3,5-diiodo-L-thyronine (T-2) has selective thyromimetic effects in vivo and in vitro

Recent data have suggested that the iodothyronine, 3,5-diiodo-l-thyronine (T-2), has selective thyromimetic activity. In vivo, T-2 has been shown to suppress TSH levels at doses that do not produce significant peripheral manifestations of thyroid hormone activity. Furthermore, T-2 has been shown to produce smaller increments in peripheral Indices of thyroid status than does T-3, when doses resulting in equivalent suppression of circulating TSH are compared. We have assessed the selective thyromimetic activity of T-2 in vivo and in vitro, and performed in vitro studies to assess the potential molecular basis for these selective properties. T-2 was 100-fold less potent than T-3 in stimulating GH mRNA levels in GH(3) cells. In contrast, the iodothyronines were almost equivalent in their ability to downregulate TR beta 2 mRNA levels in this cell line. Both 3,3'-diiodo-L-thyronine and thyronine exhibited no significant thyromimetic effects on either process. In vivo, doses of T-2 and T-3 that were equivalent in their induction of hepatic malic enzyme (ME) mRNA did not produce equivalent suppression of circulating TSH, with T-2, being only 27% as effective as T-3. T-2 was up to 500-fold less potent than T-3 in displacing [I-125]-T-3 from in vitro translated specific nuclear receptors (TRs) and GH(3) cell nuclear extracts. Electrophoretic mobility shift assays, assessing the ability of T-2 to produce dissociation of TR beta 1 homodimers from inverted palindrome T-3 response elements, indicated that T-2 was also 1000-fold less potent than T-3 in this respect. These data confirm that T-2 has significant thyromimetic activity, and that this activity is selective both in vivo and in vitro. However, there are no data to support a selective central effect, T-2 being relatively more potent in stimulating hepatic ME mRNA than in suppression of TSH in vivo. The basis for this differential thyromimetic activity is not selective affinity of the different TR isoforms for T-2, or divergent properties of T, in competitive binding and functional assays in vitro.