Bioinorganic Chemistry in Thyroid Gland: Effect of Antithyroid Drugs on Peroxidase-Catalyzed Oxidation and Iodination Reactions

Abstract

Propylthiouracil (PTU) and methimazole (MMI) are the most commonly used antithyroid drugs. The available data suggest that these drugs may block the thyroid hormone synthesis by inhibiting the thyroid peroxidase (TPO) or diverting oxidized iodides away from thyroglobulin. It is also known that PTU inhibits the selenocysteine-containing enzyme ID-1 by reacting with the selenenyl iodide intermediate (E-SeI). In view of the current interest in antithyroid drugs, we have recently carried out biomimetic studies to understand the mechanism by which the antithyroid drugs inhibit the thyroid hormone synthesis and found that the replacement of sulfur with selenium in MMI leads to an interesting compound that may reversibly block the thyroid hormone synthesis. Our recent results on the inhibition of lactoperoxidase (LPO)-catalyzed oxidation and iodination reactions by antithyroid drugs are described.

References

1. A Taurog, “Hormone synthesis: thyroid iodine,” in Werner and Ingbar's the Thyroid, L E Braverman and R D Utiger, Eds., pp. 51–97, Lippincott Williams & Wilkins, Philadelphia, Pa, 1991. View at: Google Scholar
2. A Taurog, M Dorris, and D R Doerge, “Evidence for a radical mechanism in peroxidase-catalyzed coupling. 1. Steady-state experiments with various peroxidases,” Archives of Biochemistry and Biophysics, vol. 315, no. 1, pp. 82–89, 1994. View at: Publisher Site | Google Scholar
3. D R Doerge, A Taurog, and M L Dorris, “Evidence for a radical mechanism in peroxidase-catalyzed coupling. II. Single turnover experiments with horseradish peroxidase,” Archives of Biochemistry and Biophysics, vol. 315, no. 1, pp. 90–99, 1994. View at: Publisher Site | Google Scholar
4. D R Doerge and R L Divi, “Porphyrin $\pi$-cation and protein radicals in peroxidase catalysis and inhibition by anti-thyroid chemicals,” Xenobiotica, vol. 25, no. 7, pp. 761–767, 1995. View at: Google Scholar
5. A Taurog, M L Dorris, and D R Doerge, “Mechanism of simultaneous iodination and coupling catalyzed by thyroid peroxidase,” Archives of Biochemistry and Biophysics, vol. 330, no. 1, pp. 24–32, 1996. View at: Publisher Site | Google Scholar
6. D Behne, A Kyriakopoulos, H Meinhold, and J Köhrle, “Identification of type I iodothyronine $5^{\prime }$-deiodinase as a selenoenzyme,” Biochemical and Biophysical Research Communications, vol. 173, no. 3, pp. 1143–1149, 1990. View at: Publisher Site | Google Scholar
7. M J Berry, L Banu, and P R Larsen, “Type I iodothyronine deiodinase is a selenocysteine-containing enzyme,” Nature, vol. 349, no. 6308, pp. 438–440, 1991. View at: Publisher Site | Google Scholar
8. M J Berry, J D Kieffer, J W Harney, and P R Larsen, “Selenocysteine confers the biochemical properties characteristic of the type I iodothyronine deiodinase,” Journal of Biological Chemistry, vol. 266, no. 22, pp. 14155–14158, 1991. View at: Google Scholar
9. J Köhrle, “Thyroid hormone deiodination in target tissues-a regulatory role for the trace element selenium?” Experimental and Clinical Endocrinology, vol. 102, no. 2, pp. 63–89, 1994. View at: Google Scholar
10. P R Larsen and M J Berry, “Nutritional and hormonal regulation of thyroid hormone deiodinases,” Annual Review of Nutrition, vol. 15, pp. 323–352, 1995. View at: Publisher Site | Google Scholar
11. D L St. Germain and V A Galton, “The deiodinase family of selenoproteins,” Thyroid, vol. 7, no. 4, pp. 655–668, 1997. View at: Google Scholar
