Kolaja K L, Petrick J S, Klaassen C D
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Toxicology. 2000 Feb 21;143(2):195-202. doi: 10.1016/s0300-483x(99)00172-9.
Propylthiouracil (PTU) or low-iodine diet (LID) treatment increases thyroid-follicular-cell proliferation, possibly by disrupting the movement of small molecules (< 1.2 kD) through membrane channels called gap junctions. Numerous tumor promoters and proliferative disease states exhibit inhibited gap-junctional-intercellular communication (GJIC) prior to the induction of cell proliferation, yet the association between GJIC and apoptosis is unclear. In the present study, we used an ex vivo method to examine whether GJIC is inhibited in the thyroid of PTU- or LID-treated rats. In addition, the effect of these models of hypothyroidism on thyroid-follicular-cell proliferation and apoptosis was examined to determine the association between GJIC and cell homeostasis. After 14 days of treatment of either PTU or LID (plus 1% KClO4 in the drinking water), serum tri-iodothyronine (T3) and thyroxine, (T4) was decreased to nearly undetectable levels and serum TSH was increased in PTU- and LID-treated rats. At the same time point, GJIC was decreased 30-35% in PTU- and LID-treated rats while thyroid-follicular-cell proliferation increased nearly threefold in both treatment groups. Interestingly, apoptosis increased twofold in both hypothyroid treatment groups. These data suggest that PTU or LID treatment inhibit thyroid GJIC during a state of increased thyroid-follicular-cell proliferation and apoptosis. While the increase in proliferation was anticipated, the paradoxical increase in apoptosis during decreased GJIC in thyroid-follicular cells warrants further examination.
丙硫氧嘧啶（PTU）或低碘饮食（LID）治疗可增加甲状腺滤泡细胞增殖，可能是通过破坏小分子（<1.2 kD）通过称为缝隙连接的膜通道的移动来实现的。许多肿瘤促进剂和增殖性疾病状态在细胞增殖诱导之前表现出缝隙连接细胞间通讯（GJIC）受到抑制，然而GJIC与细胞凋亡之间的关联尚不清楚。在本研究中，我们使用体外方法来检查PTU或LID处理的大鼠甲状腺中GJIC是否受到抑制。此外，研究了这些甲状腺功能减退模型对甲状腺滤泡细胞增殖和凋亡的影响，以确定GJIC与细胞内稳态之间的关联。在PTU或LID治疗14天（饮用水中加1% KClO4）后，PTU和LID处理的大鼠血清三碘甲状腺原氨酸（T3）和甲状腺素（T4）降至几乎无法检测的水平，血清促甲状腺激素（TSH）升高。在同一时间点，PTU和LID处理的大鼠GJIC降低了30-35%，而两个治疗组的甲状腺滤泡细胞增殖增加了近三倍。有趣的是，两个甲状腺功能减退治疗组的细胞凋亡均增加了两倍。这些数据表明，PTU或LID治疗在甲状腺滤泡细胞增殖和凋亡增加的状态下抑制甲状腺GJIC。虽然增殖增加是预期的，但甲状腺滤泡细胞中GJIC降低时细胞凋亡的反常增加值得进一步研究。
