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Extrathyroidal actions of antithyroid thionamides
Toxicology Letters 128 (2002) 117– 127 www.elsevier.com/locate/toxlet
Review article
Extrathyroidal actions of antithyroid thionamides Uday Bandyopadhyay, Kausik Biswas, Ranajit K. Banerjee * Department of Physiology, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Jada6pur, Calcutta 700 032, India Dedicated to the late Philip Chambers
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. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Antithyroid thionamides; Peroxidases; Gastric secretions; Blood cells and immune suppression; Flavin monooxygenase; Prostaglandin synthase
1. Introduction Compounds identified to inhibit thyroid hormone formation are used as antithyroid compounds in the treatment of hyperthyroid patients. Among these drugs, antithyroid compounds hav* Corresponding author. Tel.: + 91-33-473-3491; fax: + 9133-473-0284. E-mail address: [email protected] (R.K. Banerjee).
ing 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 sum-
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marizing some important observations following the use of thionamide drugs in animals and humans.
2. 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 half-life of mercaptomethylimidazole (MMI) in plasma has been estimated to be between 6 and 13 h. The drug crosses the placenta and may also be found in milk; therefore, woman taking such drugs should not breast-feed their infants. Approximately 40% of MMI is excreted in urine as a polar metabolite (Marchant and Alexander, 1972). The polar metabolite has not been fully characterized, but its properties are different from those of MMI, inorganic sulfate or the glucuronic acid conjugate
Fig. 1. Structure of known thionamides.
of MMI. In addition to this metabolite, small amounts of sulfate are also excreted in urine after the administration of 35S-labeled MMI. Studies on the tissue distribution of thiourelene metabolites have shown that the thyroid gland contains the highest amounts of inorganic sulfate produced by the metabolism of MMI (Marchant and Alexander, 1972). Sulfate is formed from the thiourelene structure by an oxidative attack on the sulfur atom, followed by hydrolytic cleavage to inorganic sulfate (Marchant and Alexander, 1972). The concentration of metabolites per gram of tissue is higher in liver than in plasma, or in tissues other than the thyroid (Marchant and Alexander, 1972). The oxidation of thiourelene is catalyzed by a mixed function oxidase, known as flavin monooxygenase (FMO) (Ziegler, 1990), in the microsomal fraction of liver (Poulsen et al., 1974). The oxidation products obtained with MMI suggest that the thiourelene is oxidized to the sulfinate and then hydrolyzed to sulfite and N-methylimidazole. The formation of the sulfinates requires incorporation of two atoms of oxygen; the addition of the second oxygen could occur through disproportionation or by enzyme action.
3. 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 Hidaka, 1976). Thionamide inhibits the TPO-catalyzed iodination reaction as well as the oxidation of guaiacol, and the inhibition is either reversible or irreversible, depending on the drug to iodide ratio in the assay system. When this ratio is high, the inactivation is irreversible, and when the ratio is low it is re-
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versible (Taurog, 1976). The irreversible inactivation of TPO by thionamide in presence of H2O2 could also be prevented by I− or SCN− (Davidson et al., 1978). The initial in vivo action of these drugs is due to the block of iodination mediated through trapping of the oxidized form of iodide by the drugs (Taurog, 1976). Spectrophotometric data indicate that inactivation of TPO by MMI and PTU involves a reaction between the drugs and the oxidized heme group produced by interaction between TPO and H2O2 (Engler et al., 1982). In stopped flow experiments with purified hog TPO, MMI accelerated the conversion of compound I to compound II followed by its reaction with the latter to an inactive form which is spectrophotometrically discernible (Ohtaki et al., 1982).
4. 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 coli, without killing lactobacilli. A new dimension to LPO activity has been added by reports on interaction of LPO with sIgA. This combination can significantly enhance the antimicrobial effect of LPO against S. mutans (Tenovuo et al., 1982). MMI irreversibly inactivates the enzyme, and iodide protects the inactivation, favoring oxidation of MMI (Michot et al., 1979). The effect of MMI on the first phase of reaction of LPO with H2O2 was studied spectrophotometrically by the stopped flow technique (Ohtaki et al., 1982). The results indicated that accumulation of compound I was very small during the conversion from the ferric enzyme to compound II in the presence of MMI. This indicates that the conversion of compound I to com-
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Fig. 2. ESR spectra of DMPO– MMI thiyl radical adduct. ESR measurements were carried out in a Varian E-104 spectrometer equipped with a TM110 microwave cavity and an aqueous flat cell. (A) ESR spectrum was obtained with 13 mM LPO, 10 mM MMI, 400 mM H2O2 and 1 mM DETAPAC in 50 mM Tris – HCl buffer, pH 8.0 containing 90 mM DMPO in a final volume of 1 ml. (B) as for A but in the absence of H2O2. (C) as for A but in absence of LPO.
