Document Detail

Peroxidative metabolism of beta2-agonists salbutamol and fenoterol and their analogues.
MedLine Citation:
PMID:  19462961     Owner:  NLM     Status:  MEDLINE    
Phenolic beta(2)-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 beta(2)-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 beta(2)-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 beta(2)-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 beta(2)-agonists.
Krzysztof J Reszka; Dennis W McGraw; Bradley E Britigan
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Chemical research in toxicology     Volume:  22     ISSN:  1520-5010     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-06-15     Completed Date:  2009-09-09     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1137-50     Citation Subset:  IM    
Research Services and Department of Internal Medicine, Department of Veterans Affairs Medical Center, Cincinnati, Ohio 45220, USA.
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MeSH Terms
Adrenergic beta-2 Receptor Agonists*
Adrenergic beta-Agonists / chemistry,  metabolism*
Albuterol / analogs & derivatives,  chemistry,  metabolism*
Electron Spin Resonance Spectroscopy
Fenoterol / analogs & derivatives,  chemistry,  metabolism*
Free Radicals / chemistry,  metabolism
Hydrogen Peroxide / chemistry,  metabolism
Lactoperoxidase / chemistry,  metabolism
Grant Support
Reg. No./Substance:
0/Adrenergic beta-2 Receptor Agonists; 0/Adrenergic beta-Agonists; 0/Free Radicals; 13392-18-2/Fenoterol; 18559-94-9/Albuterol; 7722-84-1/Hydrogen Peroxide; EC 1.11.1.-/Lactoperoxidase
Erratum In:
Chem Res Toxicol. 2009 Aug;22(8):1490

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