Review articleExtrathyroidal actions of antithyroid thionamides
Introduction
Compounds identified to inhibit thyroid hormone formation are used as antithyroid compounds in the treatment of hyperthyroid patients. Among these drugs, antithyroid compounds having thionamide structures, such as mercaptomethylimidazole (methimazole) are extensively used. The classification and chemical structures of various antithyroid compounds, along with their mechanism of action, have been well documented (Green, 1971). However, during the last three decades reports have been accumulating on extrathyroidal actions of the antithyroid drugs, especially of the thionamide group, causing several undesirable side effects. This review aims at summarizing some important observations following the use of thionamide drugs in animals and humans.
Section snippets
Chemistry and metabolism of known thionamides
Drugs having thionamide structures (Fig. 1) inhibit thyroid functions (Astwood et al., 1945). Mercaptomethylimidazole (methimazole, the active metabolite of carbimazole) and propylthiouracil (PTU) are known as thionamide as well as thiourelene antithyroid drugs, as they contain a specific thiourelene group (Fig. 1). Heterocyclic compounds containing a thiourelene group make up the majority of the known antithyroid agents effective in man. The compounds are concentrated in the thyroid gland. The
Mechanism of antithyroid action of thionamides
The possibility that antithyroid compounds exert their inhibitory effect on thyroid function by blocking thyroid peroxidase (TPO) had been suggested even before there was convincing evidence that peroxidase plays a role in thyroid hormone formation. Although Alexander (1959) could convincingly prove inhibition of iodide peroxidase activity of thyroid gland by thionamide, the mechanism of inhibition was also studied in vitro, using the pure enzyme, by several workers (Taurog, 1970, Nagasaka and
Antithyroid thionamide and lactoperoxidase activity
Lactoperoxidase (LPO) (Pruitt and Tenovuo, 1985), a soluble peroxidase present in mammary gland and secreted in milk is responsible for antibacterial actions (Morrison and Allen, 1966) through oxidation of SCN to OSCN. LPO contributes to the microbiocidal activities of a number of mammalian exocrine gland secretions (Pruitt and Tenovuo, 1985) that protect a variety of mucosal surfaces. In bovine milk, activation of the LPO system in vivo can result in bactericidal activity against Escherichia
Antithyroid thionamide and gastric secretions
Alteration of gastric physiology is one of the remarkable side effects found in animals after MMI treatment, which has been extensively studied. MMI stimulates gastric acid and pepsinogen secretion (Table 1) in rats and mice (Bhattacharjee et al., 1989, Bhattacharjee et al., 1990, Bhattacharjee et al., 1998, Bandyopadhyay et al., 1992, Bandyopadhyay et al., 1993, Bandyopadhyay et al., 1997, Bandyopadhyay et al., 1999). It partially induces gastric acid secretion through the activation of the
Antithyroid thionamide and blood cells and immune function
The major adverse reactions of antithyroid thionamides are hematological dysfunctions and immunosuppression (Haynes, 1990, Weetman et al., 1984, Mezquita et al., 1998, Rojano et al., 1998, Gessl and Waldhausl, 1998, Corrales et al., 1996, Corrales et al., 1997, Escobar-Morreale et al., 1996, Chabernaud et al., 1995, Chabernaud et al., 1996, Mak et al., 1995). Serious hematological complications are aplastic anemia (Escobar-Morreale et al., 1997) and agranulocytosis (Gotoh et al., 1998, Miyasaka
Antithyroid thionamide as substrate for microsomal oxidase
Antithyroid thinamides, particularly MMI, modulate several oxidases by acting as inhibitor or substrate. MMI is known to be oxidized by the FMO system, and this MMI oxidation is used as a marker for this enzyme activity (Poulsen et al., 1974, Jacoby and Ziegler, 1990, Ziegler, 1990). MMI is a better substrate for FMO 1 than for FMO 3 or FMO 5 (Cherrington et al., 1998). MMI, acting as a flavoprotein inhibitor, favors metabolism of several drugs (Kadiyala and Spain, 1998, Le Champion et al., 1997
Antithyroid thionamide and prostaglandin synthase activity
The oxidation of xenobiotics by peroxidases, especially by the hydroperoxidase activity of prostaglandin H synthase, has been proposed as a mechanism for activation of chemical carcinogens, particularly in extrahepatic tissues. MMI inhibits the prostaglandin H synthase-catalyzed oxidation of benzidine, phenylbutazone and aminopyrine (Petry and Eling, 1987). MMI does not inhibit xenobiotic oxidation catalyzed by prostaglandin H synthase through direct interaction with the enzyme, but rather
