In vivo formation of diiodotyrosine by extrathyroidal thyroxine ether-link cleavage and effects of mononitrotyrosine on this pathway in the rat.
The formation of DIT from T4 was quantitatively studied in thyroidectomized (T) rats given 16 micrograms synthetic T4 daily. Measurement of the elimination of radioiodinated DIT and T4 tracers from serum yielded MCRs of 19.0 ml/h X 100 g body weight for DIT and 0.65 ml/h X 100 g body weight for T4. Mean serum concentrations +/- SD (nanomoles per liter; n = 8) measured by RIA 24 and 48 h after the last T4 administration were as follows: DIT, 0.243 +/- 0.130 and 0.150 +/- 0.070, respectively; T4, 173 +/- 34 and 97 +/- 20, respectively. In T rats which had not received T4, DIT and iodothyronines in serum were undetectable. From the results of kinetic studies and RIA measurements, the fraction of circulating T4 converted to DIT was calculated to be 3.9-4.3%. After administration of the iodotyrosine inhibitor 3-nitro-L-tyrosine (MNT) to T4-treated T rats at a dosage of 50 mumol/day for 1 week or longer, it was possible to observe, on the one hand, the expected delay of DIT tracer elimination from serum resulting in a decreased MCR of 9.9 ml/h X 100 g body weight. On the other hand, MNT treatment led to a strong decline of DIT serum levels below the detection limit in all animal groups. This effect of MNT on the peripheral T4-to-DIT conversion requires further studies using other experimental systems for confirmation and elucidation of its mechanism. It is concluded that peripheral DIT formation in the animal model used occurs via ether-link cleavage of administered T4 and/or some of its iodothyronine metabolites. On the basis of data from recent studies, the peripheral DIT turnover resulting from iodothyronine degradation can be estimated to be about 35% in intact rats. Our data confirm the in vivo generation of extrathyroidal DIT from T4 in the rat. Although the experiments were performed at unphysiologically high T4 serum levels and our quantitative data, therefore, cannot be applied to euthyroid conditions with absolute certainty, the results suggest that ether-link cleavage of T4 yielding DIT is not an insignificant pathway of peripheral T4 metabolism in the rat.
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Meinhold
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Buchholz
D000818:Animals; D004105:Diiodotyrosine / Q000097:blood*; D005260:Female; D008657:Metabolic Clearance Rate; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D013965:Thyroidectomy; D013974:Thyroxine / Q000097:blood* / Q000494:pharmacology; D014284:Triiodothyronine / Q000097:blood; D014285:Triiodothyronine, Reverse / Q000097:blood; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D014284:Triiodothyronine; C002744:3-nitrotyrosine; D014443:Tyrosine; D014285:Triiodothyronine, Reverse; D004105:Diiodotyrosine; D013974:Thyroxine