Liver glutathione S ‐transferase α expression is decreased by 3,5,3′‐triiodothyronine in hypothyroid but not in euthyroid mice

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.