Man is exposed to toxic derivatives of thiourea (thiocarbamides) in the environment from agricultural, industrial and medicinal sources. Since the thyroid gland is the principal target organ for thiocarbamides, the mechanism of inhibition of thyroid peroxidase (TPX) will be determined. Suicide inactivation of TPX will also be defined from the stoichiometry of free and enzyme-bound products which result from inactivation by thiocarbamides. The locus of binding to TPX will be determined by using specifically- radiolabelled inactivators. The catalysis of S-oxygenation reactions by the peroxidase of bone marrow and blood elements, myeloperoxidase, and the hepatic monooxygenases will be investigated since bone marrow and liver toxicity are severe side effects which limit the use of thiocarbamide antithyroid drugs. The production of reactive intermediates from thiocarbamides catalyzed by peroxidases and monooxygenases will be studied by measuring the binding of radiolabelled thiocarbamides to heme, protein and nucleic acid functional groups. Reactive S- oxygenated intermediates from thiocarbamides will be generated in chemical model systems to determine their reactivity with biologically relevant acceptor molecules. This research will correlate the enzymology of thiocarbamide metabolism with the chemistry of putative reactive intermediates to define toxicological mechanisms and health hazards of this significant class of environmental chemicals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004622-03
Application #
3252713
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1988-02-01
Project End
1992-01-31
Budget Start
1990-02-01
Budget End
1992-01-31
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Hawaii
Department
Type
Schools of Earth Sciences/Natur
DUNS #
121911077
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Decker, C J; Doerge, D R; Cashman, J R (1992) Metabolism of benzimidazoline-2-thiones by rat hepatic microsomes and hog liver flavin-containing monooxygenase. Chem Res Toxicol 5:726-33
Doerge, D R; Cooray, N M; Brewster, M E (1991) Peroxidase-catalyzed S-oxygenation: mechanism of oxygen transfer for lactoperoxidase. Biochemistry 30:8960-4
Decker, C J; Doerge, D R (1991) Rat hepatic microsomal metabolism of ethylenethiourea. Contributions of the flavin-containing monooxygenase and cytochrome P-450 isozymes. Chem Res Toxicol 4:482-9
Doerge, D R; Takazawa, R S (1990) Mechanism of thyroid peroxidase inhibition by ethylenethiourea. Chem Res Toxicol 3:98-101
Doerge, D R; Niemczura, W P (1989) Suicide inactivation of lactoperoxidase by 3-amino-1,2,4-triazole. Chem Res Toxicol 2:100-3