12. J Köhrle, “The trace element selenium and the thyroid gland,” Biochimie, vol. 81, no. 5, pp. 527–533, 1999. View at: Publisher Site | Google Scholar
13. A C Bianco, D Salvatore, B Gereben, M J Berry, and P R Larsen, “Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases,” Endocrine Reviews, vol. 23, no. 1, pp. 38–89, 2002. View at: Publisher Site | Google Scholar
14. J Köhrle, “Iodothyronine deiodinases,” Methods in Enzymology, vol. 347, pp. 125–167, 2002. View at: Publisher Site | Google Scholar
15. J Köhrle, “Selenium and the control of thyroid hormone metabolism,” Thyroid, vol. 15, no. 8, pp. 841–853, 2005. View at: Publisher Site | Google Scholar
16. J Köhrle, F Jakob, B Contempré, and J E Dumont, “Selenium, the thyroid, and the endocrine system,” Endocrine Reviews, vol. 26, no. 7, pp. 944–984, 2005. View at: Publisher Site | Google Scholar
17. J L Leonard and T J Visser, “Biochemistry of deiodination,” in Thyroid Hormone Metabolism, G Hennemann, Ed., pp. 189–229, Marcel Dekker, New York, NY, 1986. View at: Google Scholar
18. A Goswami and I N Rosenberg, “Stimulation of iodothyronine outer ring monodeiodinase by dihydrolipoamide,” Endocrinology, vol. 112, no. 4, pp. 1180–1187, 1983. View at: Google Scholar
19. J Buxeraud, A-C Absil, J Claude, C Raby, G Catanzano, and C Beck, “Antithyroid agents: structure-activity relationship. II. Interpretation of mechanism of action by complexation of charge transfer,” European Journal of Medicinal Chemistry, vol. 20, no. 1, pp. 43–50, 1985. View at: Google Scholar
20. C Raby, J-F Lagorce, A-C Jambut-Absil, J Buxeraud, and G Catanzano, “The mechanism of action of synthetic antithyroid drugs: iodine complexation during oxidation of iodide,” Endocrinology, vol. 126, no. 3, pp. 1683–1691, 1990. View at: Google Scholar
21. R Basosi, N Niccolai, and C Rossi, “Coordination behaviour of antithyroid drugs against the Fe(I)${\left(\text{NO}\right)}_2$ group in solution: ESR and FT-NMR study,” Biophysical Chemistry, vol. 8, no. 1, pp. 61–69, 1978. View at: Publisher Site | Google Scholar
22. W-W du Mont, G Mugesh, C Wismach, and P G Jones, “Reactions of organoselenenyl iodides with thiouracil drugs: an enzyme mimetic study on the inhibition of iodothyronine deiodinase,” Angewandte Chemie. International Edition, vol. 40, no. 13, pp. 2486–2489, 2001. View at: Publisher Site | Google Scholar
23. G Roy and G Mugesh, “Chemistry in thyroid gland: iodothyronine deiodinases and anti-thyroid drugs,” Phosphorus, Sulfur and Silicon and the Related Elements, vol. 180, no. 3-4, pp. 891–902, 2005. View at: Publisher Site | Google Scholar
24. G Roy, B K Sarma, P P Phadnis, and G Mugesh, “Selenium-containing enzymes in mammals: chemical perspectives,” Journal of Chemical Sciences, vol. 117, no. 4, pp. 287–303, 2005. View at: Google Scholar
25. T J Visser, E Kaptein, and H Y Aboul-Enein, “Selenouracil derivatives are potent inhibitors of the selenoenzyme type I iodothyronine deiodinase,” Biochemical and Biophysical Research Communications, vol. 189, no. 3, pp. 1362–1367, 1992. View at: Publisher Site | Google Scholar
26. H Y Aboul-Enein, A A Awad, and N M Al-Andis, “Synthesis and the antiperoxidase activity of seleno analogues of the antithyroid drug propylthiouracil,” Journal of Enzyme Inhibition, vol. 7, no. 2, pp. 147–150, 1993. View at: Google Scholar
27. A Taurog, M L Dorris, L J Guziec, and F S Jr Guziec, “The selenium analog of methimazole. Measurement of its inhibitory effect on type I $\mathrm{5\prime }$-deiodinase and of its antithyroid activity,” Biochemical Pharmacology, vol. 48, no. 7, pp. 1447–1453, 1994. View at: Publisher Site | Google Scholar
