van der Deen Margaretha, Homan Sandra, Timmer-Bosscha Hetty, Scheper Rik J, Timens Wim, Postma Dirkje S, de Vries Elisabeth G
Department of Medical Oncology, University Medical Center Groningen, The Netherlands.
Int J Chron Obstruct Pulmon Dis. 2008;3(3):469-75. doi: 10.2147/copd.s2817.
Smoking is the principle risk factor for development of chronic obstructive pulmonary disease (COPD). Multidrug resistance-associated protein 1 (MRP1) is known to protect against toxic compounds and oxidative stress, and might play a role in protection against smoke-induced disease progression. We questioned whether MRP1-mediated transport is influenced by pulmonary drugs that are commonly prescribed in COPD.
The immortalized human bronchial epithelial cell line 16HBE14o- was used to analyze direct in vitro effects of budesonide, formoterol, ipratropium bromide and N-acetylcysteine (NAC) on MRP1-mediated transport. Carboxyfluorescein (CF) was used as a model MRP1 substrate and was measured with functional flow cytometry.
Formoterol had a minor effect, whereas budesonide concentration-dependently decreased CF transport by MRP1. Remarkably, addition of formoterol to the highest concentration of budesonide increased CF transport. Ipratropium bromide inhibited CF transport at low concentrations and tended to increase CF transport at higher levels. NAC increased CF transport by MRP1 in a concentration-dependent manner.
Our data suggest that, besides their positive effects on respiratory symptoms, budesonide, formoterol, ipratropium bromide, and NAC modulate MRP1 activity in bronchial epithelial cells. Further studies are required to assess whether stimulation of MRP1 activity is beneficial for long-term treatment of COPD.
吸烟是慢性阻塞性肺疾病（COPD）发生的主要危险因素。已知多药耐药相关蛋白1（MRP1）可抵御有毒化合物和氧化应激，可能在预防烟雾诱导的疾病进展中发挥作用。我们质疑MRP1介导的转运是否受COPD常用肺部药物的影响。
使用永生化人支气管上皮细胞系16HBE14o-分析布地奈德、福莫特罗、异丙托溴铵和N-乙酰半胱氨酸（NAC）对MRP1介导转运的直接体外作用。以羧基荧光素（CF）作为MRP1底物模型，采用功能性流式细胞术进行检测。
福莫特罗作用较小，而布地奈德浓度依赖性地降低MRP1介导的CF转运。值得注意的是，在布地奈德最高浓度时加入福莫特罗可增加CF转运。异丙托溴铵在低浓度时抑制CF转运，在较高浓度时倾向于增加CF转运。NAC以浓度依赖性方式增加MRP1介导的CF转运。
我们的数据表明，除了对呼吸道症状有积极作用外，布地奈德、福莫特罗、异丙托溴铵和NAC可调节支气管上皮细胞中的MRP1活性。需要进一步研究来评估刺激MRP1活性对COPD长期治疗是否有益。
