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Modulation of the expression of ABC transporters in murine (J774) macrophages exposed to large concentrations of the fluoroquinolone antibiotic moxifloxacin.
- Source :
-
Toxicology [Toxicology] 2011 Dec 18; Vol. 290 (2-3), pp. 178-86. Date of Electronic Publication: 2011 Sep 17. - Publication Year :
- 2011
-
Abstract
- 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.<br /> (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)
- Subjects :
- ATP-Binding Cassette Transporters metabolism
Animals
Anti-Infective Agents administration & dosage
Anti-Infective Agents pharmacokinetics
Aza Compounds administration & dosage
Aza Compounds pharmacokinetics
Cell Line
Ciprofloxacin administration & dosage
Ciprofloxacin pharmacokinetics
Dose-Response Relationship, Drug
Fluoroquinolones
Gene Expression Regulation drug effects
Macrophages metabolism
Mice
Moxifloxacin
Quinolines administration & dosage
Quinolines pharmacokinetics
ATP-Binding Cassette Transporters drug effects
Anti-Infective Agents toxicity
Aza Compounds toxicity
Ciprofloxacin toxicity
Macrophages drug effects
Quinolines toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1879-3185
- Volume :
- 290
- Issue :
- 2-3
- Database :
- MEDLINE
- Journal :
- Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 21946100
- Full Text :
- https://doi.org/10.1016/j.tox.2011.09.003