pound II is markedly accelerated by MMI. Compound II was then converted to an MMIcomplex in a similar manner as reported with other thiourelene and thiol compounds (Ohtaki et al., 1982; Michot et al., 1979; Nakamura et al., 1984; Pommier and Cahnmann, 1979). The spectral characteristics of the LPO–MMI adduct have been extensively studied, and the product has been designated as sulflactoperoxidase (Nakamura et al., 1984). Experimental support is also available for a mechanism-based inhibition of LPO by thiocarbamide goitrogen (Doerge, 1986). The inactivation was presumed to be due to covalent interaction of the compound with the enzyme as previously shown for MMI-modified TPO (Engler et al., 1982). S-Oxygenation reactions catalyzed by LPO (Doerge, 1991) provided a rationale for the suicide inactivation of LPO by sulfur-containing compounds in the presence of H2O2. A mechanism of heme modification by active site produced formamidine sulfenic acid from the Soxygenation of thiocarbomides by LPO compound II is consistent with the chemistry of these compounds. A direct evidence that MMI acts as a suicidal substrate to irreversibly inactivate LPO through the generation of a thiyl radical in LPO– H2O2 system has been provided (Bandyopadhyay et al., 1995). MMI is oxidized, via one-electron transfer by LPO, and the product, the thiyl radical of MMI (Fig. 2), is incorporated into the
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adjacent electron-rich site of the heme porphyrin to cause inactivation (Bandyopadhyay et al., 1995). Inactivation of LPO by MMI thus seriously affects the antibacterial or bactericidal activity of exocrine secretions containing this enzyme.
5. 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, 1990, 1998; Bandyopadhyay et al., 1992, 1993, 1997, 1999). It partially induces gastric acid secretion through the activation of the histamine H2 receptor of the parietal cell by histamine release (Banerjee et al., 1990), and partially through an intracellular mechanism (Bhattacharjee et al., 1998). MMI-stimulated acid secretion correlates well with the inactivation of gastric peroxidase (GPO), an important H2O2 metabolizing enzyme of the gastric mucosa (Banerjee and Datta, 1981; De and Banerjee, 1986; Bandyopadhyay et al., 1992; Das et al., 1995). MMI inactivates catalytically active GPO by acting as a suicidal substrate (Bandyopadhyay et al., 1993). MMI also activates the parietal cell for acid secretion in vitro (Table 2) which is sensitive to omeprazole (Bandyopadhyay et al., 1997). Peroxidase and catalase activities of the isolated parietal cell are irreversibly inactivated by MMI, thus creating a favorable condition for endogenous accumula-
tion of H2O2 which may act as a second messenger for acid secretion (Bandyopadhyay et al., 1997). MMI also stimulates pepsinogen secretion which could be dissociated from acid secretion by the use of cimetidine and omeprazole which effectively block the acid secretion without affecting the pepsinogen output, indicating that MMI stimulates pepsinogen secretion through a different mechanism (Bhattacharjee et al., 1990).
6. 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, 1997; Escobar-Morreale et al., 1996; Chabernaud et al., 1995, 1996; Mak et al., 1995). Serious hematological complications are aplastic anemia (Escobar-Morreale et al., 1997) and agranulocytosis (Gotoh et al., 1998; Miyasaka et al., 1997; Tajiri et al., 1997; Bartalena et al., 1996), with the appearance of sore throat or fever and sometimes of purpura (Haynes, 1990; Bartalena et al., 1996). Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are two important peroxidases present in polymorphonuclear neutrophils and eosinophils, respectively. They offer unique cellmediated innate immunity against pathogens via phagocytosis (Rosen and Klebanoff, 1977; Slungaard and Mahoney, 1991). These peroxidases in
Table 1 Effect of MMI on gastric secretions in rat and mice Rat
Control Control+MMI
Mice
Acid secretion (total H+, mmol)
Pepsinogen secretion (total unit)
Acid secretion (total H+, mmol)
Pepsinogen secretion (total unit)
22 9 3 61 94*
948 9 130 30859 516*
2.3 9 0.15 20.52 9 1.38*
38.6 93.14 323.5 920.3*
To study the effect of MMI on gastric acid and pepsinogen secretion, MMI (30 mg/kg.b.w for rat, 22 mg/kg.b.w for mice) was administered intraperitoneally and after 2.5 h, gastric fluid was collected for the assay of acid and pepsinogen secretion. * PB0.001 vs. control.
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Table 2 Effect of MMI on activation, acid secretion, peroxidase and catalase activity in isolated parietal cells and gastric glands
Control Control+MMI
O2 consumption (nmole/106 cell/min)
[14C] aminopyrine uptake (CPM)
Peroxidase activity (Units/mg protein)
Catalase activity (O2 evolved nmols/min/mg protein)
9.2 90.3 20.0 91.6*
4509 42 10069 85***
70 98 7 92**
170 9 10 100 9 8*
O2 consumption was monitored in oxygraph by incubating parietal cells (106) in absence or presence of MMI (0.1 mM) as a measure for activation. [14C]aminopyrine uptake (as a measure of acid secretion) was measured in rabbit gastric gland by incubating with 0.1 mM MMI in presence of 1 mCi [14C]aminopyrine for 30 min. For the assay of catalase activity, an aliquot of cell free homogenate was preincubated for 5 min with 100 mM H2O2 in presence of 0.2 mM MMI followed by measurement of O2 evolution in oxygraph after addition of 100 mM H2O2. For peroxidase assay, incubation of cell free homogenate was carried out for 3 min in presence of 0.2 mM MMI and 100 mM H2O2 before assaying an aliquot for peroxidase activity. * PB0.01 vs. control. ** PB0.001 vs. control. *** PB0.02 vs. control.
