Structure-Activity Relationships of Inhibition of Hepatic Monodeiodination of Thyroxine to 3,5,3′-Triiodothyronine by Thiouracil and Related Compounds*

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Abstract
We have compared the relative potencies of various thiouracils (TUs) and related compounds in inhibition of 5′-monodeiodination of T4 to T3 by rat liver homogenate. T4 (2.5 (μM) was incubated with 0.13 geq liver homogenate in 0.1 M Tris buffer (pH 7.4) for 30 min in the presence or absence of various test agents, and the amount of T3 produced was quantitated by a specific RIA. Thiourea, thiobarbiturate (2-thiobarbituric acid), imidazoles and imidazolines (2-thiohydantoin, 2,4-dihydroxy-5- thiohydantoin, and 2-mercaptoimidazole), and thiopyrimidines (4-mercaptopyrimidine and 2,4-hydroxy-5-thiopyrimidine) had 3% or less of the activity of 2-TU. Among TU derivatives, 5-iodo-2-TU was the most active agent, with about a 30-fold greater inhibiting activity (on a molar basis) than 2-TU. 6-N-propyl TU (PTU) exhibited 2.5 times the inhibiting activity of TU, whereas 6-carbethoxy-2-TU had 1.4 times the activity, and others followed in descending order: 5-N-butyl-6-methyl-TU (1.3 times), 4-hydroxy-6-methyl-TU (0.4 times), 5-carbethoxy-2-TU (0.4 times), 6-methyl-TU (0.29 times), and 5-carboxy-2-TU (0.19 times). The kinetics of hepatic 5′-monodeiodination of T4 (to T3) in the presence or absence of 2-TU and 5-iodo-2-TU suggested that these agents are noncompetitive inhibitors of the monodeiodination. The various data suggested that: 1) the thiourea group of TU by itself is not sufficient to inhibit extrathyroidal conversion of T4 to T3 (thiourea and thiobarbituric acid, which have this group, were essentially inactive); and 2) inhibition of the conversion is produced by a compound containing the thiourea moiety in a six-member ring structure. The inhibition is markedly enhanced by substitution of a multiple member carbon (e.g. a propyl or a butyl) chain at position 5 or 6 or an iodine at position 5. On the other hand, the inhibition is impaired by substitution of a carboxy or a carbethoxy group at position 5 or a methyl group at position 6. The status of the oxidation of the sulfhydryl group of the thiourea or that of the ketone group at position 4 has little impact on inhibitory potency.