ethylenethiourea and tetramethylthiourea

N,N,N',N'-Tetramethylthiourea (TMTU) is a rat goitrogen inducing thyroid hyperplasia, hypertrophy, and tumor formation. Little is known about the exact underlying mechanism of action. As thyroid peroxidase (TPO) and type I iodothyronine deiodinase (ID-I) have been established as targets of goitrogenic thiourea derivatives, we investigated interactions of TMTU with target enzymes using a partially purified fraction from hog thyroids or solubilized hog thyroid microsomes and 10,000g supernatant from rat liver homogenate, respectively, as enzyme sources. For comparison, comprehensively characterized goitrogenic thiourea derivatives were studied as well. In contrast to propylthiouracil (PTU), and like ethylenethiourea (ETU), TMTU only marginally affected TPO-catalyzed oxidation of guaiacol. TMTU, like ETU, concentration-dependently suppressed TPO-catalyzed iodine formation with concomitant oxidative metabolism. Suppression ceased upon consumption of thiourea derivatives, the rate of the reappearing iodine formation was similar to that of controls. TMTU, like ETU, also suppressed non-enzymatic and TPO-catalyzed monoiodination of l-tyrosine with a stoichiometry of 2:1, i.e., one molecule of thiourea derivative suppressed two times monoiodination. TMTU and ETU were unable to irreversibly inhibit TPO. In contrast to PTU, TMTU did not inhibit ID-I. These findings provide evidence that TMTU interferes with thyroid hormone synthesis at the level of iodination and demonstrate a metabolic route for the oxidative detoxification of TMTU in the thyroid suggesting that low-level or intermittent exposure to TMTU would have only minimal effects on thyroid hormone synthesis. Finally, it can be concluded that meaningful toxicological studies on TPO inhibition can be performed without a need for highly purified TPO.

Topics: Amitrole; Animals; Antithyroid Agents; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Enzyme Inhibitors; Ethylenethiourea; Goiter; Guaiacol; Hydrogen Peroxide; Iodide Peroxidase; Iodine; Oxidation-Reduction; Propylthiouracil; Rats; Swine; Thiourea; Time Factors; Tyrosine

Tetramethyl and ethylene thiourea are collected from air using midget impingers containing 15 mL water. Ethylene thiourea may also be collected from air using PVC or cellulose ester membrane filters which are then extracted with water. Pentacyanoamineferrate reagent is added to the filter-extract or to the impinger contents to form a colored coordination complex. The absorbance of the solution is measured spectrophotometrically at 590 nm, and the unknown concentration of tetramethyl or ethylene thiourea samples is determined from calibration curves. The detection limit is 0.75 microg/sample for ethylene thiourea and 3 microg/sample for tetramethyl thiourea. Experimental results indicate that this method can be used as a general analytical method for the analysis of other thiourea-derived compounds.

Topics: Ethylenethiourea; Spectrum Analysis; Thiourea