the phagocytic cells utilize H2O2 to oxidize Cl− and SCN−, to form hypochlorous acid or hypothiocyanite ion, which have very strong bactericidal –antimicrobial activity. Hypochlorous acid (or hypochlorite) is an effective oxidant of sulfhydryl groups in bacterial cells. Hypochlorite will also react with bacterial cell amines and amides. These reactions lead to fragmentation of bacterial proteins and to cell death. Hypochlorous acid also inactivates alpha-1-proteinase inhibitor present in serum. This inactivation allows neutrophil-released proteolytic enzymes to attack bacterial cells. Antithyroid drugs inhibit MPO-mediated hypochlorous acid formation and prevent neutrophil-mediated inactivation of alpha-1proteinase inhibitor with concomitant blockage of proteolytic activity (Ross et al., 1998). The intestinal peroxidase and the estrogen-induced uterine peroxidase (Klebanoff, 1965; Lyttle and Jellinck, 1972) may exert bactericidal and antiparasitic acidity in the intestine (Slungaard and Mahoney, 1991), or are involved in the catabolism of estradiol in the uterus (Lyttle and Jellinck, 1972). Antithyroid thionamides inhibit EPO (Lee et al., 1988), and may affect intestinal defense against bacteria and parasites, and the catabolism of estradiol in the uterus. MMI and propylthiouracil (PTU) inhibit MPO, both reversibly and irreversibly (Taurog and Dorris, 1992), in a manner similar to that previously described for TPO.
Thionamides also in vivo inactivate bone marrow peroxidase by altering the heme structure (Lee et al., 1988). PTU which causes bone marrow depression inhibits both MPO and EPO in vivo (Lee et al., 1988). EPR spectra have indicated that the structure of MPO surrounding the heme iron changes from a rhombic form into an axial one after thionamide treatment (Lee et al., 1988). Also, massive plasmocytosis due to methimazole may be induced by bone marrow toxicity (Breier et al., 2001). Methimazole inhibits MPO activity even at clinical concentrations (Schlaifer et al., 1994). MMI therapy in Graves’ disease influences the abnormal expression of CD 69 (early activation antigen) on T cells (Corrales et al., 1997). The abnormal CD 69 expression is significantly reduced by MMI therapy, and this represents a new effect of this antithyroid drug (Gessl and Waldhausl, 1998). Expression of the low-affinity receptor of IL-2 (CD 25); another early T cell activation marker, is not altered in Graves’ disease, but the binding of IL-2 and IL-6 to T cells exhibits a progressive and parallel increase during the first 30 days of the therapy, which decreases thereafter. Immunosuppressive action of MMI has also been known for a long time, and this is due to inhibition of formation of oxygen radicals by resting and stimulated monocytes (Weetman et al., 1984). The hematological effects of thionamides are shown in Fig. 3.
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7. 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; Walsh Clang and Aleo, 1997; Chung and Cha, 1997; Lopez-Garcia et al., 1998). Formation of a reactive intermediate (an S-oxide) in the metabolism of methimazole by
olfactory microsomal FMO causes damage of the olfactory mucosa (Genter et al., 1995). Methimazole-induced toxicity in the olfactory mucosa is also mediated by a cytochrome P450-dependent metabolic activation of the compound into reactive metabolites that are bound to tissue components (Bergman and Brittebo, 1999).
8. 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
Fig. 3. Hematological actions of thionamides.
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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 inhibits accumulation of the oxidation products of the xenobiotics via reduction of free radical derived metabolites. MMI offers a unique antiinflammatory effect by decreasing the level of blood prostaglandin E2 through inhibition of the peroxidase part of prostaglandin H synthase (Lagorce et al., 1997). MMI also inhibits PG-synthetase activity of the gastric mucosal microsomal fraction and stimulates acid secretion by inhibiting prostaglandin synthesis (Bhattacharjee et al., 1998).
9. 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 causing nearly complete destruction of the olfactory epithelium due to generation of a reactive intermediate (an S-oxide) formed from the oxidation of methimazole by olfactory microsomal FMO (Genter et al., 1995). Carbimazole (2-carbethoxythio-1-methylimidazole) treatment in hyperthyroidism has been reported to cause impairment of taste and olfaction and loss of hearing (Genter, 1998). A structurally similar compound, MMI, also leads to damage of taste and olfaction in humans and is an olfactory toxicant by both oral and intraperitoneal routes in rodents (Genter, 1998). Histopathological evaluation of nasal cavities from rats after treatment with thionamide has revealed olfactory mucosal damage due to the generation of olfactory toxic metabolites via NADPH-dependent system (Gen-
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ter, 1998; Brittebo, 1995) and the transient olfactory deficit is attributed to defective olfactory function (Genter et al., 1996).
