Mechanism of clobazam-induced thyroidal oncogenesis in male rats

Abstract

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 (T 4)-UDP-glucuronosyltransferase (T 4-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 (T 3) and T 4 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 [ 125 I ] T 4 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 T 4-UDPGT activity leading to acceleration of T 4-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.