Airway Peroxidases Catalyze Nitration of the β₂-Agonist Salbutamol and Decrease Its Pharmacological Activity

Abstract

␤ 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 ␤ 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 Ϫ ), 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 ␤ 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 Ϫ being the most affected. Functionally, nitrated salbutamol showed decreased affinity for ␤ 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 ␤ 2 -agonists may be subject to peroxidase-catalyzed nitration that could potentially diminish their therapeutic efficacy.

The Novel Anthracenedione, Pixantrone, Lacks Redox Activity and Inhibits Doxorubicinol Formation in Human Myocardium: Insight to Explain the Cardiac Safety of Pixantrone in Doxorubicin-Treated Patients

“…Incubations contained 10 mM anthracenedione and 0.01 mM horseradish peroxidase (HRP) in 10 mM ammonium acetate (pH 7.0, 37°C). Oxidation was started by 100 mM H 2 O 2 and was terminated after 30 minutes by inhibiting HRP with 0.5 mM methimazole (Reszka et al, 2011).…”

Inflammation, Immunity and Redox Signaling

“…Induction of both iNOS and NADPH oxidases at the inflammation site leads to simultaneous increases in O 2 .-and NO that combine to form ONOO -, which ultimately can react with tyrosine residues in protein, forming the more stable product, nitrotyrosine (Diagram 3) (Brennan et al 2002). Indeed, increased levels of NO in exhaled breath and protein nitration have been observed in patients with asthma, correlating NO with inflammation (Reszka et al 2011). NO is highly diffusible, allowing it to potentially form ONOO -in areas spatially separated from the site of NO synthesis, limited only by its potent capacity to react with macromolecules (Lancaster and Gaston 2004).…”

New phenethylamine derivatives from Arenibacter nanhaiticus sp. nov. NH36AT and their antimicrobial activity

“…Phenethylamine (PEA), the simplest endogenous aromatic amine and potential pharmacophore, provides the basic chemical structure for several classes of drugs with wide biological activity. [1][2][3][4] Owing to this reason, PEA derivatives have attracted intensive interests recently and a series of new ones has been obtained from natural organisms and chemical syntheses, which exhibited diverse bioactivities, including bronchiectasia, antidepressant, stimulant, etc. 5,6 Nowadays, they have emerged as a promising biologically active scaffold in the search of new agents against human diseases.…”

“…In our ongoing work to search for antimicrobial components from marine microorganisms, five new PEA derivatives (1)(2)(3)(4)(5) were isolated from the strain of Arenibacter nanhaiticus sp. nov. NH36A T derived from the marine sediment of the South China Sea.…”

“…nov. NH36A T derived from the marine sediment of the South China Sea. Here, we reported the isolation and structural elucidation of new compounds (1)(2)(3)(4)(5). Moreover, the chiral resolution of enantiomers and the determination of their absolute configurations were also discussed.…”