Identification of P-glycoprotein inhibitors in contaminated freshwater sediments.
Environ Sci Technol
; 47(9): 4813-21, 2013 May 07.
Article
en En
| MEDLINE
| ID: mdl-23570494
ABSTRACT
P-glycoprotein (P-gp, ABCB1) is an important part of the multixenobiotic resistance (MXR) defense system in aquatic organisms. The main goal of this study was identification of P-gp inhibitors in contaminated sediments using the effect-directed analysis (EDA) approach. The samples were collected from the Gorjak creek (Zagreb, Croatia), a recipient of wastewater effluents from the pharmaceutical industry. Sediment samples were extracted and fractionated using a two-tiered approach. Resulting nonpolar, medium polar, and polar fractions were tested on the inhibition of P-gp activity using P-gp overexpressing PLHC-1/dox cells and calcein-AM as model substrate. The obtained EC50 values (up to 757 µg/g, expressed in toxicity equivalents of model P-gp inhibitor cyclosporine A) revealed high inhibitory potential of polar fractions of investigated sediments and clearly reflected the impact of pharmaceutical wastewater. P-gp specific ATPase assay and the cytotoxicity modulation experiments with colchicine indicated that most of the observed P-gp inhibition was due to the presence of noncompetitive inhibitors. A detailed chemical analysis by ultrahigh-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-QTOFMS) revealed nonionic surfactants, including alcohol polyethoxylates (LAEOs) and polypropylene glycols (PPGs), as the major components of the most active subfractions. Testing of several LAEO and PPG commercial mixtures confirmed their potential to inhibit the fish P-glycoprotein and modulate toxicity of other xenobiotics present in complex environmental samples.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Contaminantes Químicos del Agua
/
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP
/
Sedimentos Geológicos
/
Agua Dulce
Tipo de estudio:
Diagnostic_studies
Límite:
Animals
Idioma:
En
Revista:
Environ Sci Technol
Año:
2013
Tipo del documento:
Article
País de afiliación:
Croacia