Hood A, Liu J, Klaassen C D
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Toxicol Sci. 1999 Jul;50(1):45-53. doi: 10.1093/toxsci/50.1.45.
Reduced thyroid hormone concentrations (T4 and/or T3) and increased thyroid-stimulating hormone (TSH) have been proposed to mediate the thyroid tumor promoting effects of hepatic microsomal enzyme inducers (MEI) and antithyroid drugs. TSH is known to stimulate thyroid gland function and growth, as well as neoplasia. Thyroid weight has been used as an indicator of thyroid gland growth in MEI studies, but little is known about the effects of these inducers on thyroid cell proliferation. Therefore, we determined the time-course of thyroid cell proliferation of rats treated with MEI, and with the antithyroid drug propylthiouracil (PTU). Male Sprague-Dawley rats were fed either a basal diet or a diet containing phenobarbitol (PB) (1200 ppm), PCN (500 ppm), or PTU (30 ppm) for 3, 7, 14, 21, 30, 45, 60, or 90 days. PB and PCN treatments did not affect T3, but PTU reduced T3 60%. PB and PCN treatments reduced T4 25%, whereas PTU treatment reduced T4 90%. PB and PCN treatments increased thyroid weight 80%, and PTU increased thyroid weight 500%. TSH was not appreciably altered in PB-treated rats, but was increased 75% and 830% in PCN- and PTU-treated rats, respectively. Thyroid cell proliferation was increased 260, 330, and 850% in rats treated with PB, PCN, or PTU, respectively, for 7 days, but returned to control levels by the 45th treatment day. In conclusion, treatment with MEI that produced mild increases in TSH resulted in dramatic increases in thyroid cell proliferation, which peaked after 7 days of treatment and then returned to control values. This result is similar to that of antithyroid drugs, which produce large increases in TSH. These findings may have important implications for the role thyroid follicular cell proliferation has in mediating the thyroid tumor promoting effects of MEI.
甲状腺激素浓度（T4和/或T3）降低以及促甲状腺激素（TSH）升高被认为介导了肝微粒体酶诱导剂（MEI）和抗甲状腺药物的甲状腺肿瘤促进作用。已知TSH可刺激甲状腺功能和生长以及肿瘤形成。在MEI研究中，甲状腺重量已被用作甲状腺生长的指标，但对于这些诱导剂对甲状腺细胞增殖的影响知之甚少。因此，我们确定了用MEI和抗甲状腺药物丙硫氧嘧啶（PTU）处理的大鼠甲状腺细胞增殖的时间进程。将雄性Sprague-Dawley大鼠喂食基础饮食或含有苯巴比妥（PB）（1200 ppm）、氯丙嗪（PCN）（500 ppm）或PTU（30 ppm）的饮食3、7、14、21、30、45、60或90天。PB和PCN处理不影响T3，但PTU使T3降低60%。PB和PCN处理使T4降低25%，而PTU处理使T4降低90%。PB和PCN处理使甲状腺重量增加80%，PTU使甲状腺重量增加500%。PB处理的大鼠TSH没有明显改变，但PCN和PTU处理的大鼠TSH分别增加了75%和830%。用PB、PCN或PTU处理7天的大鼠甲状腺细胞增殖分别增加了260%、330%和850%，但在第45天治疗时恢复到对照水平。总之，用导致TSH轻度升高的MEI处理导致甲状腺细胞增殖急剧增加，在治疗7天后达到峰值，然后恢复到对照值。这一结果与抗甲状腺药物相似，抗甲状腺药物可使TSH大幅升高。这些发现可能对甲状腺滤泡细胞增殖在介导MEI的甲状腺肿瘤促进作用中的作用具有重要意义。
