate (or refute) the presence of cholehepatic cycling as a mechanism of hypercholeresis; the experimental approach will involve pharmocological, physiological, and imaging approaches. In collaborative studies, attempts will be made to identify the canalicular carrier for bile acid glucuronides using photo-affinity labelling techniques and canalicular membrane preparations. Studies will be carried out to test whether active ductular reabsorption of solutes filtered into canalicular bile (such as glucose and amino acids) influences bile flow. Aspects of passive and active intestinal transport of BA in mammals including man will be investigated by a novel intestinal perfusion technique. Attempts will be made to isolate the protein involved in active transport by the terminal ileum. Multicompartmental modelling of the metabolism and enterohepatic circulation of BA in man will be continued in collaborative studies. Biliary bile acid and phospholipid composition in a spectrum of vertebrates will be defined to develop principles of BA evolution An attempt will be made to develop a cell culture technique for studying biliary secretion since available techniques are unsatisfactory. If successful, experiments proposed in this application should give rise to new methods for studying biliary secretion and should permit biliary bile flow and biliary lipid secretion to be described by general principles; elucidation of these principles should lead to new prophylactic and therapeutic approaches to cholelithiasis and cholestasis, and possibly to liver cell injury.
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