The specific aims of this application are: (1) To elucidate the products of non-conjugative alternate pathways for bilirubin excretion and detoxification which are manifested in patients with the Crigler-Najjar syndrome and in the Gunn rat animal model, and which may also function in infants with severe unconjugated hyperbilirubin emia. (2) To determine the chemical or biochemical molecular mechanisms involved in these pathways. (3) To study the effect of tinprotoporphyrin and other related metal loporphyrins on serum bilirubin levels in animals (Gunn rats) with pre-existing hyperbilirubinemia both under hemolytic and nonhemolytic conditions, and to assess the photo-biological safety of these agents. (4) To characterize the bilirubin degradatiion products formed by mitchondrial bilirubin oxygenase from rat and guinea pig brain, and determine whether these products are formed in vivo in Gunn rats with congenital hyper-bilirubinemia. The overall long-term objectives of this application are to understand the mechanism of bilirubin toxicity and to devise safe and effective methods for reducing unconjugated bilirubin accumulation and toxicity in newborns and in patients with the Crigler-Najjar syndrome. The studies will involve bioorganic, chemical, biochemical, spectroscopic, chromatographic and metabolic techniques. They are particularly relevant to liver metabolism, care of the newborn and the development of brain damage and cerebral palsy in infants.
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