Deiodination of thyroid hormone by human liver.
Liver is an important site for the peripheral production of T3 by outer ring deiodination (ORD) of T4 as well as for the clearance of plasma rT3, which is produced by inner ring deiodination (IRD) of T4 in other tissues. However, little is known about the underlying enzymatic reactions, and current concepts about thyroid hormone deiodination are largely based on studies in rat tissue. Here we describe the results of detailed studies of the catalytic properties of the iodothyronine deiodinase activity of human liver. The results demonstrated a high degree of similarity with the type I deiodinase of rat liver. The enzyme activity was found in the microsomal fraction. rT3 was the preferred substrate, since its ORD was catalyzed roughly 400 times more efficiently than the ORD or IRD of T4 or the IRD of T3. The deiodination of sulfated substrates was more rapid, as demonstrated by the roughly 30-fold increase in the IRD of T3 sulfate (T3S) compared with T3. The deiodinations exhibited ping-pong-type kinetics with dithiothreitol as the cofactor. Inhibition by propylthiouracil was uncompetitive with substrate and competitive with dithiothreitol, and PTU was an equally effective inhibitor of the ORD of rT3 and the IRD of T3S (Ki, 0.10-0.16 mumol/L). Various compounds with widely different inhibitory potencies had similar effects on ORD (rT3) and IRD (T3S). These results suggest that in human liver microsomes a single enzyme catalyzes the deiodination of the outer as well as the inner ring of iodothyronines by the same catalytic mechanism and with the same substrate specificity as the type I deiodinase of rat liver.
Visser
T J
TJ
Department of Internal Medicine, Erasmus University Medical School, Rotterdam, The Netherlands.
Kaptein
E
E
Terpstra
O T
OT
Krenning
E P
EP
D001667:Binding, Competitive / Q000187:drug effects; D002384:Catalysis; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007453:Iodide Peroxidase / Q000378:metabolism; D007455:Iodine / Q000378:metabolism*; D007457:Iodine Radioisotopes; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D013379:Substrate Specificity / Q000187:drug effects; D013963:Thyroid Hormones / Q000378:metabolism*; D013997:Time Factors
D007457:Iodine Radioisotopes; D013963:Thyroid Hormones; D007455:Iodine; D007453:Iodide Peroxidase