Peroxidative metabolism of β2-agonists salbutamol and fenoterol and their analogues

Krzysztof J. Reszka, Dennis W. McGraw, Bradley E. Britigan

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Phenolic β2-adrenoreceptor agonists salbutamol, fenoterol, and terbutaline relax smooth muscle cells that relieve acute airway bronchospasm associated with asthma. Why their use sometimes fails to relieve bronchospasm and why the drugs appear to be less effective in patients with severe asthma exacerbations remains unclear. We show that in the presence of hydrogen peroxide, both myeloperoxidase, secreted by activated neutrophils present in inflamed airways, and lactoperoxidase, which is naturally present in the respiratory system, catalyze oxidation of these β2-agonists. Azide, cyanide, thiocyanate, ascorbate, glutathione, and methimazole inhibited this process, while methionine was without effect. Inhibition by ascorbate and glutathione was associated with their oxidation to corresponding radical species by the agonists' derived phenoxyl radicals. Using electron paramagnetic resonance (EPR), we detected free radical metabolites from β2- agonists by spin trapping with 2-methyl-2-nitrosopropane (MNP). Formation of these radicals was inhibited by pharmacologically relevant concentrations of methimazole and dapsone. In alkaline buffers, radicals from fenoterol and its structural analogue, metaproteronol, were detected by direct EPR. Analysis of these spectra suggests that oxidation of fenoterol and metaproterenol, but not terbutaline, causes their transformation through intramolecular cyclization by addition of their amino nitrogen to the aromatic ring. Together, these results indicate that phenolic β2-agonists function as substrates for airway peroxidases and that the resulting products differ in their structural and functional properties from their parent compounds. They also suggest that these transformations can be modulated by pharmacological approaches using appropriate peroxidase inhibitors or alternative substrates. These processes may affect therapeutic efficacy and also play a role in adverse reactions of the β2-agonists. Copyright. Published 2009 by American Chemical Society.

Original languageEnglish (US)
Pages (from-to)1137-1150
Number of pages14
JournalChemical Research in Toxicology
Volume22
Issue number6
DOIs
StatePublished - Jun 15 2009

Fingerprint

Fenoterol
Albuterol
Metabolism
Methimazole
Terbutaline
Bronchial Spasm
Electron Spin Resonance Spectroscopy
Oxidation
Peroxidase
Glutathione
Paramagnetic resonance
Asthma
Metaproterenol
Respiratory system
Lactoperoxidase
Spin Trapping
Peroxidases
Dapsone
Azides
Cyclization

ASJC Scopus subject areas

  • Toxicology

Cite this

Peroxidative metabolism of β2-agonists salbutamol and fenoterol and their analogues. / Reszka, Krzysztof J.; McGraw, Dennis W.; Britigan, Bradley E.

In: Chemical Research in Toxicology, Vol. 22, No. 6, 15.06.2009, p. 1137-1150.

Research output: Contribution to journalArticle

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