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 and metabolism of bilirubin and related compounds by the liver.
Specific aims are: 1. To characterize the molecular structures and properties of phototherapy intermediates and identify factors that influence their formation and excretion kinetics in vivo. 2. To determine why the excretion of phototherapy intermediates is less efficient in human patients than in the jaundiced. rat animal model. 3. To locate the tissue site(s) where the most important photochemical reactions of phototherapy occur. 4. To define the importance of molecular shape, lipophilicity, and hydrogen bonding in the transhepatic transport and intracellular partitioning of bilirubin and related compounds. 5. To characterize the topography and molecular recognition targets of bilirubin glucuronyl transferase. 6. To investigate the effects of volatile general anesthetics on the structure of albumin-bound bilirubin. 7. To measure the chiroptical properties of bilirubin glucuronides and develop methods for their synthesis.
These aims will be achieved by measuring the physicochemical properties of bilirubin and related compounds in vitro; by investigating the effects of light on jaundiced rats; and by studying the transport and metabolism of phototherapy intermediates and bilirubin model compounds in normal rats, in mutant rats with congenital defects in bilirubin metabolism, and in isolated perfused liver preparations from these animals. The project is directly related to the prevention of bilirubin-induced brain damage in infants and in patients with the Crigler-Najjar syndrome, to the diagnosis and understanding of hepatobiliary disease, to the therapeutic and biological effects of light on humans, and to the physiologic effects and mechanism of general anesthetics. The work will lead to safer and more effective methods for the treatment of familial hyperbilirubinemia and jaundice in the newborn.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK026307-16
Application #
2137847
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Serrano, Jose
Project Start
1980-07-01
Project End
1997-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
16
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
McDonagh, Antony F; Vreman, Hendrik J; Wong, Ronald J et al. (2009) Photoisomers: obfuscating factors in clinical peroxidase measurements of unbound bilirubin? Pediatrics 123:67-76
Zunszain, Patricia A; Ghuman, Jamie; McDonagh, Antony F et al. (2008) Crystallographic analysis of human serum albumin complexed with 4Z,15E-bilirubin-IXalpha. J Mol Biol 381:394-406
McDonagh, Antony F (2008) Photolysis and photoisomerization of bilirubin in serum specimens exposed to room lighting. Clin Chim Acta 393:130;author reply 131
McDonagh, Antony F; Boiadjiev, Stefan E; Lightner, David A (2008) Slipping past UGT1A1 and multidrug resistance-associated protein 2 in the liver: effects of steric compression and hydrogen bonding on the hepatobiliary elimination of synthetic bilirubins. Drug Metab Dispos 36:930-6
McDonagh, Antony F (2007) Bilirubin toxicity to human erythrocytes: a more sanguine view. Pediatrics 120:175-8
McDonagh, Antony F; Lightner, David A (2007) Influence of conformation and intramolecular hydrogen bonding on the acyl glucuronidation and biliary excretion of acetylenic bis-dipyrrinones related to bilirubin. J Med Chem 50:480-8
McDonagh, Antony F; Maisels, M Jeffrey (2006) Bilirubin unbound: deja vu all over again? Pediatrics 117:523-5
McDonagh, Antony F (2006) Ex uno plures: the concealed complexity of bilirubin species in neonatal blood samples. Pediatrics 118:1185-7
Toietta, Gabriele; Mane, Viraj P; Norona, Wilma S et al. (2005) Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector. Proc Natl Acad Sci U S A 102:3930-5
Woydziak, Zachary R; Boiadjiev, Stefan E; Norona, Wilma S et al. (2005) Synthesis and hepatic transport of strongly fluorescent cholephilic dipyrrinones. J Org Chem 70:8417-23

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