Antithyroid thionamide and olfactory and auditory system
Methimazole may affect the sense of smell and taste in humans. It binds in the Bowman's glands in the olfactory mucosa and may cause extensive lesions in the olfactory mucosa (Bergman and Brittebo, 1999). Methimazole-induced toxicity in the olfactory mucosa is mediated by a cytochrome P450-dependent metabolic activation of methimazole into reactive metabolites that bind to components of the olfactory mucosa (Bergman and Brittebo, 1999). Methimazole acts as a toxicant to the olfactory system by
Antithyroid thionamide and gene expression
MMI and PTU increase thyroglobulin gene expression and increase thyroid specific mRNA concentration in human thyroid FRTL-5 cells (Leer et al., 1991a, Leer et al., 1991b). MMI can suppress the interferon gamma (IFN-γ)-induced increase in HLA-DR alpha gene expression as a function of time and concentration; MMI simultaneously decreases IFN-γ-induced endogenous antigen presentation by rat FRTL-5 thyrocytes (Montani et al., 1998). Antithyroid thiourelenes are effective in the oral and tropical
Miscellaneous actions of antithyroid thionamides
Antithyroid drugs also lead to other toxic symptoms. They may cause arthritis (Bajaj et al., 1998, Tosum et al., 1995) with pain and stiffness in the joints, urticarial papular rash, paresthesias, headache, nausea and loss or depigmentation of hair (Haynes, 1990, Bartalena et al., 1996). In the MMI-induced hypothyroid state, there is marked alteration of homeostasis of zinc, magnesium and calcium (Simsek et al., 1997). Erythrocyte zinc and calcium concentrations were found to be increased,
Conclusion
Antithyroid thionamides clearly exhibit a number of extrathyroidal actions. Special care should be taken during the medication by these drugs for those who have gastroduodenal ulcer and impaired hematological, immunological, liver and olfactory functions to avoid untoward effects. Future studies should develop antithyroid thionamides devoid of extrathyroidal actions, by suitable modifications of the available compounds.
Acknowledgments
Dr. Uday Bandyopadhyay gratefully acknowledges the receipt of Senior Research Associateship of the Council of Scientific and Industrial Research (CSIR), New Delhi, India, for this work.
References (94)
Iodide peroxidase in rat thyroid and salivary glands and its inhibition by antithyroid compounds
J. Biol. Chem.
(1959)- et al.
Activation of parietal cell by mercaptomethylimidazole—a novel inducer of gastric acid secretion
Biochem. Pharmacol.
(1997) - et al.
Gastric peroxidase and its role in cellular control of gastric acid secretion
- et al.
Methimazole toxicity in rodents: covalent binding in the olfactory mucosa and detection of glial fibrillary acidic protein in the olfactory bulb
Toxicol. Appl. Pharmacol.
(1999) - et al.
Histamine H2-receptor-mediated stimulation of gastric acid secretion by mercaptomethylimidazole
Biochem. Pharmacol.
(1989) - et al.
Dissociation of gastric acid and pepsinogen secretion in response to mercaptomethylimidazole— a new secretory compound
Biochem. Pharmacol.
(1990) - et al.
Inhibition of gastric mucosal prostaglandin synthetase activity by mercaptomethylimidazole—an inducer of gastric acid secretion—plausible involvement of endogenous H2O2
Biochem. Pharmacol.
(1998) - et al.
Lymphoproliferative activity of methimazole: free SH group dependency
Gen. Pharmacol.
(1995) - et al.
Methimazole inhibits peripheral lymphocyte proliferation by inducing S-quiescent phase arrest
Int. J. Immunopharmacol.
(1996) - et al.
Oxidation of caffeine to theobromine and theophyline is catalyzed primarily by flavin-containing monooxygenase in liver microsomes
Biochem. Biophys. Res. Commun.
(1997)
Mechanism of inactivation of thyroid peroxidase by thiourelene drugs
Biochem. Pharmacol.
Characterization of olfactory deficits in the rat following administration of 2,6-dichlorobenzonitrile (dichlobenil), 3,3′iminodipropionitrile, or methimazole
Fundam. Appl. Toxicol.
Elevated CD 69 expression on native peripheral blood T-cells in hyperthyroid Graves’ disease and autoimmune thyroiditis: discordant effect of methimazole on HLA-DR and CD 69
Clin. Immunol. Immunopathol.
Severe malformations in infant born to hyperthyroid woman on methimazole
Lancet
Inactivation of peroxidases of rat bone marrow by repeated administration of propylthiouracil is accompanied by a change in the heme structure
Biochem. Pharmacol.
Methimazole and propylthiouracil increase thyroglobulin gene expression in FRTL-5-cells
Mol. Cell. Endocrinol.
