[PMID]: | 18489081 |
[Au] Autor: | Siraki AG; Deterding LJ; Bonini MG; Jiang J; Ehrenshaft M; Tomer KB; Mason RP |
[Ad] Endereço: | Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, 111 Alexander Dr., Research Triangle Park, NC 27709, USA. sirakia@niehs.nih.gov |
[Ti] Título: | Procainamide, but not N-acetylprocainamide, induces protein free radical formation on myeloperoxidase: a potential mechanism of agranulocytosis. |
[So] Source: | Chem Res Toxicol;21(5):1143-53, 2008 May. |
[Is] ISSN: | 1520-5010 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | Procainamide (PA) is a drug that is used to treat tachycardia in postoperative patients or for long-term maintenance of cardiac arrythmias. Unfortunately, its use has also been associated with agranulocytosis. Here, we have investigated the metabolism of PA by myeloperoxidase (MPO) and the formation of an MPO protein free radical. We hypothesized that PA oxidation by MPO/H 2O 2 would produce a PA cation radical that, in the absence of a biochemical reductant, would lead to the free radical oxidation of MPO. We utilized a novel anti-DMPO antibody to detect DMPO (5,5-dimethyl-1-pyrroline N-oxide) covalently bound to protein, which forms by the reaction of DMPO with a protein free radical. We found that PA metabolism by MPO/H 2O 2 induced the formation of DMPO-MPO, which was inhibited by MPO inhibitors and ascorbate. N-acetyl-PA did not cause DMPO-MPO formation, indicating that the unsubstituted aromatic amine was more oxidizable. PA had a lower calculated ionization potential than N-acetyl-PA. The DMPO adducts of MPO metabolism, as analyzed by electron spin resonance spectroscopy, included a nitrogen-centered radical and a phenyl radical derived from PA, either of which may be involved in the free radical formation on MPO. Furthermore, we also found protein-DMPO adducts in MPO-containing, intact human promyelocytic leukemia cells (HL-60). MPO was affinity-purified from HL-60 cells treated with PA/H 2O 2 and was found to contain DMPO using the anti-DMPO antibody. Mass spectrometry analysis confirmed the identity of the protein as human MPO. These findings were also supported by the detection of protein free radicals with electron spin resonance in the cellular cytosolic lysate. The formation of an MPO protein free radical is believed to be mediated by free radical metabolites of PA, which we characterized by spin trapping. We propose that drug-induced free radical formation on MPO may play a role in the origin of agranulocytosis. |
[Mh] Termos MeSH primário: |
Radicais Livres/metabolismo Granulócitos/patologia Peroxidase/metabolismo Procainamida/farmacologia
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[Mh] Termos MeSH secundário: |
Acecainida/química Acecainida/farmacologia Ácido Ascórbico/farmacologia Linhagem Celular Tumoral Espectroscopia de Ressonância de Spin Eletrônica Inibidores Enzimáticos/farmacologia Ensaio de Imunoadsorção Enzimática Seres Humanos Peróxido de Hidrogênio/farmacologia Íons/química Espectrometria de Massas Estrutura Molecular Peroxidase/antagonistas & inibidores Procainamida/química Procainamida/metabolismo
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[Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., INTRAMURAL |
[Nm] Nome de substância:
| 0 (Enzyme Inhibitors); 0 (Free Radicals); 0 (Ions); 910Q707V6F (Acecainide); BBX060AN9V (Hydrogen Peroxide); EC 1.11.1.7 (Peroxidase); L39WTC366D (Procainamide); PQ6CK8PD0R (Ascorbic Acid) |
[Em] Mês de entrada: | 0807 |
[Cu] Atualização por classe: | 170220 |
[Lr] Data última revisão:
| 170220 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 080521 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1021/tx700415b |
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