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Deiodination of Thyroid Hormone by Human Liver

Departments of Internal Medicine HI (T.J.V., E.K., E.P.K.), Surgery (O.T.T.), and Nuclear Medicine (E.P.K.), Erasmus University Medical School Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Theo J. Visser, Ph.D., Department of Internal Medicine III, Erasmus University Medical School, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.

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 (K_i, 0.10–0.16 µmol/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.

Received June 18, 1987.

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