Long-term objectives of this proposal are to fully elucidate the mechanism and effects of phototherapy of neonatal jaundice, to improve its effectiveness and safety, and to define the molecular mechanisms involved in the transport, metabolism and excretion of the jaundice pigment bilirubin (BR) and related compounds by the liver.
Specific aims are: To fully characterize the photoisomers and other photoproducts of BR and its glucuronides formed during light exposure of humans (particularly jaundiced neonates undergoing phototherapy), elucidate their hepatic transport and metabolism, measure their production with light-emitting diodes of different wavelength emission, and determine whether BR photoisomers interfere with """"""""free"""""""" BR measurements by the peroxidase method. To study BR-sensitized degradation of copper-porphyrins under physiologic conditions and identify the products. To identify and characterize the products of alternate, non-glucuronide, pathways of BR metabolism in the jaundiced Gunn rat animal model. To investigate the mechanisms of bilirubin glucuronidation and the role of the canalicular membrane transporter Mrp2 in the biliary efflux of organic anions and glucuronides using novel synthetic di and tetrapyrroles as molecular probes of the influence of shape, hydrogen bonding and constitutional structure. To develop chemical inhibitors of BR formation that could be used to prevent the development of infant jaundice.
These aims will be achieved by studying the chemistry, photochemistry, and metabolism of BR and specially designed synthetic model compounds both in vitro and in vivo in animals with congenital defects in liver metabolism. The project is directly related to the prevention of BR-induced brain damage in babies and in patients with the Crigler-Najjar syndrome, to the diagnosis and understanding of liver and biliary disease and jaundice, to the therapeutic and biological effects of light on humans, to the metabolism and elimination of acid drugs by the liver, and to protection from free radicals and oxidative stress. The work will lead to safer more effective treatment of familial hyperbilirubinemia and jaundice in the newborn.
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