Inactivation of peroxidases of rat bone marrow by repeated administration of propylthiouracil is accompanied by a change in the heme structure

doi:10.1016/0006-2952(88)90574-6

Biochemical Pharmacology

Volume 37, Issue 11, 1 June 1988, Pages 2151-2153

https://doi.org/10.1016/0006-2952(88)90574-6 Get rights and content

Abstract

Myeloperoxidase and eosinophil peroxidase were isolated from the bone marrow cells of rats treated with or without propylthiouracil (PTU) which caused bone marrow depression. PTU treatment decreased the activity of myeloperoxidase but not of eosinophil peroxidase using guaiacol as the electron donor. However, when KI, N-N′-dimethyl-p-phenylenediamine and pyrogallol were used as the electron donor, the activity of only eosinophil peroxidase was inhibited by PTU treatment. EPR spectra indicated that the structure of myeloperoxidase surrounding the heme iron changed from a rhombic form into an axial one by the repeated administration of PTU. Therefore, the inactivation of peroxidases by PTU treatment was accompanied by an alteration of their structures surrounding the heme.

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Cited by (73)

A patient with sudden hearing loss induced by propylthiouracil
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Among such drugs, thiouracil derivatives are reportedly associated with a higher prevalence of ANCA positivity and clinical vasculitis [3, 4]. PTU-mediated actions involving neutrophils might provide pathological mechanisms underlying the induction of ANCA: alterations in the configuration of granules containing myeloperoxidase [5], direct binding to myeloperoxidase [6] and oxidization of PTU itself by myeloperoxidase [7]. To the best of our knowledge, our report is the first to show sudden hearing loss to be reversed in a patient with Graves' disease solely by the withdrawal of PTU.
A 39-year-old man with type 1 diabetes, who had a 4-year history of Graves' disease being treated with propylthiouracil (PTU), had developed sudden hearing loss. However, he showed no other clinical manifestations. Intratympanic administration with dexamethasone had failed, and his hearing had deteriorated. Magnetic resonance imaging showed the contrast effect on T1-weighted image in both cochleae, and the serum immunological analysis showed the high titers for anti-neutrophil cytoplasmic antibodies (ANCA). Therefore, his sudden hearing loss was presumed to be initial presentation of ANCA-associated vasculitis owing to PTU. His hearing was rapidly restored by a PTU withdrawal while no use of immunosuppressive agents, and he confirmed his hearing improvement in ordinary conversation. The patient's clinical course suggests that bilateral sensorineural hearing loss that occurs during treating hyperthyroidism could be initial presentation of ANCA-associated vasculitis, and discontinuing anti-thyroid drugs should be considered before treating with glucocorticoids.
Myeloperoxidase: Mechanisms, reactions and inhibition as a therapeutic strategy in inflammatory diseases
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Although these compounds show some efficacy as inhibitors of MPO-mediated HOCl formation, these species were much more effective in purified systems, than in the presence of O2-• (e.g. from xanthine oxidase or activated neutrophils), resulting in the conclusion that O2-• can act as an antagonist of inhibition via recycling of Compound II (Kettle et al., 1993). In the light of the discovery that propylthiouracil (a drug used to treat hyperthyroidism), inhibits the related heme enzyme TPO (Cooper, 2005), this compound and analogues have been tested as MPO inhibitors (Lee et al., 1988). A synthetic derivative, 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide, developed by Pfizer (PF-06282999), has been shown to be oxidized by Compound I of MPO to give a thiyl radical that can selectively and irreversibly inhibit MPO activity by forming a covalent bond with the heme (Dong et al., 2016; Ruggeri et al., 2015).
