The experiments in this proposal will determine the site and structure of the covalent modifications produced on proteins, including aldehyde dehydrogenase, by disulfiram and its metabolites using in vitro and in vivo systems. The results will assist in determining whether disulfiram inhibits aldehyde dehydrogenase preferentially through thiocarbamoylation. Determination of the mechanism of disulfiram- mediated inhibition of aldehyde dehydrogenase will assist in the design of more effective alcohol aversion therapies, development of biomarkers for monitoring disulfiram therapy, identification of susceptible individuals and determine if protein modification should be evaluated as a contributing mechanism for disulfiram-mediated neurotoxicity and hepatoxicity. Because of the structural similarities, these studies are also relevant to the biological effects of dithiocarbamates, monothiocarbamates, and dithiocarbamate disulfides used in agriculture and industry.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AA005569-02
Application #
6371279
Study Section
Special Emphasis Panel (ZRG1-SSS-3 (02))
Program Officer
Russo, Denise A
Project Start
2001-09-15
Project End
Budget Start
2001-09-15
Budget End
2002-09-14
Support Year
2
Fiscal Year
2001
Total Cost
$40,196
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Zimmerman, Lisa J; Valentine, Holly L; Valentine, William M (2004) Characterization of S-(N,N-Dialkylaminocarbonyl)cysteine Adducts and Enzyme Inhibition Produced by Thiocarbamate Herbicides in the Rat. Chem Res Toxicol 17:258-67
Tonkin, Elizabeth G; Valentine, Holly L; Zimmerman, Lisa J et al. (2003) Parenteral N,N-diethyldithiocarbamate produces segmental demyelination in the rat that is not dependent on cysteine carbamylation. Toxicol Appl Pharmacol 189:139-50
Zimmerman, Lisa J; Valentine, Holly S; Amarnath, Kalyani et al. (2002) Identification of a S-hexahydro-1H-azepine-1-carbonyl adduct produced by molinate on rat hemoglobin beta(2) and beta(3) chains in vivo. Chem Res Toxicol 15:209-17