28. L J Guziec and F S Jr Guziec, “A directed metalation route to the selenium analog of methimazole,” Journal of Organic Chemistry, vol. 59, no. 16, pp. 4691–4692, 1994. View at: Publisher Site | Google Scholar
29. A Taurog, M L Dorris, W-X Hu, and F S Jr Guziec, “The selenium analog of 6-propylthiouracil. Measurement of its inhibitory effect on type I iodothyronine deiodinase and of its antithyroid activity,” Biochemical Pharmacology, vol. 49, no. 5, pp. 701–709, 1995. View at: Publisher Site | Google Scholar
30. G Roy, M Nethaji, and G Mugesh, “Biomimetic studies on anti-thyroid drugs and thyroid hormone synthesis,” Journal of the American Chemical Society, vol. 126, no. 9, pp. 2712–2713, 2004. View at: Publisher Site | Google Scholar
31. G Roy and G Mugesh, “Anti-thyroid drugs and thyroid hormone synthesis: effect of methimazole derivatives on peroxidase-catalyzed reactions,” Journal of the American Chemical Society, vol. 127, no. 43, pp. 15207–15217, 2005. View at: Publisher Site | Google Scholar
32. A Taurog, M L Dorris, and L Lamas, “Comparison of lactoperoxidase- and thyroid peroxidase-catalyzed iodination and coupling,” Endocrinology, vol. 94, no. 5, pp. 1286–1294, 1974. View at: Google Scholar
33. R E Childs and W G Bardsley, “The steady-state kinetics of peroxidase with 2, $\mathrm{2\prime }$-azino-di-(3-ethyl-benzthiazoline-6-sulphonic acid) as chromogen,” The Biochemical Journal, vol. 145, no. 1, pp. 93–103, 1975. View at: Google Scholar
34. C Laurence, M J El Ghomari, J-Y Le Questel, M Berthelot, and R Mokhlisse, “Structure and molecular interactions of antithyroid drugs. Part 3. Methimazole: a diiodine sponge,” Journal of the Chemical Society, Perkin Transactions 2, no. 7, pp. 1545–1552, 1998. View at: Publisher Site | Google Scholar
35. G Roy, D Das, and G Mugesh, “Bioinorganic chemistry aspects of the inhibition of thyroid hormone biosynthesis by anti-hyperthyroid drugs,” Inorganica Chimica Acta. In press. http://dx.doi.org/10.1016/j.ica.2006.07.052. View at: Google Scholar
36. H Engler, A Taurog, C Luthy, and M L Dorris, “Reversible and irreversible inhibition of thyroid peroxidase-catalyzed iodination by thioureylene drugs,” Endocrinology, vol. 112, no. 1, pp. 86–95, 1983. View at: Google Scholar
37. A Taurog, “The mechanism of action of the thioureylene antithyroid drugs,” Endocrinology, vol. 98, no. 4, pp. 1031–1046, 1976. View at: Google Scholar
38. T Nogimori, L E Braverman, A Taurog, S-L Fang, G Wright, and C H Emerson, “A new class of propylthiouracil analogs: comparison of $5^{\prime }$-deiodinase inhibition and antithyroid activity,” Endocrinology, vol. 118, no. 4, pp. 1598–1605, 1986. View at: Google Scholar
39. A Taurog, M L Dorris, and F S Jr Guziec, “Metabolism of ${}^{35}\text{S}$- and ${}^{14}\text{C}$-labeled 1-methyl-2-mercaptoimidazole in vitro and in vivo,” Endocrinology, vol. 124, no. 1, pp. 30–39, 1989. View at: Google Scholar
40. D R Doerge, “Oxygenation of organosulfur compounds by peroxidases: evidence of an electron transfer mechanism for lactoperoxidase,” Archives of Biochemistry and Biophysics, vol. 244, no. 2, pp. 678–685, 1986. View at: Publisher Site | Google Scholar
41. S Kobayashi, M Nakano, T Goto, T Kimura, and A P Schaap, “An evidence of the peroxidase-dependent oxygen transfer from hydrogen peroxide to sulfides,” Biochemical and Biophysical Research Communications, vol. 135, no. 1, pp. 166–171, 1986. View at: Publisher Site | Google Scholar
42. D R Doerge, “Mechanism-based inhibition of lactoperoxidase by thiocarbamide goitrogens,” Biochemistry, vol. 25, no. 16, pp. 4724–4728, 1986. View at: Publisher Site | Google Scholar