Heme peroxidases are a major source of reactive oxidants at sites of inflammation in biological systems. The formation of some of these oxidants (e.g. hypochlorous acid, HOCl) is important in the innate immune response of activated neutrophils and leukocytes to invading pathogens (e.g. bacteria, yeasts, fungi parasites), and responsible for the anti-microbial activity present in excreted fluids (e.g. hypothiocyanous acid, HOSCN, generated by lactoperoxidase). Other oxidants formed by heme peroxidase family members are important in tissue development (e.g. hypobromous acid, HOBr, formation by peroxidasin) and in the synthesis of thyroid hormones (hypoiodous acid, HOI, synthesized by thyroid peroxidase). However, inadvertent, misplaced or poorly-controlled production of these species can result in host tissue damage, and this underlies the strong association between high levels of some of these enzymes and multiple inflammatory pathologies. As a consequence, there is widespread interest in understanding the kinetics and mechanisms of biomolecule modification by these species, which differ dramatically in their actions, the nature of the products formed (as some of these are specific biomarkers of enzyme activity), and the biological consequences of these reactions in a wide range of diseases associated with acute or chronic inflammation. Increased knowledge of these processes, has allowed the development of a number of alternative and complementary strategies that allow modulation of oxidant formation and subsequent damage. This review discusses developments in these fields and the prospects for tailored inhibition of specific members of this enzyme family.
Influence of myeloperoxidase-catalyzing reaction on the binding between myeloperoxidase and anti-myeloperoxidase antibodies
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In the current study, whether myeloperoxidase (MPO)–catalyzing reaction could influence the antigenicity of MPO was investigated. Hypochlorite acid, the main product of the catalytic reaction, could lower the binding between MPO–antineutrophil cytoplasmic antibodies (ANCA) and MPO when the available chlorine was higher than 0.031×10⁻³ g/l. After MPO-catalyzing reaction with H₂O₂ lower than 0.469 g/l, the binding level between MPO–ANCAcontaining plasma and MPO increased slightly. The peak binding level was 1.135 ± 0.205 (expressed by the absorbance value at 405 nm). However, with the existence of hydrogen donor (o-phenylenediamine) in the reaction system, the peak binding level between MPO-ANCA–containing plasma and post-catalyzing MPO was significantly higher (1.367 ± 0.321 vs 1.135 ± 0.205, p = 0.023). Moreover, at the approximately physical concentration of H₂O₂ (0.02 g/l), MPO-ANCA exhibited higher titer to post-catalyzing MPO than to pre-catalyzing MPO (3.91 ± 0.84 vs 3.57 ± 0.84, p < 0.001, expressed as the lgT). These data demonstrated that MPO-catalyzing reaction could potentially increase the antigenicity of MPO.
The environment, geoepidemiology and ANCA-associated vasculitides
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The pathogenesis of PTU-induced AAV is still not yet clear. Lee et al. demonstrated that the structure of MPO could partially be changed by the repeated administration of PTU [33]. Jiang et al. proposed that activated neutrophils in the presence of hydrogen peroxidase release MPO from their granules, which converts PTU into cytotoxic products [34].
Anti-neutrophil cytoplasmic antibodies, directed against constituents of granules of neutrophils and lysosomes of monocytes, are serological markers of small vessel vasculitides, including Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and renal-limited vasculitis. These vasculitides are collectively termed ANCA-associated vasculitides (AAV). Environmental factors have been considered important in the development of ANCA, including silica, infection especially with Staphylococcus aureus, and drugs. Accelerated apoptosis of neutrophils induced through intratracheal instillation of silica may act as a trigger in the development of AAV. Inhaled silica may activate alveolar macrophages and not only induce inflammation and activation of fibroblasts, but also stimulate lymphocytes through T-cell receptors and attract neutrophils. Staphylococcus aureus is associated with initiation and relapse of Wegener's granulomatosis. Peptides from complementary PR3 show strong homology with peptides from S. aureus, which could underlie the development of PR3–ANCA. There is increasing recognition that drugs, especially propylthiouracil (PTU), may cause AAV. Patients with PTU-induced AAV have better prognosis than those with primary AAV. The disease spectrum of AAV in various geographic regions is different, which may suggest that the initiating factor in AAV has a different geographical distribution. Differences in genetic background may also be important in determining the response to triggering or initiating factors.
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2023, Rheumatology and Immunology Research

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Inactivation of peroxidases of rat bone marrow by repeated administration of propylthiouracil is accompanied by a change in the heme structure

Abstract

Archs Biochem. Biophys.

Biochim. biophys. Acta

Jap. J. Pharmac.

J. biol. Chem.