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Liver glutathione S ‐transferase α expression is decreased by 3,5,3′‐triiodothyronine in hypothyroid but not in euthyroid mice
Author(s) -
Faustino Larissa C.,
Pires Rachel M.,
Lima Ana Claudia,
Cordeiro Aline,
Souza Luana L.,
OrtigaCarvalho Tânia M.
Publication year - 2011
Publication title -
experimental physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.925
H-Index - 101
eISSN - 1469-445X
pISSN - 0958-0670
DOI - 10.1113/expphysiol.2011.058172
Subject(s) - euthyroid , triiodothyronine , endocrinology , medicine , biology , thyroid
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.