Effect of COPD treatments on MRP1-mediated transport in bronchial epithelial cells.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
van der Deen
Margaretha
M
Department of Medical Oncology, University Medical Center Groningen, The Netherlands.
Homan
Sandra
S
Timmer-Bosscha
Hetty
H
Scheper
Rik J
RJ
Timens
Wim
W
Postma
Dirkje S
DS
de Vries
Elisabeth G
EG
D000111:Acetylcysteine / Q000378:metabolism / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D001980:Bronchi / Q000166:cytology*; D001993:Bronchodilator Agents / Q000378:metabolism* / Q000627:therapeutic use; D019819:Budesonide / Q000378:metabolism / Q000627:therapeutic use; D018680:Cholinergic Antagonists / Q000378:metabolism / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000502:physiology*; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D004983:Ethanolamines / Q000378:metabolism / Q000627:therapeutic use; D005100:Expectorants / Q000378:metabolism / Q000627:therapeutic use; D005434:Flow Cytometry; D000068759:Formoterol Fumarate; D006801:Humans; D066298:In Vitro Techniques; D009241:Ipratropium / Q000378:metabolism / Q000627:therapeutic use; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects* / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000378:metabolism*
D000111:Acetylcysteine; D001993:Bronchodilator Agents; D019819:Budesonide; D018680:Cholinergic Antagonists; D004983:Ethanolamines; D005100:Expectorants; D000068759:Formoterol Fumarate; D009241:Ipratropium; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1