Studies on the goitrogenic mechanism of action of N,N,N',N'-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.
Freyberger
Alexius
A
Bayer HealthCare AG, PH R&D PD Toxicology, Department of Molecular and Special Toxicology, Aprather Weg 18, D-42096 Wuppertal, Germany. alexius.freyburger@bayerhealthcare.de
Ahr
Hans-Jürgen
HJ
D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D013956:Antithyroid Agents / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005031:Ethylenethiourea / Q000008:administration & dosage / Q000633:toxicity; D006042:Goiter / Q000139:chemically induced* / Q000201:enzymology; D006139:Guaiacol / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007455:Iodine / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011441:Propylthiouracil / Q000494:pharmacology; D051381:Rats; D013552:Swine; D013890:Thiourea / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
D013956:Antithyroid Agents; D004791:Enzyme Inhibitors; D005031:Ethylenethiourea; D014443:Tyrosine; D006139:Guaiacol; D011441:Propylthiouracil; D007455:Iodine; D006861:Hydrogen Peroxide; C109812:iodothyronine deiodinase type I; D007453:Iodide Peroxidase; D013890:Thiourea; C019107:tetramethylthiourea; D000640:Amitrole