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Characteristics and Thyroid State-Dependent Regulation of Iodothyronine Deiodinases in Pigs

Department of Internal Medicine (F.W.J.S.W, G.G.J.M.K, E.K., W.K., T.J.V.) and Department of Experimental Cardiology (D.J.D.), Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: George Kuiper, Department of Internal Medicine, Room Ee 502, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail: g.kuiper{at}erasmusmc.nl.

Three iodothyronine deiodinases (D1, D2, and D3) regulate local and systemic availability of thyroid hormone. D1 and D2 activate the prohormone T₄ to the thyromimetic T₃, and D3 inactivates T₄ and T₃ to rT₃ and 3,3'-diiodothyronine, respectively. The expression of the three deiodinases is tightly regulated with regard to developmental stage and cell type to provide fine tuning of T₃ supply to target cells. Most studies regarding distribution and regulation of deiodinases have been carried out in rodents. However, in different respects, rodents do not seem to be the optimal experimental model for human thyroid hormone physiology. For instance, D2 expression has been observed in human thyroid and skeletal muscle but not in these tissues in rodents. In this study, we have explored the pig as an alternative model. Porcine D1, D2, and D3 were cloned by RT-PCR, and their catalytic properties were shown to be virtually identical to those reported for human and rodent deiodinases. The tissue distribution of deiodinases was studied in normal pigs and in pigs made hypothyroid by methimazole treatment or in pigs made hyperthyroid by T₄ treatment. D1 activity in liver and kidney was increased in T₄-treated pigs. D2 activities in cerebrum and pituitary were decreased after T₄ treatment and strongly increased after methimazole treatment. Remarkably, D2 activity in thyroid and skeletal muscle was induced in hypothyroid pigs. Significant expression of D3 was observed in cerebrum and was positively regulated by thyroid state. In conclusion, the pig appears to be a valuable model for human thyroid hormone physiology. The expression of D2 activity in thyroid and skeletal muscle is of particular interest for studies on the importance of this enzyme in (hypothyroid) humans.

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