Airway Peroxidases Catalyze Nitration of the beta(2)-Agonist Salbutamol and Decrease Its Pharmacological Activity

Department of Internal Medicine, Veterans Affairs Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0557, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.86). 10/2010; 336(2):440-9. DOI: 10.1124/jpet.110.170027
Source: PubMed

ABSTRACT β(2)-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 β(2)-agonist, is subject to potentially inactivating nitration. When salbutamol was exposed to myeloperoxidase, eosinophil peroxidase or lactoperoxidase in the presence of hydrogen peroxide (H(2)O(2)) and nitrite (NO(2)(-)), 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 pK(a) 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 β(2)-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/H(2)O(2)/NO(2)(-) being the most affected. Functionally, nitrated salbutamol showed decreased affinity for β(2)-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 β(2)-agonists may be subject to peroxidase-catalyzed nitration that could potentially diminish their therapeutic efficacy.

Download full-text


Available from: Dennis W. McGraw, Jun 21, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiotoxicity from the antitumor anthracycline, doxorubicin, correlates with doxorubicin cardiac levels, redox activation to superoxide anion (O(2)(._)) and hydrogen peroxide (H(2)O(2)), formation of the long-lived secondary alcohol metabolite, doxorubicinol. Cardiotoxicity may first manifest during salvage therapy with other drugs, such as the anthracenedione mitoxantrone. Minimal evidence for cardiotoxicity in anthracycline-pretreated patients with refractory-relapsed non Hodgkin's lymphoma was observed with the novel anthracenedione, pixantrone. We characterized whether pixantrone and mitoxantrone caused different effects on doxorubicin levels, redox activation, doxorubicinol formation. Pixantrone and mitoxantrone were probed in a validated ex vivo human myocardial strip model that was either doxorubicin-naïve or preliminarily subjected to doxorubicin loading and washouts to mimic doxorubicin treatment and elimination in the clinical setting. In doxorubicin-naive strips, pixantrone showed higher uptake than mitoxantrone; however, neither drug formed O(2)(._) or H(2)O(2). In doxorubicin-pretreated strips, pixantrone or mitoxantrone did not alter the distribution and clearance of residual doxorubicin. Mitoxantrone showed an unchanged uptake, lacked effects on doxorubicin levels, but synergized with doxorubicin to form more O(2)(._) and H(2)O(2), as evidenced by O(2)(._) -dependent inactivation of mitochondrial aconitase or mitoxantrone oxidation by H(2)O(2) -activated peroxidases. In contrast, pixantrone uptake was reduced by prior doxorubicin exposure; moreover, pixantrone lacked redox synergism with doxorubicin, and formed an N-dealkylated product that inhibited metabolism of residual doxorubicin to doxorubicinol. Redox inactivity and inhibition of doxorubicinol formation correlate with the cardiac safety of pixantrone in doxorubicin-pretreated patients. Redox inactivity in the face of high cardiac uptake suggests that pixantrone might be safe also in doxorubicin-naive patients.
    Journal of Pharmacology and Experimental Therapeutics 11/2012; 344(2). DOI:10.1124/jpet.112.200568 · 3.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Asthma is characterized by repeated episodes of airway obstruction and an ongoing cycle of airway inflammation. Reactive oxygen species (ROS) produced by inflammatory cells in the lung play a key role in the pathogenesis as well as amplification of inflammation in asthmatic airways. Several enzymatic and non-enzymatic antioxidants are available in the lung and systemic circulation to counteract ROS mediated damage on various biomolecules such as lipid membranes, proteins, and DNA; however during asthmatic inflammation these defenses are overwhelmed due to excessive production of ROS thereby leading to inflammatory events in the airways/systemic circulation. ROS-mediated damage may result in increased vascular permeability, mucus hyper secretion, smooth muscle contraction, epithelial shedding and impairment in the responsiveness of β-adrenergic receptors. Strategies aimed to boost the endogenous antioxidants either through dietary or pharmacological intervention to redress oxidant-antioxidant imbalance in asthma is the current area of research in many laboratories throughout the world. This review aims at providing a comprehensive overview of the available literature on oxidative stress and antioxidants imbalance in asthma with a focus both on lung and blood components and bring forth correlations between lung/blood oxidative stress/antioxidant parameters and lung function.
    Pulmonary Pharmacology &amp Therapeutics 06/2014; DOI:10.1016/j.pupt.2014.06.001 · 2.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Five new phenethylamine (PEA) derivatives (1-5) were isolated from the strain of Arenibacter nanhaiticus sp. nov. NH36A(T) derived from the marine sediment of the South China Sea by bioassay-guided fractionation. Their structures were elucidated by spectroscopic methods including UV, IR, HR-MS and NMR. Interestingly, compounds 1-4 existed as enantiomers, which were resolved by chiral liquid chromatography. The resolved configuration of each enantiomer was assigned by the Marfey's method. Of these compounds, 5 showed weak antimicrobial activity against Staphylococcus aureus and Bacillus subtilis with MIC values of 0.50 and 0.25 mg ml(-1), respectively.The Journal of Antibiotics advance online publication, 17 July 2013; doi:10.1038/ja.2013.65.
    The Journal of Antibiotics 07/2013; 66(11). DOI:10.1038/ja.2013.65 · 2.04 Impact Factor