Thyroid hormone inhibitors

Van Beeren HC, Jong WMC, Kaptein E et al (2003) Dronedarone acts as a selective inhibitor of 3,5,3 -triiodothyronine binding to thyroid hormone receptor-a. in vitro and in vivo evidence. Endocrinology 144 552-558... 

Barres BA, Lazar MA, Raff MC 1994 A novel role for thyroid hormone, glucocorticoids and retinoic acid in timing oligodendrocyte development. Development 120 1097-1108 deNooij JC, Letendre MA, Hariharan IK 1996 A cyclin-dependent kinase inhibitor, Dacapo, is necessary for timely exit from the cell cycle during Drosophila embryogenesis. Cell 87 ... 

The answers are 450-a, 451-b, 452-b. (Katzung, p 652. Hardman, pp 1397—1406.) Agents that can interfere directly or indirectly with the synthesis of thyroid hormone are called thyroid inhibitors. Perchlorate, an ionic inhibitor, interferes with the ability of the thyroid to concentrate F by acting as a competitive inhibitor. It is used in patients with iodide-induced hypothyroidism, such as can occur with the antiarrhythmic agent amio-darone. 

Z)-2,3-Methanothyronine 59 and its dibromo derivative 60 have comparable activity with the thyroxine 61, a thyroid hormone [66], which exhibited thyro-mimetic activities in basal metabolism and antigoiter tests (comparison of oxygen consumption and heart rate in normal and thyroidectomized rats) but did not have an inhibitory action on the metabolism developed by triiodothyronine [66]. (Z)-2,3-Methanohistidine 62, tested on rat liver, is an effective inhibitor of histidine decarboxylase, Eq. (23) [67]. 

MAO inhibitors, phenothiazines, propafenone, quinidine, quinolones (ciprofloxacin), thioamines, and thyroid hormones. 

Rifampin is known to induce the hepatic microsomal enzymes that metabolize various drugs such as acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, disopyramide, estrogens, hydantoins, mexiletine, quinidine, sulfones, sulfonylureas, theophyllines, tocainide, verapamil, digoxin, enalapril, morphine, nifedipine, ondansetron, progestins, protease inhibitors, buspirone, delavirdine, doxycycline, fluoroquinolones, losartan, macrolides, sulfonylureas, tacrolimus, thyroid hormones, TCAs, zolpidem, zidovudine, and ketoconazole. The therapeutic effects of these drugs may be decreased. 

Levodopa or dopamine agonists produce diverse dyskinesias as a dose-related phenomenon in patients with Parkinson s disease dose reduction reverses them. Chorea may also develop in patients receiving phenytoin, carbamazepine, amphetamines, lithium, and oral contraceptives, and it resolves with discontinuance of the offending medication. Dystonia has resulted from administration of dopaminergic agents, lithium, serotonin reuptake inhibitors, carbamazepine, and metoclopramide and postural tremor from theophylline, caffeine, lithium, valproic acid, thyroid hormone, tricyclic antidepressants, and isoproterenol. 

While they are often prescribed, the lower costs of codeine, ACE inhibitors, beta-blockers, thyroid hormones, calcium blockers, and benzodiazepines keep them off the list of top sales. Conversely, the higher cost of erythropoietins, antineo monoclonal antibodies, angiotensin II antagonists, antiarthritis drugs, and bisphosphonates put them on the list of top sales but not top prescriptions. 

It has been suggested that potassium perchlorate should be used in the treatment of type 1 hyperthyroidism and glucocorticoids in the treatment of type 2 (SEDA-21, 199). Since hypothyroidism due to amiodarone tends to occur in areas in which there is sufficient iodine in the diet, it has been hypothesized that an iodinated organic inhibitor of hormone synthesis is formed and that the formation of this inhibitor is inhibited by perchlorate to a greater extent than thyroid hormone iodination is inhibited, since the iodinated lipids that are thought to be inhibitors require about 10 times more iodide than the hormone. However, there is a high risk of recurrence after treatment with potassium perchlorate, and it can cause serious adverse effects (SED-13,1281). 

Recent investigations of the metabolism of iodothyronines in different tissues especially of the rat have led to the recognition of at least three different iodothyron-ine-deiodinating enzymes [5-8] (Table I). These deiodinases have in common that they are located in the membrane fractions of the tissues and that they are stimulated by sulfhydryl (SH) compounds, especially dithiols [5-8]. However, important differences exist between the specificities and catalytic mechanisms of these enzymes, their tissue distribution, sensitivity to PTU and other inhibitors, and regulation by thyroid hormone [5-8]. The characteristics of the different deiodinases will be discussed in more detail in Sections 2 and 3. 

Thiourea derivatives are known for their anti-thyroid effects due to inhibition of thyroid peroxidase [1], Two thiourea compounds especially, have found wide application in the treatment of patients with hyperthyroidism, i.e., PTU and 2-mer-capto-l-methylimidazole (methimazole). It was soon recognized, however, that while methimazole only blocks thyroid hormone synthesis PTU has an additional effect on thyroid hormone metabolism [13]. These clinical findings have been confirmed in vitro showing that PTU, but not methimazole, is a potent inhibitor of the type I deiodinase [5-8]. Structure-activity studies of thiourea analogues [44,45] have... 

As discussed in previous sections, the stepwise deiodination of T4 is mediated by at least three different enzymes. Deiodination of the outer ring of T4 and reverse T3 is mediated by the type I and II enzymes while deiodination of the inner ring of T4 and T3 is catalysed by the type I and III enzymes. The contribution of the different enzymes to the peripheral production and clearance of T3 and rT3 can be estimated using PTU as a specific inhibitor of the type I deiodinase (for potential pitfalls of this approach, see Section 3.3). Thyroid hormone has a positive effect on the type I and type III enzymes but down-regulates the type II deiodinase. 

In addition to the obvious deactivating role of deiodinases, there has been recent evidence that a relationship exists between regulation of deiodination of thyroid hormones in target cells and the intracellular effects of T4 and T3 on pituitary and hypothalamus function. In the rat pituitary, and probably the human, type-II deiodinase-catalyzed conversion of T4 to T3 is a prerequisite for inhibition of TRH release. rT3, produced from T4 by type-III deiodinase, is a potent inhibitor of type-II deiodinase. In a postulated regulatory circuit, rT3 formed from T4 by type-III deiodinase in surrounding CNS (Central Nervous System) tissue enters the pituitary and inhibits type-II enzyme. The resulting decrease in T3 concentration, in turn, causes an increase in TSH secretion49. 

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