10. 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,b). MMI can suppress the interferon gamma (IFN-g)-induced increase in HLA-DR alpha gene expression as a function of time and concentration; MMI simultaneously decreases IFN-g-induced endogenous antigen presentation by rat FRTL-5 thyrocytes (Montani et al., 1998). Antithyroid thiourelenes are effective in the oral and tropical treatment of patients suffering from chronic plaque psoriasis. Following treatment with PTU and MMI, PCNA staining (as a marker of cellular proliferation) in psoriatic epidermis is significantly decreased (Elias et al., 1995). Fas ligand expression is very weak to undetectable in normal thyroid tissue and cultured thyrocytes, whereas it is strong in thionamidetreated glands and cultured thyrocytes (Mitsiades et al., 2000). MMI-treated thyrocytes induce Fasligand dependent apoptosis in cocultured lymphocytes whereas MMI treatment of lymphocytes grown in the absence of thyrocytes have no such effect (Mitsiades et al., 2000). Fas ligand is highly expressed in follicular cells of thyroid glands obtained from thionamide-treated Graves’ patients and may contribute to the immunomodulatory effect of thionamides in this disease (Mitsiades et al., 2000).
11. 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
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alteration of homeostasis of zinc, magnesium and calcium (Simsek et al., 1997). Erythrocyte zinc and calcium concentrations were found to be increased, whereas magnesium concentration was decreased. (Simsek et al., 1997). A report is available for bilateral choanal atresia, hypoplastic nipples and developmental delay in a 3-year-old boy who had been exposed to carbimazole in utero because of maternal Graves’ disease, a rare case of MMI teratogenicity, probably related to first trimester exposure (Wilson et al., 1998). Severe malformations in infants born to hyperthyroid woman after methimazole treatment have been reported (Johnsson et al., 1997). Generalized maculopapular and papular purpuric eruptions are perhaps the most common thionamide-induced reactions (Bartalena et al., 1996). Cutaneous vasculitis after PTU and MMI treatment occurs in 3 –5% of adults (Yarman et al., 1997; Bartalena et al., 1996). Methimazole, by acting as an inhibitor of microsomal FMO, facilitates the bioavailability of albendazole (an anti-helminthic drug) by limiting its oxidation in liver (Lopez-Garcia et al., 1998; Solano et al., 2000). Methimazole affects the liver cell turnover and slows hepatocyte streaming as demonstrated in rats (Oren et al., 1997). Cryofibrinogenemia is a cryopathy with hypersensitivity to cold as the prominent feature. Methimazole therapy is known to develop cryofibrinogenemia (Hasoi et al., 1997). Antithyroid drugs elevate serum creatine kinase (Suzuki et al., 1997) and cause severe pancytopenia during treatment of patients suffering from Graves’ disease (Macia et al., 1997). Pituitary gonadotrophin and prolactin deficiency and testis enlargement in hypothyroid rat have been caused by methimazole (Kimura and Furudate, 1996). Methimazole induces cholestatic liver injury (Arab et al., 1995), mimicking sclerosing cholangitis (Schwab et al., 1996) and aplasia cutis congenita (Vogt et al., 1995). Cats with hyperthyroidism have increased glomeruler filtration rates which decrease after methimazole treatment (Becker et al., 2000). Methimazole causes liver injury characterized by centrilobular necrosis of hepatocytes and an increase in serum alanine transaminase activity in GSH depleted mice (Mizutani et al., 2000). Methimazole also causes acute pancreatitis and parotitis in
a patient with Graves’ disease (Taguchi et al., 1999). 12. 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. Acknowledgements 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 Alexander, N.M., 1959. Iodide peroxidase in rat thyroid and salivary glands and its inhibition by antithyroid compounds. J. Biol. Chem. 234, 1530 – 1533. Arab, D.M., Malatjalian, D.A., Rittmaster, R.S., 1995. Severe cholestatic jaundice in uncomplicated hyperthyroidism treated with methimazole. J. Clin. Endocrinol. Metabol. 80, 1083 – 1085. Astwood, E.B., Bissel, A., Huges, A.M., 1945. Further studies on the chemical nature of compounds which inhibit the function of the thyroid gland. Endocrinology 37, 456 – 481. Bajaj, S., Bell, M.J., Shumak, S., Briones-Urbina, R., 1998. Antithyroid arthritis syndrome. J. Rheumatol. 25, 1235 – 1239. Bandyopadhyay, U., Bhattacharyya, D.K., Chatterjee, R., Banerjee, R.K., 1992. Localization of gastric peroxidase and its inhibition by mercaptomethylimidazole, an inducer of gastric acid secretion. Biochem. J. 284, 305 – 312. Bandyopadhyay, U., Bhattacharyya, D.K., Banerjee, R.K., 1993. Mechanism-based inactivation of gastric peroxidase by mercaptomethylimidazole. Biochem. J. 296, 79 – 84. Bandyopadhyay, U., Bhattacharyya, D.K., Chatterjee, R., Banerjee, R.K., 1995. Irreversible inactivation of lactoperoxidase by mercaptomethylimidazole through generation of a thiyl radical: its use as a probe to study the active site. Biochem. J. 306, 751 – 757.
