A common result of prolonged alcohol consumption is liver damage. There is a considerable body of evidence that implicates the first metabolite of ethanol oxidation, acetaldehyde. and malondialdehyde as the precursors to hepatotoxicity. When hepatic proteins are incubated with both aldehydes, hybrid protein adducts are generated. At long reaction times the adducts are highly fluorescent while non-fluorescent adducts predominate at the early stages of reaction. It has been determined that the structure of the fluorescent adduct is a 1,4-dihydopyridine 3,5-dicarboxaldehyde, formed by a Hantzsch reaction of acetaldehyde, malondialdehyde, and the epsilon amino group of a lysine residue. Recent evidence indicates that the structure of the non-fluorescent adduct is a 2-formyl-3-alkylamino-butanol. The research proposed here will focus on two areas. One project is aimed at identifying the conditions necessary for formation of the these adducts. This will involve monitoring the reaction between acetaldehyde, malondialdehyde, and small peptides by nuclear magnetic resonance (NMR) and fluorescence spectroscopy. The peptides will have lysine residues sandwiched between various amino acids in order to identify local environments which enhance the production of one or both adducts. The second project is aimed at clarifying the reaction mechanism which accounts for the formation of the non-fluorescent adduct. The reaction between acetaldehyde, malondialdehyde, and a primary amine will monitored by NMR to determine the structures of any intermediate species.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Small Research Grants (R03)
Project #
5R03AA011627-02
Application #
6168386
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Purohit, Vishnu
Project Start
1999-07-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2000
Total Cost
$44,271
Indirect Cost
Name
Creighton University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
053309332
City
Omaha
State
NE
Country
United States
Zip Code
68178
Tuma, D J; Kearley, M L; Thiele, G M et al. (2001) Elucidation of reaction scheme describing malondialdehyde-acetaldehyde-protein adduct formation. Chem Res Toxicol 14:822-32