The objective of this project is to define the role of iron mobilization in the pathogenesis of alcohol-induced liver injury. We will expand our previous studies of ethanol induced hepatic lipid peroxidation focusing on the hypothesis that liver injury is primarily mediated by the mobilization of reduced iron(Fe++) from hepatic ferritin during ethanol metabolism. The mechanism(s) of iron mobilization will be investigated and assessed with respect to the role of alcohol dehydrogenase induced redox changes and xanthine oxidase generated superoxide radicals. Our preliminary in vitro observations of enhanced mobilization due to increased redox changes and low oxygen tension and increased peroxidation due to microsomal induction will be studied extensively in isolated hepatocytes and in rodent models of acute and chronic alcohol administration to determine the cause of the increased susceptibility of the perivenular zone-the earliest site of progressive liver damage. Iron mobilization due to acute ethanol will be studied in vivo in rodent models of acute and chronic ethanol administration under a variety of conditions including iron overloading, iron chelation, inhibition of xanthine oxidase and altered redox changes to elucidate the mechanism of mobilization and its link to cellular injury. The impact of two effects of chronic feeding will be examined: increased hepatic storage iron which may enhance mobilization and microsomal induction which may potentiate peroxidation due to free iron. Ferroxidases I and II, copper containing compounds that are known to oxidize reduced iron will be evaluated for their possible protective role. The ultimate goal of this study is to understand the role of iron and its mobilization by ethanol in the pathogenesis of alcohol-induced liver injury and thus provide a rationale for treatment and prevention. The proposed project will permit the applicant to establish himself as an independent investigator and continue his studies in the field of alcohol-induced liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007212-05
Application #
2043731
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1987-03-01
Project End
1993-02-28
Budget Start
1991-03-01
Budget End
1993-02-28
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029