Inhibition of Peroxidase-Catalyzed Reactions by Arylamines: Mechanism for the Anti-Thyroid Action of Sulfamethazine

Doerge, Daniel R.; Decker, Carolin

doi:10.1021/tx00038a008

Cited by 49 publications

(34 citation statements)

References 22 publications

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“…The mammalian peroxidases including LPO are also involved in catalyzing the single electron oxidation of various physiologically important organic aromatic substrates including phenols (23,24), catecholamines, and catechols (25)(26)(27) as well as other experimental model compounds such as aromatic amines (28), polychlorinated biphenyls (29), steroid hormones (30 -32), and polycyclic aromatic hydrocarbons (33). However, the mode of binding of aromatic ligands and associated functional implications are not yet clearly understood.…”

Section: Lactoperoxidase (Lpo)mentioning

confidence: 99%

Binding Modes of Aromatic Ligands to Mammalian Heme Peroxidases with Associated Functional Implications

Singh

Sinha

et al. 2009

Journal of Biological Chemistry

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Lactoperoxidase (LPO) 4 (EC 1.11.1.7) is a member of the family of glycosylated mammalian heme-containing peroxidase enzymes which also includes myeloperoxidase (MPO), eosinophil peroxidase (EPO), and thyroid peroxidase. These enzymes also show functional similarities to non-homologous plant and fungal peroxidases because they follow a similar scheme of reaction (1-3), but their modes of ligand binding differ considerably. Furthermore, the association of the prosthetic heme group in mammalian peroxidases is through covalent bonds (4 -9), whereas covalent linkages are absent in other peroxidases (10 -14). Among the four mammalian peroxidases, the prosthetic heme group is linked through three covalent bonds in MPO, whereas in LPO, EPO, and thyroid peroxidase only two covalent linkages are formed. So far the detailed crystal structures of only two mammalian peroxidases, MPO and LPO,. One of the most striking differences between these two mammalian peroxidases is concerned with the basic structural organization in which MPO exists as a covalently linked dimer, whereas LPO is a monomeric protein.At present the fundamental questions pertaining to mammalian heme peroxidases are (i) what distinguishes between the aromatic ligands that one ligand acts as a substrate, whereas the other ligand works as an inhibitor and (ii) how the substrate and inhibitor specificities differ between two enzymes lactoperoxidase and myeloperoxidase.Lactoperoxidase oxidizes inorganic ions, preferentially thiocyanate (SCN Ϫ ), and to a lesser extent, bromide (Br Ϫ ), whereas in the case of myeloperoxidase the chloride (Cl Ϫ ) ion is a preferred substrate (21,22). The mammalian peroxidases including LPO are also involved in catalyzing the single electron oxidation of various physiologically important organic aromatic substrates including phenols (23, 24), catecholamines, and catechols (25-27) as well as other experimental model compounds such as aromatic amines (28), polychlorinated biphenyls (29), steroid hormones (30 -32), and polycyclic aromatic hydrocarbons (33). However, the mode of binding of aromatic ligands and associated functional implications are not yet clearly understood. Surprisingly, the structural data on the complexes of mammalian peroxidases with aromatic ligands are conspicuously lacking. The only available structural report is on the complex of MPO with salicylhydroxamic acid (SHA) (34). Even in this case, the coordinates of this structure are not available for a detailed analysis. In the case of non-homologous plant peroxidases, a few crystal structures of their complexes with aromatic compounds are available (35-38), but their modes of binding are not very similar to those of mammalian peroxidases because the distal ligand binding sites in mammalian and plant peroxidases differ markedly. In this regard it is pertinent to note

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Section: Lactoperoxidase (Lpo)mentioning

confidence: 99%

Binding Modes of Aromatic Ligands to Mammalian Heme Peroxidases with Associated Functional Implications

Singh

Sinha

et al. 2009

Journal of Biological Chemistry

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“…The first step is iodination of thyroglobulin tyrosyl residues, followed by oxidative coupling to yield T 4 and T 3 . Inhibition of porcine TPO activity is a mechanism common to many classes of synthetic antithyroid compounds (27)(28)(29)(30)(31) and naturally occurring flavonoids (32,33). Lactoperoxidase (LPO) is often used as a model for TPO, based on many shared structural and functional properties.…”

Section: Biosynthesis Of Thyroid Hormones and Inhibition By Antithyromentioning

confidence: 99%

Goitrogenic and estrogenic activity of soy isoflavones.

