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.
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