Polybrominated diphenyl ethers (PBDEs), a group of 209 individual congeners distinguishable by the number and position of bromines, are produced for use as flame retardants in consumer goods. PBDEs have become ubiquitous environmental contaminants, present in increasing levels in the environment and humans. In the present study, 10 individual monofluorinated analogues of PBDEs (F-PBDEs) and one difluorinated PBDE (FF-PBDE) were synthesized and characterized, and their gas chromatographic (GC) and mass spectrometric (MS) characteristics determined. The synthesis method utilized a nucleophilic reaction of bromophenols with diphenyliodonium salts and the perbromination of fluorosubstituted diphenyl ethers. Reaction yields were between 10% and 59% with ≥98% purity. Apart from the aromatic ring carrying the fluorine atom, only minor chemical nuclear magnetic resonance (NMR) shift changes were observed in comparison to the corresponding parent PBDEs, with the exception that the J F,H coupling was stronger. Our preliminary data show that F-PBDEs and PBDEs have comparable retention times in gas chromatography with F-PBDEs demonstrating in general shorter or identical retention times, depending on the pattern of fluorine substitution. We also calculated the torsion angles and the dipole moments for both and report that there is a good correlation between GC retention times and the torsion angles but not with dipole moments. In MS, the difference of the ion peaks of the F-PBDE/PBDE pairs is m/z 19 (F), which allows a simultaneous MS detection without separation. On the basis of GC separation, simultaneous MS detection, and the stability of fluorine due to its generally resistance to nucleophilic displacement, we propose that F-PBDEs may function as valuable potential standards, markers, and tracers in environmental analysis.
Macrolide antibiotics such as erythromycin (EM) and azithromycin (AZM) are beneficial in the treatment of mucus hypersecretion in inflammatory pulmonary diseases. Several indirect and direct mechanisms of action have been proposed. This study investigates the direct effect of macrolides on secretory function of isolated submucosal mucous gland cells (SMGCs). We hypothesize that macrolides inhibit the calcium influx necessary for evoked mucus secretion. To test this, we quantified mucin protein release using enzyme-linked immunosorbent assay, calcium-activated K ϩ (K Ca ), and calcium-activated Cl Ϫ (Cl Ca ) currents. We measured nonselective cation current (NSCC) using whole-cell patch-clamp techniques; intracellular calcium concentration ([Ca 2ϩ ] i ) was measured using fura-2 Ca 2ϩ imaging. We found that both EM and AZM are agonists at muscarinic receptors. EM (10 M) evoked a small but significant increase in mucin release but inhibited the mucin release induced by subsequent acetylcholine (ACh) treatment. Both EM and AZM (10 M) evoked K Ca and Cl Ca whole-cell currents, which were blocked by atropine. EM and AZM also accelerated the decay of inositol trisphosphate-induced K Ca and Cl Ca currents without changing the peak current amplitudes. Likewise, internal application of AZM (10 M) enhanced the decay rate of ACh-induced K Ca and Cl Ca currents. EM (1-10 M) and AZM (0.1-10 M) slowly (over 25-30 min) inhibited thapsigargin (TG)-induced Ca 2ϩ entry when applied during the plateau phase of Ca 2ϩ entry but blunted TG-induced Ca 2ϩ entry by 70% after a 5-min pretreatment before initiating calcium entry. EM blocked TG-induced NSCC. We conclude that macrolide antibiotics are partial agonists at muscarinic receptors but inhibit stimulated mucus release by inhibiting calcium entry in SMGCs.
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