Mechanism of clobazam-induced thyroidal oncogenesis in male rats
| Autor: | Izuru Miyawaki, Hitoshi Funabashi, Matsuko Moriyasu, Masashi Yasuba, Nobuo Matsuoka |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Male
endocrine system medicine.medical_specialty endocrine system diseases Thyroid Gland Administration Oral Thyrotropin Biology Toxicology Follicular cell Muscle hypertrophy Rats Sprague-Dawley Benzodiazepines Thyroid-stimulating hormone Internal medicine Follicular phase medicine Animals Thyroid Neoplasms Glucuronosyltransferase Triiodothyronine Thyroid General Medicine Organification Hypertrophy Organ Size Rats Thyroxine Endocrinology medicine.anatomical_structure Liver Clobazam Anticonvulsants Hormone |
| Zdroj: | Toxicology letters. 145(3) |
| ISSN: | 0378-4274 |
| Popis: | In order to elucidate the mechanisms by which long-term treatment with clobazam (CLB), 1,5-benzodiazepine, induces thyroid follicular cell tumors in male rats, male Sprague-Dawley (SD) rats were treated orally with 400 mg/kg of CLB for up to 4 weeks, and the contribution of feedback through elevated thyroid stimulating hormone (TSH) was investigated. Measurements taken after 1, 2, and 4 weeks of treatment revealed that thyroxine (T4)-UDP-glucuronosyltransferase (T4-UDPGT) activity was higher than that of untreated animals. This change was accompanied by increase in liver weights and centrilobular hepatocyte hypertrophy. In addition, plasma total triiodothyronine (T3) and T4 levels were lower than in the untreated rats when measured after 1 week of treatment. However, a high plasma TSH level was sustained throughout the 4-week treatment. Thyroid follicular cell hypertrophy began after 1 week of treatment, followed by increased thyroid weight after 2 weeks. Clearance of exogenous [125I] T4 from the blood of treated rats, determined after 4 weeks of treatment, was significantly faster than that in untreated rats, whereas iodine uptake and organification in the thyroid glands were not affected. These results suggest that CLB increases hepatic T4-UDPGT activity leading to acceleration of T4-clearance, which results in decreased plasma thyroidal hormones followed by compensatory increase of TSH biosynthesis and secretion. Chronic high levels of TSH would exert a continuous growth pressure on the thyroid, under which hypertrophic follicular cells can ultimately progress to frank neoplasms. |
| Databáze: | OpenAIRE |
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