Laboratório de Endocrinologia Molecular, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Exp Physiol. 2011 Aug;96(8):790-800. doi: 10.1113/expphysiol.2011.058172. Epub 2011 May 6.
As previously reported, the activity of liver glutathione S-transferases, an important family of enzymes for detoxification processes, is regulated by thyroid hormone levels. Here, we specifically studied glutathione S-transferase α (Gsta) gene expression in livers of mice. First, in wild-type (WT) mice, hypothyroidism was induced by 5 weeks of a diet containing 5-propyl-2-thiouracil plus water containing metimazole, whereas hyperthyroidism was induced by daily injections of 50 μg (100 g body weight)(-1) of 3,3, 5-triiodo-L-thyronine (L-T(3)) for 15 days. Importantly, hypothyroidism induced liver Gsta mRNA (>500%) and protein levels (70%; P < 0.01), indicating an important role of baseline thyroid hormone levels to repress this gene; however, surprisingly, no differences were seen in hyperthyroid mice. To further investigate Gsta repression by T(3), we used animals expressing a naturally occurring mutation of the gene for thyroid hormone receptor (TR)-β (Δ337T), which prevents T(3) binding and causes a general resistance to thyroid hormone. At baseline, homozygous animals showed increased Gsta levels (mRNA 3.5 times, protein 1.3 times) similar to those found in hypothyroid animals. After a T(3) suppression test, we found a blunted response of liver Gsta after the lower doses of T(3) in homozygous animals, as expected. However, after the highest dose of T(3), we observed a decrease in Gsta expression (80%), similar to normal animals, explained by a higher expression of TR-α1 (60%; P < 0.01) and a lower expression of Src1 (steroid coactivator receptor) in the mutant animals (50% decrease). In summary, a decrease in Gsta expression caused by T(3) was observed only in the hypothyroid state. In addition, an essential role of TR-β1 is to mediate Gsta suppression in response to T(3) and, in the absence of a functional TR-β, there is a compensatory action of TR-α1 that depends on low levels of Src1.
如前所述，肝脏谷胱甘肽 S-转移酶（ GSTs）的活性是解毒过程中的一个重要酶家族，其受到甲状腺激素水平的调节。在这里，我们专门研究了小鼠肝脏中的谷胱甘肽 S-转移酶α（ Gsta ）基因表达。首先，在野生型（ WT ）小鼠中，通过 5 周的含有 5-丙基-2-硫代尿嘧啶和甲巯咪唑的水的饮食诱导甲状腺功能减退症，而通过每天注射 50μg（ 100g 体重）（-1）的 3,3,5-三碘-L-甲状腺素（ L-T （ 3 ））诱导甲状腺功能亢进症 15 天。重要的是，甲状腺功能减退症诱导肝 Gsta mRNA （ > 500％）和蛋白水平（ 70％； P < 0.01 ）升高，表明基础甲状腺激素水平对抑制该基因具有重要作用；然而，令人惊讶的是，在甲状腺功能亢进症小鼠中未见差异。为了进一步研究 T （ 3 ）对 Gsta 的抑制作用，我们使用表达甲状腺激素受体（ TR ）-β（ Δ337T ）天然突变的动物，该突变阻止 T （ 3 ）结合并导致对甲状腺激素的普遍抗性。在基线时，纯合动物表现出 Gsta 水平升高（ mRNA 升高 3.5 倍，蛋白升高 1.3 倍），类似于甲状腺功能减退症动物。在 T （ 3 ）抑制试验后，我们发现预期在纯合动物中较低剂量 T （ 3 ）后肝 Gsta 的反应减弱。然而，在用最高剂量的 T （ 3 ）处理后，我们观察到 Gsta 表达降低（ 80％），类似于正常动物，这是由于突变动物中 TR-α1 的表达增加（ 60％； P < 0.01 ）和 Src1 的表达降低（ 50％降低）。总之，仅在甲状腺功能减退症状态下观察到 T （ 3 ）引起的 Gsta 表达降低。此外， TR-β1 的一个基本作用是介导对 T （ 3 ）的 Gsta 抑制，并且在缺乏功能性 TR-β的情况下，存在依赖于低水平 Src1 的 TR-α1 的代偿作用。
