The elaboration of bile is a major hepatic function which is frequently disturbed during the course of various illnesses. Yet, the mechanisms controlling this function are poorly understood. The present project is designed to study the postnatal development of the bile secretory, metabolic and structural functions of the liver. Using puppies of 0 to 42 days of age and adult dogs, these studies will analyze the time-course of development of: 1) Determinants of bile secretion, including a) bile acid dependent and independent canalicular flow and bile acid independent ductular flow, b) permeability characteristics of the biliary tree using 14C-erythritol as a marker of canalicular water, 3H-inulin to assess the """"""""leakiness"""""""" of the junctional complexes and 3H-sucrose as a marker of paracellular water movement; c) choleretic response to glucagon, cyclic AMP, theophylline and hydrocortisone; d) hepatic transport maximum (Tmax) for sodium tairocholate and taurodehydrocholate. 2) Hepatic membrane function, including determination of activity of a) plasma membrane enzymes, Na+, K+-ATPase, Mg++-ATPase, 5'-nucleotidase and glucagon stimulated adenylate cyclase; b) microsomal enzymes P450, glucose-6-phosphatase and UDP-glucuronyl transferase. 3) Hepatic structure, including a) transmission and scanning electron microscopy of parenchymal and biliary epithelial cells and their surroundings; b) morphometric analysis of smooth endoplasmic reticulum, Golgi apparatus, mitochondria and lysosomes, 4) Hepatic hemodynamics, including determination of a) total liver blood flow; b) hepatic arterial blood flow; c) blood flow distribution through the liver lobes. 5) Hepatic bilirubin transport mechanisms, including a) plasma disappearance kinectics, plasma clearance and biliary elimination of labeled bilirubin diglucuronide and unconjugated bilirubin; b) hepatic Tmax for conjugated and unconjugated bilirubin; c) comparison of these results with the time-course of development of UDP-glucuronyl transferase activity, described in 2c. These studies will not only advance knowledge of developmental aspects of bile secretory physiology, but will also provide a basis for understanding of the pathogenesis of some cholestatic syndromes and physiologic hyperbilirubinemia of the newborn infant.
