The overall hypothesis of these proposed studies is that the hepatic metabolism of ethanol results in the formation of an active metabolite, acetaldehyde, which covalently binds to hepatocellular proteins and thereby alters hepatocellular structure and function ultimately resulting in liver cell injury. The initial objective is to described a chemical reaction sequence that leads to stable acetaldehyde-protein adduct formation. In this regard, identification of the particular amino acids participating in the reaction of acetaldehyde with protein and the determination of reaction products i.e., structures of modified amino acid residues, will be the major aims. Secondly, examination of various conditions in the liver that could modify covalent binding of acetaldehyde to hepatic protein will be undertaken. Relevant factors which include depletion of hepatic thiol groups; altered redox state; ascorbic acid; and chronic ethanol feeding will be tested as to their influence on acetaldehyde-protein adduct formation during ethanol oxidation. Establishment of an in vivo model which will verify and further characterize the formation of stable and unstable acetaldehyde-protein adducts in the liver during ethanol oxidation is another important objective. With this model, such event as the time-course formation of adducts, their subcellular distribution, duration of their existence in the liver as well as factors that influence these events will be explored. Finally, studies will be initiated that will examine the relationship between covalent binding and impaired structure and/or function of proteins at the molecular, subcellular and hepatocellular levels. These proposed studies hopefully will give valuable information concerning the basic molecular mechanisms of alcohol-induced hepatotoxicity and suggest a possible rational approach to thereapy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA004961-07
Application #
3108933
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1981-05-01
Project End
1988-04-30
Budget Start
1987-05-01
Budget End
1988-04-30
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
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Schaffert, C S; Sorrell, M F; Tuma, D J (2001) Expression and cytoskeletal association of integrin subunits is selectively increased in rat perivenous hepatocytes after chronic ethanol administration. Alcohol Clin Exp Res 25:1749-57
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
McVicker, B L; Tuma, D J; Casey, C A (2000) Hyperphosphorylation of the asialoglycoprotein receptor in isolated rat hepatocytes following ethanol administration. Biochem Pharmacol 60:343-51
Rolla, R; Vay, D; Mottaran, E et al. (2000) Detection of circulating antibodies against malondialdehyde-acetaldehyde adducts in patients with alcohol-induced liver disease. Hepatology 31:878-84

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