Methimazole increases thyroid specific mRNA concentration in human thyroid cells and FRTL-5-cells
Mol. Cell. Endocrinol.
Methimazole-mediated enhancement of albendazole oral bioavailability and anthelminthic effects against parenteral stages of Trichinella spiralis in mice: the influence of the dose regime
Vet. Parasitol.
Iodide binding and regulation of lactoperoxidase activity toward thyroid goitrogens
J. Biol. Chem.
Reactions of purified hog thyroid peroxidase with H2O2, tyrosine, and methylmercaptoimidazole (goitrogen) in comparison with bovine lactoperoxidase
J. Biol. Chem.
The mechanism for the inhibition of prostaglandin H synthase-catalyzed xenobiotic oxidation by methimazole. Reaction with free radical oxidation products
J. Biol. Chem.
S-oxidation of thiourelenes catalyzed by a microsomal flavoprotein mixed function oxidase
Biochem. Pharmacol.
Interaction of lactoperoxidase with thiols and diiodotyrosine
J. Biol. Chem.
Formation of singlet oxygen by the myeloperoxidase-mediated antimicrobial system
J. Biol. Chem.
Thiocyanate is the major substrate for eosinophil peroxidase in physiologic fluids
J. Biol. Chem.
Thyroid peroxidase and thyroxine biosynthesis
Recent Prog. Horm. Res.
Myeloperoxidase-catalyzed iodination and coupling
Arch. Biochem. Biophys.
Flavin-containing monooxygenases: enzymes adapted for multisubstrate specificity
Trends Pharmacol. Sci.
Severe cholestatic jaundice in uncomplicated hyperthyroidism treated with methimazole
J. Clin. Endocrinol. Metabol.
Further studies on the chemical nature of compounds which inhibit the function of the thyroid gland
Endocrinology
Antithyroid arthritis syndrome
J. Rheumatol.
Localization of gastric peroxidase and its inhibition by mercaptomethylimidazole, an inducer of gastric acid secretion
Biochem. J.
Mechanism-based inactivation of gastric peroxidase by mercaptomethylimidazole
Biochem. J.
Irreversible inactivation of lactoperoxidase by mercaptomethylimidazole through generation of a thiyl radical: its use as a probe to study the active site
Biochem. J.
Role of reactive oxygen species in mercaptomethylimidazole-induced gastric acid secretion and stress-induced gastric ulceration
Curr. Sci.
Gastric peroxidase-localization, catalytic properties and possible role in extrathyroidal thyroid hormone formation
Acta Endocrinol.
Adverse effects of thyroid hormone preparations and antithyroid drugs
Drug Saf.
Effects of methimazole on renal function in cats with hyperthyroidism
J. Am. Anim. Hosp. Assoc.
Massive plasmocytosis due to methimazole-induced bone marrow toxicity
Am. J. Hematol.
Metabolism-dependent toxicity of methimazole in the olfactory nasal mucosa
Pharmacol. Toxicol.
Physiological factors affecting protein expression of flavin-containing monooxygenase 1, 2 and 5
Xenobiotica
Serial analysis of the effects of methimazole therapy on circulating B cell subsets in Graves’ disease
J. Endocrinol.
Methimazole therapy in Graves’ disease influences the abnormal expression of CD 69 (early activation antigen) on T cells
J. Endocrinol.
The irreversible inactivation of thyroid peroxidase by methylmercaptoimidazole, thiouracil and propylthiouracil in vitro and its relationship to in vitro finding
Endocrinology
Thiocyanate, a plausible physiological electron donor of gastric peroxidase
Biochem. J.
Purification, characterization and origin of rat gastric peroxidase
Eur. J. Biochem.
Mechanism-based inhibition of lactoperoxidase by thiocarbamide goitrogens
Biochemistry
Cited by (61)
Overview of Thyroid and Parathyroid Disease—The Endocrinology Perspective
2024, Otolaryngologic Clinics of North AmericaPharmacology of the Thyroid
2022, Comprehensive PharmacologyEffect of thiamazole on kainic acid-induced seizures in mice
2021, Saudi Journal of Biological SciencesDevelopment and validation of a colorimetric method for the quantitative analysis of thioamide derivatives
2019, Spectrochimica Acta - Part A: Molecular and Biomolecular SpectroscopyCitation Excerpt :Thioamide is a functional group with the general structure R-CS-NR′R″. Numerous compounds containing thioamide core have shown diverse biological activities such as antifungal, anti HIV, anti-inflammatory and anti-cancer [1–3]. For example a methimazole is used in humans for the treatment of hyperthyroidism by inhibiting a thyroid enzyme, the thyroid peroxidase [3].