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Review article
Extrathyroidal actions of antithyroid thionamides Uday Bandyopadhyay, Kausik Biswas, Ranajit K. Banerjee * Department of Physiology, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Jada6pur, Calcutta 700 032, India Dedicated to the late Philip Chambers
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. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Antithyroid thionamides; Peroxidases; Gastric secretions; Blood cells and immune suppression; Flavin monooxygenase; Prostaglandin synthase
1. Introduction Compounds identified to inhibit thyroid hormone formation are used as antithyroid compounds in the treatment of hyperthyroid patients. Among these drugs, antithyroid compounds hav* Corresponding author. Tel.: + 91-33-473-3491; fax: + 9133-473-0284. E-mail address: [email protected] (R.K. Banerjee).
ing 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 sum-
0378-4274/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 4 2 7 4 ( 0 1 ) 0 0 5 3 9 - 2
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marizing some important observations following the use of thionamide drugs in animals and humans.
2. 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 half-life of mercaptomethylimidazole (MMI) in plasma has been estimated to be between 6 and 13 h. The drug crosses the placenta and may also be found in milk; therefore, woman taking such drugs should not breast-feed their infants. Approximately 40% of MMI is excreted in urine as a polar metabolite (Marchant and Alexander, 1972). The polar metabolite has not been fully characterized, but its properties are different from those of MMI, inorganic sulfate or the glucuronic acid conjugate
Fig. 1. Structure of known thionamides.
of MMI. In addition to this metabolite, small amounts of sulfate are also excreted in urine after the administration of 35S-labeled MMI. Studies on the tissue distribution of thiourelene metabolites have shown that the thyroid gland contains the highest amounts of inorganic sulfate produced by the metabolism of MMI (Marchant and Alexander, 1972). Sulfate is formed from the thiourelene structure by an oxidative attack on the sulfur atom, followed by hydrolytic cleavage to inorganic sulfate (Marchant and Alexander, 1972). The concentration of metabolites per gram of tissue is higher in liver than in plasma, or in tissues other than the thyroid (Marchant and Alexander, 1972). The oxidation of thiourelene is catalyzed by a mixed function oxidase, known as flavin monooxygenase (FMO) (Ziegler, 1990), in the microsomal fraction of liver (Poulsen et al., 1974). The oxidation products obtained with MMI suggest that the thiourelene is oxidized to the sulfinate and then hydrolyzed to sulfite and N-methylimidazole. The formation of the sulfinates requires incorporation of two atoms of oxygen; the addition of the second oxygen could occur through disproportionation or by enzyme action.
3. 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 Hidaka, 1976). Thionamide inhibits the TPO-catalyzed iodination reaction as well as the oxidation of guaiacol, and the inhibition is either reversible or irreversible, depending on the drug to iodide ratio in the assay system. When this ratio is high, the inactivation is irreversible, and when the ratio is low it is re-
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versible (Taurog, 1976). The irreversible inactivation of TPO by thionamide in presence of H2O2 could also be prevented by I− or SCN− (Davidson et al., 1978). The initial in vivo action of these drugs is due to the block of iodination mediated through trapping of the oxidized form of iodide by the drugs (Taurog, 1976). Spectrophotometric data indicate that inactivation of TPO by MMI and PTU involves a reaction between the drugs and the oxidized heme group produced by interaction between TPO and H2O2 (Engler et al., 1982). In stopped flow experiments with purified hog TPO, MMI accelerated the conversion of compound I to compound II followed by its reaction with the latter to an inactive form which is spectrophotometrically discernible (Ohtaki et al., 1982).
4. 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 coli, without killing lactobacilli. A new dimension to LPO activity has been added by reports on interaction of LPO with sIgA. This combination can significantly enhance the antimicrobial effect of LPO against S. mutans (Tenovuo et al., 1982). MMI irreversibly inactivates the enzyme, and iodide protects the inactivation, favoring oxidation of MMI (Michot et al., 1979). The effect of MMI on the first phase of reaction of LPO with H2O2 was studied spectrophotometrically by the stopped flow technique (Ohtaki et al., 1982). The results indicated that accumulation of compound I was very small during the conversion from the ferric enzyme to compound II in the presence of MMI. This indicates that the conversion of compound I to com-
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Fig. 2. ESR spectra of DMPO– MMI thiyl radical adduct. ESR measurements were carried out in a Varian E-104 spectrometer equipped with a TM110 microwave cavity and an aqueous flat cell. (A) ESR spectrum was obtained with 13 mM LPO, 10 mM MMI, 400 mM H2O2 and 1 mM DETAPAC in 50 mM Tris – HCl buffer, pH 8.0 containing 90 mM DMPO in a final volume of 1 ml. (B) as for A but in the absence of H2O2. (C) as for A but in absence of LPO.
