Anti‐myeloperoxidase and anti‐cathepsin G antibodies in sulphonamide hypersensitivity

Lavergne, Sidonie N.; Drescher, Nicholas J.; Trepanier, Lauren A.

doi:10.1111/j.1365-2222.2007.02845.x

Cited by 10 publications

(13 citation statements)

References 54 publications

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“…6A) and may or may not be the most relevant target in relation to agranulocytosis. In this regard, a recent study in dogs treated with sulfonamide, an aromatic amine drug, showed that anti-MPO and anti-cathepsin G antibodies were detected in sera (64).…”

Section: Discussionmentioning

confidence: 99%

Procainamide, but notN-Acetylprocainamide, Induces Protein Free Radical Formation on Myeloperoxidase: A Potential Mechanism of Agranulocytosis

Siraki

Deterding

Jiang

et al. 2008

Chem. Res. Toxicol.

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Procainamide (PA) is a drug that is used to treat tachycardia in post-operative 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 2 O 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 only by the reaction of DMPO with a protein free radical. We found that PA metabolism by MPO/H 2 O 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 §To whom correspondence should be addressed: Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, 111 TW Alexander Dr., Research Triangle Park, NC USA, 27709. T: (919) 541-5197, F: (919) 541-1043, sirakia@niehs.nih.gov.. Abbreviations: PA, procainamide; NAPA, N-acetyl-procainamide; MPO, myeloperoxidase; ESR, electron spin resonance; DTPA, diethylenetriaminepentaacetic acid; MNP, 2-methyl-2-nitrosopropane; DMPO, 5,5-dimethyl-1-pyrroline N-oxide; ABAH, 4-aminobenzoic acid hydrazide; G/GO,Glucose / glucose oxidase. 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 . MPO was affinity-purified from HL-60 cells treated with PA/H 2 O 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. NIH Public AccessProcainamide (PA) is a sodium channel blocker which stabilizes electrical conduction in the heart. It is used for treating atrial tachycardia and is specifically recommended for atrial fibrillation of the Wolff-Parkinson-White syndrome (1). Unfortunately, agranulocytosis, an idiosyncratic adverse drug reaction, is associated with the use of procainamide (PA). This condition is characterized by severe neutropenia, where the absolute neutrophil count decreases below 500/uL (2,3), which greatly increases the risk of b...

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Section: Discussionmentioning

confidence: 99%

Procainamide, but notN-Acetylprocainamide, Induces Protein Free Radical Formation on Myeloperoxidase: A Potential Mechanism of Agranulocytosis

Siraki

Deterding

Jiang

et al. 2008

Chem. Res. Toxicol.

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Section: Introductionmentioning

confidence: 99%

“…The pathogenesis of delayed drug hypersensitivity is still not well understood . The ‘hapten hypothesis’ postulates that drugs have to bind to proteins to form potentially immunogenic protein–drug adducts . The ‘danger theory’ states that the immune system reacts in response to ‘danger’, such as cell death, oxidative stress or inflammation, rather than ‘foreignness’ …”

Section: Introductionmentioning

confidence: 99%

The effect of ‘allergenic’ and ‘nonallergenic’ antibiotics on dog keratinocyte viability in vitro

Voie

Lucas

Schaeffer

et al. 2013

Veterinary Dermatology

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“…Additionally, hypersensitivity in dogs has been shown to be associated with antidrug, antimyeloperoxidase, and anti-cathepsin G antibodies [87,88]. It is thought that the immune reaction to sulfonamide is triggered by a reactive metabolite since sulfonamides are metabolized to hydroxylamines that may be further oxidized to nitroso derivatives, which in turn may form protein adducts, culminating in antibody-and/or cell-mediated immune responses [88]. A dog may be a very good mechanistic model for sulfonamide hypersensitivity in humans since this syndrome in dogs shares many similarities with that in humans.…”

Section: Sulfonamide-induced Hypersensitivitymentioning

confidence: 99%

Idiosyncratic Drug Reactions

Wojcinski

Uetrecht

2012

Encyclopedia of Drug Metabolism and Interactions

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Idiosyncratic drug reactions (IDRs) are adverse drug reactions that are not related to the known pharmacological properties of the drug occur in only a small percentage of the population and do not show any apparent dose–response relationship. The unpredictable nature of IDRs together with the often serious adverse effects encountered pose a major health concern in the development and clinical usage of pharmaceuticals. The mechanism of IDRs is not clearly understood, and although several theories have been proposed, IDRs can be generally categorized mechanistically as either immune mediated or non‐immune‐mediated. There is circumstantial evidence that suggests that most idiosyncratic reactions are hypersensitivity reactions initiated by the formation of chemically reactive metabolites that bind to proteins and induce an immune‐mediated response. Investigations in animal models have had limited success owing to the unpredictability of IDRs in animals, which is similar to the situation in humans. However, IDRs in animals do share some similar characteristics and mechanisms observed in humans supporting the need for further study of animal models.

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Anti‐myeloperoxidase and anti‐cathepsin G antibodies in sulphonamide hypersensitivity

Cited by 10 publications

References 54 publications

Procainamide, but notN-Acetylprocainamide, Induces Protein Free Radical Formation on Myeloperoxidase: A Potential Mechanism of Agranulocytosis

Procainamide, but notN-Acetylprocainamide, Induces Protein Free Radical Formation on Myeloperoxidase: A Potential Mechanism of Agranulocytosis

The effect of ‘allergenic’ and ‘nonallergenic’ antibiotics on dog keratinocyte viability in vitro

Idiosyncratic Drug Reactions

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