Myeloperoxidase Fragments Reacting with Serum from a Patient with Myeloperoxidase-Anti-Neutrophil Cytoplasmic Antibody-Positive Glomerulonephritis

Otani, Isao; Ishida-Okawara, Akiko; Yamagoe, Satoshi; Miyoshi-Koshio, Toshiko; Arimura, Yoshihiro; Nagasawa, Toshihiko; Mizuno, Satoshi; Suzuki, Kazuo

doi:10.1007/bf02491508

Cited by 2 publications

(1 citation statement)

References 26 publications

(5 reference statements)

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“…This was further confirmed when this fragment was detected with anti-MPO. The fragments of MPO have been reported previously by others, , and the molecular weights of MPO fragments (40–46 kDa) detected previously are in accordance with our results. Thus, it is possible that the phenyl radical metabolite generated from AG might also be responsible for causing the fragmentation of MPO along with converting it into a protein radical.…”

Section: Discussionsupporting

confidence: 94%

Drug-Induced Protein Free Radical Formation Is Attenuated by Unsaturated Fatty Acids by Scavenging Drug-Derived Phenyl Radical Metabolites

Narwaley

Michail

Arvadia

et al. 2011

Chem. Res. Toxicol.

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Aromatic amine drugs like aminoglutethimide (AG) and related congeners have been shown to produce phenyl radicals through metabolism by myeloperoxidase (MPO)/H(2)O(2), which has been proposed to play a role in drug-induced agranulocytosis. AG has also been shown to induce MPO protein radical formation, but the ultimate fate of these metabolically generated phenyl radicals is still unknown. We tested the reactivity of linoleic acid (LA) and GSH with aniline-based compounds in the presence of horseradish peroxidase (HRP)/H(2)O(2) by measuring oxygen consumption. We found a qualitative correlation between drugs or xenobiotics that formed phenyl radical metabolites with the cooxidation of LA. Most compounds that reacted with LA did not react with GSH. Furthermore, an AG-derived phenyl radical was detected by EPR spin-trapping with MNP (2-methyl-2-nitrosopropane), in a reaction containing AG and HRP/H(2)O(2); these spectra were attenuated in the presence of LA and docosahexaenoic acid (DHA) indicating that phenyl radical scavenging occurred. Since it has been proposed that the phenyl radical metabolite leads to protein radical formation on MPO, we investigated the effect of LA and DHA in immuno-spin trapping experiments with MPO-containing HL-60 cell lysate. Using anti-DMPO, a protein radical was detected on a putative MPO fragment from the reaction of DMPO, AG, and glucose/glucose oxidase. When LA or DHA was included in this reaction, protein radical formation was significantly inhibited. Our results show that certain polyunsaturated fatty acids (PUFAs) act as scavengers of aromatic amine drug-derived phenyl radicals which in turn prevent protein radical formation. However, the interaction of phenyl radical drug metabolites with PUFAs will be dictated by their relative concentrations compared to those of other targets. Most importantly, it is possible to differentiate peroxidase substrates that generate phenyl radical metabolites from N-centered radicals on the basis of their reactivity toward GSH vs PUFAs, and PUFAs are targets for metabolically generated phenyl radicals.

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Section: Discussionsupporting

confidence: 94%

Drug-Induced Protein Free Radical Formation Is Attenuated by Unsaturated Fatty Acids by Scavenging Drug-Derived Phenyl Radical Metabolites

Narwaley

Michail

Arvadia

et al. 2011

Chem. Res. Toxicol.

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Neutrophil Functions of Patients With Vasculitis Related to Myeloperoxidase-Specific Anti-Neutrophil Antibody

Suzuki

2001

Int J Hematol

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Neutrophils are hypothesized to cause tissue damage resulting in the development of vasculitis and glomerulonephritis, although they are known to primarily take part in host defense functions. The infiltration of inflammatory cells. notably neutrophils and macrophages, is observed in the progression of vasculitis. Neutrophils with activated status and anti-neutrophil cytoplasmic antibodies (ANCAs), especially myeloperoxidase-specific (MPO)-ANCA, have been implicated in the development of vasculitis. The target molecule of MPG-ANCA is a lysosomal enzyme MPO that usually acts to kill bacteria, viruses, and fungi and that causes damage to the tissue due to the toxicity of its product, hypochlorite (OCl-). To elucidate the role of MPO-ANCA in the progression of vasculitis, a set of MPO-peptide fragments has been developed, and the corresponding epitope site for the specific monoclonal and/or oligoclonal antibody resulting in vasculitis has been determined. Recently some mouse models have been used for analyzing the correlation between MPO and MPO-ANCA in relation to damage of blood vessels followed by the development of vasculitis. This review focuses on the role of activated neutrophils in the development of vasculitis associated with MPO-ANCA and the target molecules of ANCA. In addition, the reactivities of ANCA and inflammatory cytokines involving leukocyte-derived chemotaxin 2 (LECT2) are also discussed.

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Myeloperoxidase Fragments Reacting with Serum from a Patient with Myeloperoxidase-Anti-Neutrophil Cytoplasmic Antibody-Positive Glomerulonephritis

Cited by 2 publications

References 26 publications

Drug-Induced Protein Free Radical Formation Is Attenuated by Unsaturated Fatty Acids by Scavenging Drug-Derived Phenyl Radical Metabolites

Drug-Induced Protein Free Radical Formation Is Attenuated by Unsaturated Fatty Acids by Scavenging Drug-Derived Phenyl Radical Metabolites

Neutrophil Functions of Patients With Vasculitis Related to Myeloperoxidase-Specific Anti-Neutrophil Antibody

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