pound II is markedly accelerated by MMI. Compound II was then converted to an MMIcomplex in a similar manner as reported with other thiourelene and thiol compounds (Ohtaki et al., 1982; Michot et al., 1979; Nakamura et al., 1984; Pommier and Cahnmann, 1979). The spectral characteristics of the LPO–MMI adduct have been extensively studied, and the product has been designated as sulflactoperoxidase (Nakamura et al., 1984). Experimental support is also available for a mechanism-based inhibition of LPO by thiocarbamide goitrogen (Doerge, 1986). The inactivation was presumed to be due to covalent interaction of the compound with the enzyme as previously shown for MMI-modified TPO (Engler et al., 1982). S-Oxygenation reactions catalyzed by LPO (Doerge, 1991) provided a rationale for the suicide inactivation of LPO by sulfur-containing compounds in the presence of H2O2. A mechanism of heme modification by active site produced formamidine sulfenic acid from the Soxygenation of thiocarbomides by LPO compound II is consistent with the chemistry of these compounds. A direct evidence that MMI acts as a suicidal substrate to irreversibly inactivate LPO through the generation of a thiyl radical in LPO– H2O2 system has been provided (Bandyopadhyay et al., 1995). MMI is oxidized, via one-electron transfer by LPO, and the product, the thiyl radical of MMI (Fig. 2), is incorporated into the
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adjacent electron-rich site of the heme porphyrin to cause inactivation (Bandyopadhyay et al., 1995). Inactivation of LPO by MMI thus seriously affects the antibacterial or bactericidal activity of exocrine secretions containing this enzyme.
5. 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, 1990, 1998; Bandyopadhyay et al., 1992, 1993, 1997, 1999). It partially induces gastric acid secretion through the activation of the histamine H2 receptor of the parietal cell by histamine release (Banerjee et al., 1990), and partially through an intracellular mechanism (Bhattacharjee et al., 1998). MMI-stimulated acid secretion correlates well with the inactivation of gastric peroxidase (GPO), an important H2O2 metabolizing enzyme of the gastric mucosa (Banerjee and Datta, 1981; De and Banerjee, 1986; Bandyopadhyay et al., 1992; Das et al., 1995). MMI inactivates catalytically active GPO by acting as a suicidal substrate (Bandyopadhyay et al., 1993). MMI also activates the parietal cell for acid secretion in vitro (Table 2) which is sensitive to omeprazole (Bandyopadhyay et al., 1997). Peroxidase and catalase activities of the isolated parietal cell are irreversibly inactivated by MMI, thus creating a favorable condition for endogenous accumula-
tion of H2O2 which may act as a second messenger for acid secretion (Bandyopadhyay et al., 1997). MMI also stimulates pepsinogen secretion which could be dissociated from acid secretion by the use of cimetidine and omeprazole which effectively block the acid secretion without affecting the pepsinogen output, indicating that MMI stimulates pepsinogen secretion through a different mechanism (Bhattacharjee et al., 1990).
6. 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, 1997; Escobar-Morreale et al., 1996; Chabernaud et al., 1995, 1996; Mak et al., 1995). Serious hematological complications are aplastic anemia (Escobar-Morreale et al., 1997) and agranulocytosis (Gotoh et al., 1998; Miyasaka et al., 1997; Tajiri et al., 1997; Bartalena et al., 1996), with the appearance of sore throat or fever and sometimes of purpura (Haynes, 1990; Bartalena et al., 1996). Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are two important peroxidases present in polymorphonuclear neutrophils and eosinophils, respectively. They offer unique cellmediated innate immunity against pathogens via phagocytosis (Rosen and Klebanoff, 1977; Slungaard and Mahoney, 1991). These peroxidases in
Table 1 Effect of MMI on gastric secretions in rat and mice Rat
Control Control+MMI
Mice
Acid secretion (total H+, mmol)
Pepsinogen secretion (total unit)
Acid secretion (total H+, mmol)
Pepsinogen secretion (total unit)
22 9 3 61 94*
948 9 130 30859 516*
2.3 9 0.15 20.52 9 1.38*
38.6 93.14 323.5 920.3*
To study the effect of MMI on gastric acid and pepsinogen secretion, MMI (30 mg/kg.b.w for rat, 22 mg/kg.b.w for mice) was administered intraperitoneally and after 2.5 h, gastric fluid was collected for the assay of acid and pepsinogen secretion. * PB0.001 vs. control.
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Table 2 Effect of MMI on activation, acid secretion, peroxidase and catalase activity in isolated parietal cells and gastric glands
Control Control+MMI
O2 consumption (nmole/106 cell/min)
[14C] aminopyrine uptake (CPM)
Peroxidase activity (Units/mg protein)
Catalase activity (O2 evolved nmols/min/mg protein)
9.2 90.3 20.0 91.6*
4509 42 10069 85***
70 98 7 92**
170 9 10 100 9 8*
O2 consumption was monitored in oxygraph by incubating parietal cells (106) in absence or presence of MMI (0.1 mM) as a measure for activation. [14C]aminopyrine uptake (as a measure of acid secretion) was measured in rabbit gastric gland by incubating with 0.1 mM MMI in presence of 1 mCi [14C]aminopyrine for 30 min. For the assay of catalase activity, an aliquot of cell free homogenate was preincubated for 5 min with 100 mM H2O2 in presence of 0.2 mM MMI followed by measurement of O2 evolution in oxygraph after addition of 100 mM H2O2. For peroxidase assay, incubation of cell free homogenate was carried out for 3 min in presence of 0.2 mM MMI and 100 mM H2O2 before assaying an aliquot for peroxidase activity. * PB0.01 vs. control. ** PB0.001 vs. control. *** PB0.02 vs. control.