43. D R Doerge, G L Pitz, and D P Root, “Organosulfur oxygenation and suicide inactivation of lactoperoxidase,” Biochemical Pharmacology, vol. 36, no. 6, pp. 972–974, 1987. View at: Publisher Site | Google Scholar
44. D R Doerge and R S Takazawa, “Mechanism of thyroid peroxidase inhibition by ethylenethiourea,” Chemical Research in Toxicology, vol. 3, no. 2, pp. 98–101, 1990. View at: Publisher Site | Google Scholar
45. D R Doerge, N M Cooray, and M E Brewster, “Peroxidase-catalyzed S-oxygenation: mechanism of oxygen transfer for lactoperoxidase,” Biochemistry, vol. 30, no. 37, pp. 8960–8964, 1991. View at: Publisher Site | Google Scholar
46. G Mugesh, W-W du Mont, and H Sies, “Chemistry of biologically important synthetic organoselenium compounds,” Chemical Reviews, vol. 101, no. 7, pp. 2125–2179, 2001. View at: Publisher Site | Google Scholar
47. U Björkman and R Ekholm, “Hydrogen peroxide degradation and glutathione peroxidase activity in cultures of thyroid cells,” Molecular and Cellular Endocrinology, vol. 111, no. 1, pp. 99–107, 1995. View at: Publisher Site | Google Scholar
48. R Ekholm and U Björkman, “Glutathione peroxidase degrades intracellular hydrogen peroxide and thereby inhibits intracellular protein iodination in thyroid epithelium,” Endocrinology, vol. 138, no. 7, pp. 2871–2878, 1997. View at: Publisher Site | Google Scholar
49. G Roy, M Nethaji, and G Mugesh, “Interaction of anti-thyroid drugs with iodine: the isolation of two unusual ionic compounds derived from Se-methimazole,” Organic and Biomolecular Chemistry, vol. 4, no. 15, pp. 2883–2887, 2006. View at: Publisher Site | Google Scholar
50. D S Cooper, “Antithyroid drugs,” The New England Journal of Medicine, vol. 352, no. 9, pp. 905–917, 2005. View at: Publisher Site | Google Scholar
51. T Inabe and Y Matsunago, “Physical properties and constitution of the 5,6:11,12- bis(epidithio)naphthacene-iodine complexes (TTT-${\text{I}}_n$),” Bulletin of the Chemical Society of Japan, vol. 51, no. 10, pp. 2813–2816, 1978. View at: Publisher Site | Google Scholar
52. Y Matsunago and Y Suzuki, “Electrical and optical properties of the iodine complexes of phenoxazine, phenoselenazine, and benzophenothiazines,” Bulletin of the Chemical Society of Japan, vol. 45, no. 11, pp. 3375–3379, 1972. View at: Publisher Site | Google Scholar
53. M Sano, K Ohno, and H Akamatu, “Thermoelectric power of the iodine complexes of aromatic diamines and thiazines,” Bulletin of the Chemical Society of Japan, vol. 44, no. 12, pp. 3269–3271, 1971. View at: Publisher Site | Google Scholar
54. K Murata, M Tokumoto, H Anjai et al., “Superconductivity with the onset at 8-K in the organic conductor beta-(BEDT-TTF${)}_2{\text{I}}_3$ under pressure,” Journal of the Physical Society of Japan, vol. 54, no. 4, pp. 1236–1239, 1985. View at: Publisher Site | Google Scholar
55. M C Aragoni, M Arca, F Demartin et al., “Anti-thyroid drug methimazole: X-ray characterization of two novel ionic disulfides obtained from its chemical oxidation by ${\text{I}}_2$,” Journal of the American Chemical Society, vol. 124, no. 17, pp. 4538–4539, 2002. View at: Publisher Site | Google Scholar
56. C D Antoniadis, G J Corban, S K Hadjikakou et al., “Synthesis and characterization of (PTU)${\text{I}}_2$ (PTU = 6-$n$-propyl-2-thiouracil) and (CMBZT)${\text{I}}_2$ (CMBZT = 5-chloro-2-mercaptobenzothiazole) and possible implications for the mechanism of action of anti-thyroid drugs,” European Journal of Inorganic Chemistry, vol. 2003, no. 8, pp. 1635–1640, 2003. View at: Publisher Site | Google Scholar
