Clinical jaundice is the most common medical diagnosis in the newborn; over 50 percent of neonates display significant unconjugated hyperbilirubinemia during the first 5 days of life. Phototherapy is the most common treatment; hundreds of thousands of babies in the U.S. are irradiated each year with white or blue light to decrease plasma levels of unconjugated bilirubin and reduce the risk of permanent brain damage. The broad, long-term objectives of the project are to understand bilirubin structure-function relationships and the molecular basis of bilirubin detoxification; to define the interdependence of 3-dimensional structure, hydrogen bonding, hydrophobicity and acidity in hepatobiliary uptake, glucuronidation and excretion; to elucidate fully the molecular mechanism of phototherapy.
The SPECIFIC AIMS are to: 1. Determine the 3-dimensional structure of bilirubin, its anions, salts, conjugates and photoisomers in biomimetic and biological environments, including human serum albumin, by molecular dynamics and spectroscopic methods. 2. Design and prepare bilirubin analogs of known chirality and varying shape, with substituents of differing size and polarity to understand physicochemical properties important in metabolic and photobiologic mechanisms. 3. Clarify the interdependence of bilirubin acidity (pKa) and hydrogen bonding in amphiphilicity and in the potential role of bilirubin as an ionophore and ion transporter. 4. Characterize new bilirubin photoreactions, their action spectra, and their importance to phototherapy. 5. Elucidate the mechanism of bilirubin photocyclization and its stereochemistry, and investigate the influence of local environment including protein binding on the channeling of bilirubin photochemical reaction pathways. 6. Synthesize chemically-designed bilirubins as molecular probes of the interrelated roles of pigment stereochemistry and intramolecular hydrogen bonding, hydrophobicity and acidity, vinyl substitution and polarity in hepatic uptake, conjugation and excretion. These studies are directly relevant to the prevention of brain damage in the jaundiced newborn, to improving our understanding of bilirubin metabolism and liver disease. They are designed to clarify how bilirubin molecular structure controls its hepatic processing and elimination and to lead to improved and safer methods for treatment of severe unconjugated hyperbilirubinemia in the neonate and in patients with Crigler-Najjar syndrome.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD017779-17
Application #
2888882
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Wright, Linda
Project Start
1986-07-01
Project End
2003-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
17
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Nevada Reno
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Pfeiffer, William P; Dey, Sanjeev K; Falk, Heinz et al. (2014) Homorubins and Homoverdins. Monatsh Chem 145:963-981
Anstine, D Timothy; Lightner, David A (2014) Intramolecular Hydrogen Bonding and Linear Pentapyrrole Conformation. Monatsh Chem 145:1117-1135
Pfeiffer, William P; Lightner, David A (2014) (m.n)-Homorubins. Syntheses and Structures. Monatsh Chem 145:1777-1801
Dey, Sanjeev K; Datta, Suchitra; Lightner, David A (2014) Hydrogen Bonding: HOC=O· · ·H-N vs. HOC=O· · ·H-C. Monatsh Chem 145:1595-1609
Datta, Suchitra; Lightner, David A (2009) Carboxylic Acid to Thioamide Hydrogen Bonding. Tetrahedron 65:77-82
Dey, Sanjeev K; Lightner, David A (2009) Amphiphilic Dipyrrinones. Methoxylated [6]-Semirubins. Tetrahedron 65:2399-2407
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
Boiadjiev, Stefan E; Lightner, David A (2007) Converting 9-Methyldipyrrinones to 9-H and 9-CHO Dipyrrinones. Tetrahedron 63:8962-8976
Roth, Steven D; Shkindel, Tetyana; Lightner, David A (2007) Intermolecularly Hydrogen-Bonded Dimeric Helices. Tripyrrindiones. Tetrahedron 63:11030-11039
Dey, Sanjeev K; Lightner, David A (2007) 1,1'-bipyrroles: synthesis and stereochemistry. J Org Chem 72:9395-7

Showing the most recent 10 out of 44 publications