the phagocytic cells utilize H2O2 to oxidize Cl− and SCN−, to form hypochlorous acid or hypothiocyanite ion, which have very strong bactericidal –antimicrobial activity. Hypochlorous acid (or hypochlorite) is an effective oxidant of sulfhydryl groups in bacterial cells. Hypochlorite will also react with bacterial cell amines and amides. These reactions lead to fragmentation of bacterial proteins and to cell death. Hypochlorous acid also inactivates alpha-1-proteinase inhibitor present in serum. This inactivation allows neutrophil-released proteolytic enzymes to attack bacterial cells. Antithyroid drugs inhibit MPO-mediated hypochlorous acid formation and prevent neutrophil-mediated inactivation of alpha-1proteinase inhibitor with concomitant blockage of proteolytic activity (Ross et al., 1998). The intestinal peroxidase and the estrogen-induced uterine peroxidase (Klebanoff, 1965; Lyttle and Jellinck, 1972) may exert bactericidal and antiparasitic acidity in the intestine (Slungaard and Mahoney, 1991), or are involved in the catabolism of estradiol in the uterus (Lyttle and Jellinck, 1972). Antithyroid thionamides inhibit EPO (Lee et al., 1988), and may affect intestinal defense against bacteria and parasites, and the catabolism of estradiol in the uterus. MMI and propylthiouracil (PTU) inhibit MPO, both reversibly and irreversibly (Taurog and Dorris, 1992), in a manner similar to that previously described for TPO.
Thionamides also in vivo inactivate bone marrow peroxidase by altering the heme structure (Lee et al., 1988). PTU which causes bone marrow depression inhibits both MPO and EPO in vivo (Lee et al., 1988). EPR spectra have indicated that the structure of MPO surrounding the heme iron changes from a rhombic form into an axial one after thionamide treatment (Lee et al., 1988). Also, massive plasmocytosis due to methimazole may be induced by bone marrow toxicity (Breier et al., 2001). Methimazole inhibits MPO activity even at clinical concentrations (Schlaifer et al., 1994). MMI therapy in Graves’ disease influences the abnormal expression of CD 69 (early activation antigen) on T cells (Corrales et al., 1997). The abnormal CD 69 expression is significantly reduced by MMI therapy, and this represents a new effect of this antithyroid drug (Gessl and Waldhausl, 1998). Expression of the low-affinity receptor of IL-2 (CD 25); another early T cell activation marker, is not altered in Graves’ disease, but the binding of IL-2 and IL-6 to T cells exhibits a progressive and parallel increase during the first 30 days of the therapy, which decreases thereafter. Immunosuppressive action of MMI has also been known for a long time, and this is due to inhibition of formation of oxygen radicals by resting and stimulated monocytes (Weetman et al., 1984). The hematological effects of thionamides are shown in Fig. 3.
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7. 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; Walsh Clang and Aleo, 1997; Chung and Cha, 1997; Lopez-Garcia et al., 1998). Formation of a reactive intermediate (an S-oxide) in the metabolism of methimazole by
olfactory microsomal FMO causes damage of the olfactory mucosa (Genter et al., 1995). Methimazole-induced toxicity in the olfactory mucosa is also mediated by a cytochrome P450-dependent metabolic activation of the compound into reactive metabolites that are bound to tissue components (Bergman and Brittebo, 1999).
8. 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
Fig. 3. Hematological actions of thionamides.
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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 inhibits accumulation of the oxidation products of the xenobiotics via reduction of free radical derived metabolites. MMI offers a unique antiinflammatory effect by decreasing the level of blood prostaglandin E2 through inhibition of the peroxidase part of prostaglandin H synthase (Lagorce et al., 1997). MMI also inhibits PG-synthetase activity of the gastric mucosal microsomal fraction and stimulates acid secretion by inhibiting prostaglandin synthesis (Bhattacharjee et al., 1998).
9. 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 causing nearly complete destruction of the olfactory epithelium due to generation of a reactive intermediate (an S-oxide) formed from the oxidation of methimazole by olfactory microsomal FMO (Genter et al., 1995). Carbimazole (2-carbethoxythio-1-methylimidazole) treatment in hyperthyroidism has been reported to cause impairment of taste and olfaction and loss of hearing (Genter, 1998). A structurally similar compound, MMI, also leads to damage of taste and olfaction in humans and is an olfactory toxicant by both oral and intraperitoneal routes in rodents (Genter, 1998). Histopathological evaluation of nasal cavities from rats after treatment with thionamide has revealed olfactory mucosal damage due to the generation of olfactory toxic metabolites via NADPH-dependent system (Gen-
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ter, 1998; Brittebo, 1995) and the transient olfactory deficit is attributed to defective olfactory function (Genter et al., 1996).
