Long-term objectives of this proposal are to elucidate the molecular mechanisms responsible for the therapeutic effects of phototherapy of neonatal jaundice; to improve the effectiveness and safety of phototherapy; and to define, at the molecular level, structural features that control the transport, metabolism and excretion of bilirubin and related compounds by the liver.
Specific aims are: To determine by 13C-nuclear magnetic resonance, circular dichroism and other spectroscopic methods, dissociation constants and three- dimensional structures of bilirubin, its glucuronides and its photoisomers in biologically relevant environments. To clarify the interdependent roles of vinyl substitution, intramolecular hydrogen bonding, acidity, and lipophilicity on the photobiology and biochemistry of bilirubin. To elucidate the mechanisms involved in photoisomerization reactions of bilirubin-albumin complexes and define factors that influence their stereoselectivities and quantum yields. To investigate the importance in phototherapy of a newly discovered photoisomer of bilirubin. To evaluate the contribution of the canalicular anion transporter c- MOAT to the biliary excretion of bilirubin photoisomers and other tetrapyrrolic carboxylate anions and glucuronides. To define the topography and substrate requirements of the active site of bilirubin glucuronyl transferase by studying the glucuronidation of chemically engineered bilirubins of defined three dimensional structure. To synthesize bilirubin glucuronides and novel bilirubins with potential research and clinical applications and test new chemotherapeutic strategies for inhibiting bilirubin production.
These aims will be achieved by measuring the chemical and biological properties of bilirubin and related compounds in vitro and by studying the transport and metabolism of phototherapy intermediates and bilirubin model compounds in normal rats and in mutant rats with congenital defects in bilirubin metabolism. The project is directly related to the prevention of bilirubin-induced brain damage in babies and in patients with the Crigler-Najjar syndrome, to the diagnosis and understanding the hepatobiliary disease and jaundice, and to the therapeutic and biological effects of light on humans. The work will lead to safer and more effective methods for the treatment of familial hyperbilirubinemia and jaundice in the newborn.
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