Extrathyroidal actions of antithyroid thionamides

doi:10.1016/S0378-4274(01)00539-2

Toxicology Letters

Volume 128, Issues 1–3, 10 March 2002, Pages 117-127

Dedicated to the late Philip Chambers

https://doi.org/10.1016/S0378-4274(01)00539-2 Get rights and content

Abstract

Some compounds having thionamide structure inhibit thyroid functions. Such antithyroid thionamides include mercaptomethylimidazole (methimazole), thiourea and propylthiouracil, of which mercaptomethylimidazole is widely used to treat hyperthyroidism. Undesirable side effects develop from these drugs due to extrathyroidal actions. Antithyroid thionamides inhibit lactoperoxidase which contributes to the antibacterial activities of a number of mammalian exocrine gland secretions that protect a variety of mucosal surfaces. These drugs stimulate both gastric acid and pepsinogen secretions, thereby augmenting the severity of gastric ulcers and preventing wound healing. Increased gastric acid secretion is partially due to the H₂ receptor activation, and also through the stimulation of the parietal cell by intracellular generation of H₂O₂ following inactivation of the gastric peroxidase–catalase system. Severe abnormalities may develop in blood cells and the immune system after thionamide therapy. It causes agranulocytosis, aplastic anemia, and purpura along with immune suppression. Olfactory and auditory systems are also affected by these drugs. Thionamide affects the sense of smell and taste and also causes loss of hearing. It binds to the Bowman's glands in the olfactory mucosa and causes extensive lesion in the olfactory mucosa. Thionamides also affect gene expression and modulate the functions of some cell types. A brief account of the chemistry and metabolism of antithyroid thionamides, along with their biological actions are presented.

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.

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Review articleExtrathyroidal actions of antithyroid thionamides

Abstract

Introduction

Section snippets

Chemistry and metabolism of known thionamides

Mechanism of antithyroid action of thionamides

Antithyroid thionamide and lactoperoxidase activity

Antithyroid thionamide and gastric secretions

Antithyroid thionamide and blood cells and immune function

Antithyroid thionamide as substrate for microsomal oxidase

Antithyroid thionamide and prostaglandin synthase activity

Antithyroid thionamide and olfactory and auditory system

Antithyroid thionamide and gene expression

Miscellaneous actions of antithyroid thionamides

Conclusion

Acknowledgments

J. Biol. Chem.

Biochem. Pharmacol.

Toxicol. Appl. Pharmacol.

Biochem. Pharmacol.

Biochem. Pharmacol.

Biochem. Pharmacol.

Gen. Pharmacol.

Int. J. Immunopharmacol.

Biochem. Biophys. Res. Commun.

Biochem. Pharmacol.

Fundam. Appl. Toxicol.

Clin. Immunol. Immunopathol.

Lancet

Biochem. Pharmacol.

Mol. Cell. Endocrinol.

Mol. Cell. Endocrinol.

Vet. Parasitol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Recent Prog. Horm. Res.

Arch. Biochem. Biophys.

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

Review article
Extrathyroidal actions of antithyroid thionamides