Distribution and Metabolism of L- and DTriiodothyronine (T3) in the Rat: Preferential Accumulation of L-T3by Hepatic and Cardiac Nuclei as a Probable Explanation of the Differential Biological Potency of T3 Enantiomers*

Previous studies have reported markedly lower biological potency of D-T3 than would be predicted from its relative affinity for the specific nuclear L-T3 receptor as measured in vitro. Studies were undertaken to define the basis of this discrepancy. In vitro studies of the relative binding affinities of [125I]L-T3 and [125I]D-T3 using either whole nuclei or partially purified solubilized receptor confirmed several previous reports which had indicated only small relative differences. The mean L/D binding ratio of all in vitro studies was 1.43. In contrast, we determined from measurement of final alpha-glycerophosphate dehydrogenase activity that the potency ratio (L/D) after seven daily injections of graded doses of L- and D-T3 was 6.7 for liver, with 95% confidence limits of 4.1 to 10.8, and 15.9 for heart, with 95% confidence limits of 5.1 to 50.2. Difference in biological potency could not be attributed to differences in the metabolism of L- and D-T3. Thus, tracer [125I]L- and [125I]D-T3 studies showed that the mean residence time, t, of L-T3 was not different from that of D-T3 [10.6 +/- (SE) 3.1 h vs. 11.4 +/- 3.8 h]. The MCR for L-T3 was 19.1 +/- 4.4 ml/h . 100 g BW and for D-T3, 26.1 +/- 5.6 ml/h . 100 g BW. The volume of distribution of L-T3 (181 ml/100 g BW) was 68% that of D-T3 (263 ml/100 g BW), in part owing to the 27% greater plasma binding (bp) of L-T3. Moreover, the calculated free hormone clearance (MCR X bp) of D-T3 was only 8% greater than for L-T3. Throughout the 24 h after injection of the [125I]L- or D-T3, concentrations of the D-enantiomer in liver were almost twice those of [125I]L-T3, whereas in heart [125I]D-T3 concentrations were half or less those of [125I]L-T3. Nevertheless, in both liver and heart, the integrated nuclear occupancy of L-T3 was 5 to 6 times that of D-T3, approaching the ratio in biological potency observed in the tissues. Thus, selective nuclear binding of L-T3 vs. D-T3 in vivo appears to be a major determinant in the relative biological effects of these enantiomers.