Mechanism of clobazam-induced thyroidal oncogenesis in male rats
Mechanism of clobazam-induced thyroidal oncogenesis in male rats
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DOI：
10.1016/j.toxlet.2003.08.002
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发表时间：
2003-12-10
影响因子：
3.5
通讯作者：
Matsuoka, N
中科院分区：
文献类型：
--
作者：
Miyawaki, I;Moriyasu, M;Matsuoka, N
为了阐明长期服用氯巴唑（clobazam, 1,5-苯二氮卓）诱导雄性大鼠甲状腺滤泡细胞肿瘤的机制，本研究以400 mg/kg的氯巴唑（CLB）口服SD大鼠4周，并通过提高促甲状腺激素（TSH）来研究反馈作用。治疗1、2和4周后测量显示，甲状腺素(T-4)- udp -葡萄糖醛酸转移酶（T-4- udpgt）活性高于未治疗的动物。这种变化伴随着肝脏重量增加和小叶中心肝细胞肥大。此外，治疗1周后，血浆总三碘甲状腺原氨酸（T-3）和T-4水平均低于未治疗组。然而，在整个4周的治疗过程中，血浆TSH水平持续升高。治疗1周后甲状腺滤泡细胞开始肥大，治疗2周后甲状腺重量增加。治疗4周后测定，治疗大鼠血液中外源性[I-125] T-4的清除速度明显快于未治疗大鼠，而甲状腺的碘摄取和组织不受影响。这些结果表明，CLB增加肝脏T-4-UDPGT活性，导致t -4清除加速，从而导致血浆甲状腺激素降低，随后代偿性增加TSH的生物合成和分泌。慢性高水平的TSH会对甲状腺施加持续的生长压力，在这种压力下，肥厚滤泡细胞最终会发展为肿瘤。2003爱思唯尔爱尔兰有限公司版权所有。
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 [I-125] 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 hyper-trophic follicular cells can ultimately progress to frank neoplasms. (C) 2003 Elsevier Ireland Ltd. All rights reserved.