Kolaja K L, Hood A M, Klaassen C D
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Toxicol Lett. 1999 Jun 1;106(2-3):143-50. doi: 10.1016/s0378-4274(99)00023-5.
Exposure to certain UDP-glucuronosyltransferase (UDP-GT) inducers leads to follicular cell hyperplasia, and ultimately thyroid gland tumors. These compounds decrease thyroid hormones, which increases serum concentrations of thyroid stimulating hormone (TSH). This induction of TSH enhances thyroid-follicular cell proliferation. In addition, treatment with classical goitrogenic compounds, such as propylthiouracil (PTU) and methimazole (MMI), induces TGF-beta1 in thyroid-follicular cells, presumably through increased TSH. In other tissues, increases in TGF-beta1 induce apoptosis, a particular form of programmed cell death. In this experiment, we sought to determine whether the UDP-GT inducers, phenobarbital (PB) and pregnenolone-16alpha-carbonitrile (PCN) modulate thyroid-follicular cell apoptosis. If so, are the induction of apoptosis and TGF-beta1 possibly linked? An additional group of rats treated with the thyroid goitrogen, PTU was included. Male Sprague-Dawley rats were treated with thyroid hormone disrupting doses of PB, PCN, or PTU for 3, 7, 14, 21, 28, 45, or 90 days. In this study, PTU treatment increased apoptosis and TGF-beta1 immunoreactive thyroid-follicular cells. PTU treatment of rats produced both a large increase number of TGF-beta1-positive cells (detected by immunohistochemistry), and apoptotic thyroid-follicular cells (detected by morphology). In PB- and PCN-treated rats, a moderate increase in apoptosis coincided with similar increases in TGF-beta1 immunoreactive thyroid-follicular cells. In summary, PB and PCN increase apoptosis and the percentage of TGF-beta1 positive thyroid-follicular cells. Thus, treatment with UDP-GT-inducing chemicals may increase the expression of TGF-beta1 and apoptosis in the thyroid to compensate for the thyroid hypertrophy and hyperplasia.
接触某些尿苷二磷酸葡萄糖醛酸基转移酶（UDP - GT）诱导剂会导致滤泡细胞增生，并最终引发甲状腺肿瘤。这些化合物会降低甲状腺激素水平，从而增加血清促甲状腺激素（TSH）的浓度。TSH的这种诱导作用会增强甲状腺滤泡细胞的增殖。此外，用经典的致甲状腺肿化合物，如丙硫氧嘧啶（PTU）和甲巯咪唑（MMI）进行治疗，大概是通过增加TSH，从而诱导甲状腺滤泡细胞中的转化生长因子β1（TGF - β1）。在其他组织中，TGF - β1的增加会诱导细胞凋亡，这是一种特定形式的程序性细胞死亡。在本实验中，我们试图确定UDP - GT诱导剂苯巴比妥（PB）和孕烯醇酮 - 16α - 腈（PCN）是否会调节甲状腺滤泡细胞凋亡。如果是这样，细胞凋亡的诱导与TGF - β1之间是否可能存在联系？另外纳入了一组用甲状腺致甲状腺肿药物PTU治疗的大鼠。雄性Sprague - Dawley大鼠接受破坏甲状腺激素剂量的PB、PCN或PTU治疗3、7、14、21、28、45或90天。在本研究中，PTU治疗增加了凋亡以及TGF - β1免疫反应性甲状腺滤泡细胞。用PTU治疗大鼠会使TGF - β1阳性细胞数量大幅增加（通过免疫组织化学检测），同时也会使甲状腺滤泡细胞发生凋亡（通过形态学检测）。在接受PB和PCN治疗的大鼠中，凋亡适度增加，同时TGF - β1免疫反应性甲状腺滤泡细胞也有类似增加。总之，PB和PCN增加了凋亡以及TGF - β1阳性甲状腺滤泡细胞的百分比。因此，用诱导UDP - GT的化学物质进行治疗可能会增加甲状腺中TGF - β1的表达和细胞凋亡，以补偿甲状腺肥大和增生。
