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Endocrinology, Vol 125, 424-432, Copyright © 1989 by Endocrine Society

ARTICLES

Metabolism of triiodothyroacetic acid (TA3) in rat liver. I. Deiodination of TA3 and TA3 sulfate by microsomes

M Rutgers, FA Heusdens and TJ Visser
Department of Internal Medicine III, Erasmus University Medical School, Rotterdam, The Netherlands.

The deiodination of the acetic acid side-chain analogs of T3 as well as 3,3'-diiodothyronine (3,3'-T2) was investigated by incubating 125I- labeled 3,3',5-triiodothyroacetic acid (TA3) and 3,3'-diiodothyroacetic acid (3,3'-TA2) with rat liver microsomes at 37 C and pH 7.2 in the presence of 5 mM dithiothreitol. TA3 sulfate (TA3S) and 3,3'-TA2S were also tested as substrate since sulfation is known to accelerate T3 and 3,3'-T2 conversion. Reaction products were analyzed on Sephadex LH-20 and HPLC. TA3 underwent only inner ring deiodination (IRD), but 3,3'- TA2 was equally converted by IRD and outer ring deiodination (ORD). TA3S was metabolized very rapidly by IRD to 3,3'-TA2S which was only observed transiently due to its rapid deiodination predominantly in the outer ring. Kinetic studies under initial reaction rate conditions yielded apparent Michaelis-Menten (Km) values (micromolar) of 1.8 for TA3, 0.8 for 3,3'-TA2, and 0.004 for TA3S, and 0.02 for 3,3'-TA2S and Vmax values (picomoles per min/mg protein) of 174 for TA3, 49 for 3,3'- TA2, 21 for TA3S, and 63 for 3,3'-TA2S. The Vmax/Km ratios for the IRD of TA3 and TA3S were 16 and 930 times higher, respectively, relative to T3. Deiodinations were sensitive to propylthiouracil inhibition, indicating the involvement of the type I iodothyronine deiodinase. Furthermore, the iodothyroacetic acid derivatives competitively inhibited the ORD of rT3 with apparent inhibition constant (Ki) values (0.45 microM for TA3, 4 nM for TA3S, and 0.04 microM for 3,3'-TA2S) in agreement with corresponding Km values. We conclude that 1) TA3 and 3,3'-TA2 are better substrates than T3 and 3,3'-T2 for the type I deiodinase of rat liver; 2) the IRD of TA3 and ORD of 3,3'-TA2 are markedly enhanced by sulfation similar to the parent iodothyronines; and 3) TA3S in the best known substrate for IRD due to its very high affinity for the type I deiodinase.


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C. A. Shepherdley, W. Klootwijk, K. W. Makabe, T. J. Visser, and G. G. J. M. Kuiper
An Ascidian Homolog of Vertebrate Iodothyronine Deiodinases
Endocrinology, March 1, 2004; 145(3): 1255 - 1268.
[Abstract] [Full Text] [PDF]


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