1. Toxicology. 2011 Dec 18;290(2-3):179-87. Epub 2011 Sep 17.

Modulation of the expression of ABC transporters in murine (J774) macrophages
exposed to large concentrations of the fluoroquinolone antibiotic moxifloxacin.

Vallet CM, Marquez B, Nhiri N, Anantharajah A, Mingeot-Leclercq MP, Tulkens PM,
Lallemand JY, Jacquet E, Van Bambeke F.

Université catholique de Louvain, Louvain Drug Research Institute, Pharmacologie 
cellulaire et moléculaire, B-1200 Brussels, Belgium.

Long-term exposure to pharmacological agents can select for cells that
overexpress efflux transporters. We previously showed that mouse J774 macrophages
cultivated for a prolonged period of time with toxic concentrations of the
fluoroquinolone ciprofloxacin overexpress the efflux transporter Mrp4 and display
a reduced accumulation of this antibiotic, but no change in the accumulation of
moxifloxacin, a closely related molecule (Antimicrob. Agents Chemother. [2006]
50, 1689-1695 and [2009] 53, 2410-2416). Because of this striking difference
between the two fluoroquinolones, we have now examined the modifications in the
expression of ABC efflux transporters induced by the prolonged exposure of J774
macrophages to high concentrations of moxifloxacin. The resulting cell line
showed (i) no difference in the accumulation of moxifloxacin but an increased
accumulation and decreased efflux of ciprofloxacin; (ii) an overexpression of the
multidrug transporters Abcb1a (P-gp), Abcc2 (Mrp2) and Abcg2 (Bcrp1), and a
decreased expression of Abcc4 (Mrp4). While P-gp and Bcrp1 were functional, they 
did not modify the cellular accumulation of fluoroquinolones. The data show that 
exposing cells to high concentrations of a drug that is not affected by active
efflux can trigger a pleiotropic response leading to a modulation in the
expression of several transporters. These changes, however, are not sufficient to
protect cells against the toxicity that fluoroquinolones may exert at large
concentrations. They could also cause unanticipated drug interactions in vivo,
should the drug exposure grossly exceed what is anticipated from its current
registered use.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

PMID: 21946100  [PubMed - in process]