Airway peroxidases catalyze nitration of the β2-agonist salbutamol and decrease its pharmacological activity

Krzysztof J. Reszka, Larry Sallans, Stephen Macha, Kari Brown, Dennis W. McGraw, Melinda Butsch Kovacic, Bradley E Britigan

Research output: Contribution to journalArticle

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Abstract

β2-Agonists are the most effective bronchodilators for the rapid relief of asthma symptoms, but for unclear reasons, their effectiveness may be decreased during severe exacerbations. Because peroxidase activity and nitrogen oxides are increased in the asthmatic airway, we examined whether salbutamol, a clinically important β2-agonist, is subject to potentially inactivating nitration. When salbutamol was exposed to myeloperoxidase, eosinophil peroxidase or lactoperoxidase in the presence of hydrogen peroxide (H2O2) and nitrite (NO2 -), both absorption spectroscopy and mass spectrometry indicated formation of a new metabolite with features expected for the nitrated drug. The new metabolites showed an absorption maximum at 410 nm and pKa of 6.6 of the phenolic hydroxyl group. In addition to nitrosalbutamol (m/z 285.14), a salbutamol-derived nitrophenol, formed by elimination of the formaldehyde group, was detected (m/z 255.13) by mass spectrometry. It is noteworthy that the latter metabolite was detected in exhaled breath condensates of asthma patients receiving salbutamol but not in unexposed control subjects, indicating the potential for β2-agonist nitration to occur in the inflamed airway in vivo. Salbutamol nitration was inhibited in vitro by ascorbate, thiocyanate, and the pharmacological agents methimazole and dapsone. The efficacy of inhibition depended on the nitrating system, with the lactoperoxidase/H2O2/NO2- being the most affected. Functionally, nitrated salbutamol showed decreased affinity for β2-adrenergic receptors and impaired cAMP synthesis in airway smooth muscle cells compared with the native drug. These results suggest that under inflammatory conditions associated with asthma, phenolic β2-agonists may be subject to peroxidase-catalyzed nitration that could potentially diminish their therapeutic efficacy.

Original languageEnglish (US)
Pages (from-to)440-449
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume336
Issue number2
DOIs
StatePublished - Feb 1 2011

Fingerprint

Peroxidases
Albuterol
Pharmacology
Peroxidase
Lactoperoxidase
Asthma
Mass Spectrometry
Eosinophil Peroxidase
Nitrogen Oxides
Methimazole
Nitrophenols
Dapsone
Bronchodilator Agents
Nitrites
Pharmaceutical Preparations
Hydroxyl Radical
Adrenergic Receptors
Hydrogen Peroxide
Formaldehyde
Smooth Muscle Myocytes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Airway peroxidases catalyze nitration of the β2-agonist salbutamol and decrease its pharmacological activity. / Reszka, Krzysztof J.; Sallans, Larry; Macha, Stephen; Brown, Kari; McGraw, Dennis W.; Kovacic, Melinda Butsch; Britigan, Bradley E.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 336, No. 2, 01.02.2011, p. 440-449.

Research output: Contribution to journalArticle

Reszka, Krzysztof J. ; Sallans, Larry ; Macha, Stephen ; Brown, Kari ; McGraw, Dennis W. ; Kovacic, Melinda Butsch ; Britigan, Bradley E. / Airway peroxidases catalyze nitration of the β2-agonist salbutamol and decrease its pharmacological activity. In: Journal of Pharmacology and Experimental Therapeutics. 2011 ; Vol. 336, No. 2. pp. 440-449.
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