Doerge

Sheehan

2002

Environ Health Perspect

252

136

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Soy is known to produce estrogenic isoflavones. Here, we briefly review the evidence for binding of isoflavones to the estrogen receptor, in vivo estrogenicity and developmental toxicity, and estrogen developmental carcinogenesis in rats. Genistein, the major soy isoflavone, also has a frank estrogenic effect in women. We then focus on evidence from animal and human studies suggesting a link between soy consumption and goiter, an activity independent of estrogenicity. Iodine deficiency greatly increases soy antithyroid effects, whereas iodine supplementation is protective. Thus, soy effects on the thyroid involve the critical relationship between iodine status and thyroid function. In rats consuming genistein-fortified diets, genistein was measured in the thyroid at levels that produced dose-dependent and significant inactivation of rat and human thyroid peroxidase (TPO) in vitro. Furthermore, rat TPO activity was dose-dependently reduced by up to 80%. Although these effects are clear and reproducible, other measures of thyroid function in vivo (serum levels of triiodothyronine, thyroxine, and thyroid-stimulating hormone; thyroid weight; and thyroid histopathology) were all normal. Additional factors appear necessary for soy to cause overt thyroid toxicity. These clearly include iodine deficiency but may also include additional soy components, other defects of hormone synthesis, or additional goitrogenic dietary factors. Although safety testing of natural products, including soy products, is not required, the possibility that widely consumed soy products may cause harm in the human population via either or both estrogenic and goitrogenic activities is of concern. Rigorous, high-quality experimental and human research into soy toxicity is the best way to address these concerns. Similar studies in wildlife populations are also appropriate.

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“…It has also been shown that ascorbic acid, cysteine, epinephrine, norepinephrine, serotonin, NADH, and NADPH can inhibit tyrosine iodination (13). More recent studies have shown that some exogenous substances such as dietary flavonoids and sulfamethazine may impair TPO activity, at least in vitro (15)(16)(17).…”

Section: Discussionmentioning

confidence: 99%

“…As suggested by this author, since the oxidized form of iodide might act to oxidize the thioureylene drugs, as well as to iodinate tyrosine residues, the thioureylenes may compete with the tyrosyl residues for the oxidized iodide and so inhibit the iodination reaction. Some authors have also demonstrated that several mechanisms can be responsible for the inhibition of TPO-and LPO-catalyzed reactions, such as suicide inactivation of the enzyme, rapid equilibrium binding, and alternate substrate competition for the iodinating intermediate (15).…”

Section: Discussionmentioning

confidence: 99%

Thyroid peroxidase activity is inhibited by amino acids

Carvalho

Ferreira

Coelho

et al. 2000

Braz J Med Biol Res

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Normal in vitro thyroid peroxidase (TPO) iodide oxidation activity was completely inhibited by a hydrolyzed TPO preparation (0.15 mg/ ml) or hydrolyzed bovine serum albumin (BSA, 0.2 mg/ml). A pancreatic hydrolysate of casein (trypticase peptone, 0.1 mg/ml) and some amino acids (cysteine, tryptophan and methionine, 50 µM each) also inhibited the TPO iodide oxidation reaction completely, whereas casamino acids (0.1 mg/ml), and tyrosine, phenylalanine and histidine (50 µM each) inhibited the TPO reaction by 54% or less. A pancreatic digest of gelatin (0.1 mg/ml) or any other amino acid (50 µM) tested did not significantly decrease TPO activity. The amino acids that impair iodide oxidation also inhibit the TPO albumin iodination activity. The inhibitory amino acids contain side chains with either sulfur atoms (cysteine and methionine) or aromatic rings (tyrosine, tryptophan, histidine and phenylalanine). Among the amino acids tested, only cysteine affected the TPO guaiacol oxidation reaction, producing a transient inhibition at 25 or 50 µM. The iodide oxidation inhibitory activity of cysteine, methionine and tryptophan was reversed by increasing iodide concentrations from 12 to 18 mM, while no such effect was observed when the cofactor (H 2 O 2 ) concentration was increased. The inhibitory substances might interfere with the enzyme activity by competing with its normal substrates for their binding sites, binding to the free substrates or reducing their oxidized form.

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Inhibition of Peroxidase-Catalyzed Reactions by Arylamines: Mechanism for the Anti-Thyroid Action of Sulfamethazine

Cited by 49 publications

References 22 publications

Binding Modes of Aromatic Ligands to Mammalian Heme Peroxidases with Associated Functional Implications

Binding Modes of Aromatic Ligands to Mammalian Heme Peroxidases with Associated Functional Implications

Goitrogenic and estrogenic activity of soy isoflavones.

Thyroid peroxidase activity is inhibited by amino acids

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