10. 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,b). MMI can suppress the interferon gamma (IFN-g)-induced increase in HLA-DR alpha gene expression as a function of time and concentration; MMI simultaneously decreases IFN-g-induced endogenous antigen presentation by rat FRTL-5 thyrocytes (Montani et al., 1998). Antithyroid thiourelenes are effective in the oral and tropical treatment of patients suffering from chronic plaque psoriasis. Following treatment with PTU and MMI, PCNA staining (as a marker of cellular proliferation) in psoriatic epidermis is significantly decreased (Elias et al., 1995). Fas ligand expression is very weak to undetectable in normal thyroid tissue and cultured thyrocytes, whereas it is strong in thionamidetreated glands and cultured thyrocytes (Mitsiades et al., 2000). MMI-treated thyrocytes induce Fasligand dependent apoptosis in cocultured lymphocytes whereas MMI treatment of lymphocytes grown in the absence of thyrocytes have no such effect (Mitsiades et al., 2000). Fas ligand is highly expressed in follicular cells of thyroid glands obtained from thionamide-treated Graves’ patients and may contribute to the immunomodulatory effect of thionamides in this disease (Mitsiades et al., 2000).
11. 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
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alteration of homeostasis of zinc, magnesium and calcium (Simsek et al., 1997). Erythrocyte zinc and calcium concentrations were found to be increased, whereas magnesium concentration was decreased. (Simsek et al., 1997). A report is available for bilateral choanal atresia, hypoplastic nipples and developmental delay in a 3-year-old boy who had been exposed to carbimazole in utero because of maternal Graves’ disease, a rare case of MMI teratogenicity, probably related to first trimester exposure (Wilson et al., 1998). Severe malformations in infants born to hyperthyroid woman after methimazole treatment have been reported (Johnsson et al., 1997). Generalized maculopapular and papular purpuric eruptions are perhaps the most common thionamide-induced reactions (Bartalena et al., 1996). Cutaneous vasculitis after PTU and MMI treatment occurs in 3 –5% of adults (Yarman et al., 1997; Bartalena et al., 1996). Methimazole, by acting as an inhibitor of microsomal FMO, facilitates the bioavailability of albendazole (an anti-helminthic drug) by limiting its oxidation in liver (Lopez-Garcia et al., 1998; Solano et al., 2000). Methimazole affects the liver cell turnover and slows hepatocyte streaming as demonstrated in rats (Oren et al., 1997). Cryofibrinogenemia is a cryopathy with hypersensitivity to cold as the prominent feature. Methimazole therapy is known to develop cryofibrinogenemia (Hasoi et al., 1997). Antithyroid drugs elevate serum creatine kinase (Suzuki et al., 1997) and cause severe pancytopenia during treatment of patients suffering from Graves’ disease (Macia et al., 1997). Pituitary gonadotrophin and prolactin deficiency and testis enlargement in hypothyroid rat have been caused by methimazole (Kimura and Furudate, 1996). Methimazole induces cholestatic liver injury (Arab et al., 1995), mimicking sclerosing cholangitis (Schwab et al., 1996) and aplasia cutis congenita (Vogt et al., 1995). Cats with hyperthyroidism have increased glomeruler filtration rates which decrease after methimazole treatment (Becker et al., 2000). Methimazole causes liver injury characterized by centrilobular necrosis of hepatocytes and an increase in serum alanine transaminase activity in GSH depleted mice (Mizutani et al., 2000). Methimazole also causes acute pancreatitis and parotitis in
a patient with Graves’ disease (Taguchi et al., 1999). 12. 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. Acknowledgements 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 Alexander, N.M., 1959. Iodide peroxidase in rat thyroid and salivary glands and its inhibition by antithyroid compounds. J. Biol. Chem. 234, 1530 – 1533. Arab, D.M., Malatjalian, D.A., Rittmaster, R.S., 1995. Severe cholestatic jaundice in uncomplicated hyperthyroidism treated with methimazole. J. Clin. Endocrinol. Metabol. 80, 1083 – 1085. Astwood, E.B., Bissel, A., Huges, A.M., 1945. Further studies on the chemical nature of compounds which inhibit the function of the thyroid gland. Endocrinology 37, 456 – 481. Bajaj, S., Bell, M.J., Shumak, S., Briones-Urbina, R., 1998. Antithyroid arthritis syndrome. J. Rheumatol. 25, 1235 – 1239. Bandyopadhyay, U., Bhattacharyya, D.K., Chatterjee, R., Banerjee, R.K., 1992. Localization of gastric peroxidase and its inhibition by mercaptomethylimidazole, an inducer of gastric acid secretion. Biochem. J. 284, 305 – 312. Bandyopadhyay, U., Bhattacharyya, D.K., Banerjee, R.K., 1993. Mechanism-based inactivation of gastric peroxidase by mercaptomethylimidazole. Biochem. J. 296, 79 – 84. Bandyopadhyay, U., Bhattacharyya, D.K., Chatterjee, R., Banerjee, R.K., 1995. Irreversible inactivation of lactoperoxidase by mercaptomethylimidazole through generation of a thiyl radical: its use as a probe to study the active site. Biochem. J. 306, 751 – 757.
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