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-thyron ine (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 o f thyroid status than does T-3, when doses resulting in equivalent sup pression of circulating TSH are compared. We have assessed the selecti ve thyromimetic activity of T-2 in vivo and in vitro, and performed in vitro studies to assess the potential molecular basis for these selec tive 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 al most equivalent in their ability to downregulate TR beta 2 mRNA levels in this cell line. Both 3,3'-diiodo-L-thyronine and thyronine exhibit ed no significant thyromimetic effects on either process. In vivo, dos es of T-2 and T-3 that were equivalent in their induction of hepatic m alic enzyme (ME) mRNA did not produce equivalent suppression of circul ating 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 ex tracts. Electrophoretic mobility shift assays, assessing the ability o f T-2 to produce dissociation of TR beta 1 homodimers from inverted pa lindrome 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 se lective central effect, T-2 being relatively more potent in stimulatin g hepatic ME mRNA than in suppression of TSH in vivo. The basis for th is differential thyromimetic activity is not selective affinity of the different TR isoforms for T-2, or divergent properties of T, in compe titive binding and functional assays in vitro.