57. M C Aragoni, M Arca, F Demartin et al., “DFT calculations, structural and spectroscopic studies on the products formed between IBr and $N,N^{\text{'}}$-dimethylbenzoiimdazole-2($3H$)-thione and -2($3H$)-selone,” Dalton Transactions, no. 13, pp. 2252–2258, 2005. View at: Publisher Site | Google Scholar
58. G J Corban, S K Hadjikakou, N Hadjiliadis et al., “Synthesis, structural characterization, and computational studies of novel diiodine adducts with the heterocyclic thioamides $N$-methylbenzothiazole-2-thione and benzimidazole-2-thione: implications with the mechanism of action of antithyroid drugs,” Inorganic Chemistry, vol. 44, no. 23, pp. 8617–8627, 2005. View at: Publisher Site | Google Scholar
59. C D Antoniadis, S K Hadjikakou, N Hadjiliadis, A Papakyriakou, M Baril, and I S Butler, “Synthesis and structures of Se analogues of the antithyroid drug 6-$n$-propyl-2-thiouracil and its alkyl derivatives: formation of dimeric Se-Se compounds and deselenation reactions of charge-transfer adducts of diiodine,” Chemistry - A European Journal, vol. 12, no. 26, pp. 6888–6897, 2006. View at: Publisher Site | Google Scholar
60. T J Visser, E van Overmeeren, D Fekkes, R Docter, and G Hennemann, “Inhibition of iodothyronine $5^{\prime }$-deiodinase by thioureylenes; structure—activity relationship,” FEBS Letters, vol. 103, no. 2, pp. 314–318, 1979. View at: Publisher Site | Google Scholar
61. F Freeman, J W Ziller, H N Po, and M C Keindl, “Reactions of imidazole-2-thiones with molecular iodine and the structures of two crystalline modifications of the 1:1 1,3- dimethylimidazole-2-thione-diiodine charge-transfer complex (${\text{C}}_5{\text{H}}_8{\text{I}}_2{\text{N}}_2\text{S}$),” Journal of the American Chemical Society, vol. 110, no. 8, pp. 2586–2591, 1988. View at: Publisher Site | Google Scholar
62. F Bigoli, P Deplano, F A Devillanova et al., “Reaction of imidazole-2-selone derivatives with diiodine - synthesis, structural and spectroscopic characterization of the adduct 1,$\mathrm{1\text{'}}$-bis(3-methyl-4-imidazolin-2- selone)methane bis(diiodine) and of the 1st examples of I-Se-I hypervalent seleniumcompounds- 1,3-dimethyl-4-imidazolin-2-ylium diiodo selenanide and 1,2-bis(3-methyl- 4-imidazolin-2-ylium diiodo selenanide)-ethane bis(dichloromethane),” Gazzetta Chimica Italiana, vol. 124, no. 11, pp. 445–454, 1994. View at: Google Scholar
63. M C Aragoni, M Arca, A J Blake et al., “1,2-Bis(3-methyl-imidazolin-2-ylium iodobromoselenanide)ethane: oxidative addition of IBr at the Se atom of $\text{a}>\text{C}=\text{Se}$ Group,” Angewandte Chemie International Edition, vol. 40, no. 22, pp. 4229–4232, 2001. View at: Publisher Site | Google Scholar
64. D J Williams, M R Fawcett-Brown, R R Raye et al., “Synthesis, characterization, and X-ray crystallographic structure of 1,3- dimeihyl-2 ($3H$)-imidazoleselone,” Heteroatom Chemistry, vol. 4, no. 4, pp. 409–414, 1993. View at: Publisher Site | Google Scholar
65. W-W du Mont, A Martens von Salzen, F Ruthe et al., “Tunning selenium—iodine contacts: from secondary soft-soft interactions to covalent bonds,” Journal of Organometallic Chemistry, vol. 623, no. 1-2, pp. 14–28, 2001. View at: Publisher Site | Google Scholar
66. P Deplano, J R Ferraro, M L Mercuri, and E F Trogu, “Structural and Raman spectroscopic studies as complementary tools in elucidating the nature of the bonding in polyiodides and in donor-${\text{I}}_2$ adducts,” Coordination Chemistry Reviews, vol. 188, no. 1, pp. 71–95, 1999. View at: Publisher Site | Google Scholar

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Copyright © 2006 Gouriprasanna Roy and G. Mugesh. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.