Identification of P-Glycoprotein Inhibitors in Contaminated Freshwater Sediments

Žaja, Roko; Terzić, Senka; Senta, Ivan; Lončar, Jovica; Popović, Marta; Ahel, Marijan; Smital, Tvrtko (2013) Identification of P-Glycoprotein Inhibitors in Contaminated Freshwater Sediments. Environmental Science and Technology, 47 (9). pp. 4813-4821. ISSN 0013-936X

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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 two-tiered approach. Resulting non-polar, 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 non-competitive 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 sub-fractions. 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.

Item Type:	Article
Uncontrolled Keywords:	multixenobiotic resistance ; P-glycoprotein inhibitors ; contaminated sediments ; effect-directed analysis (EDA) ; nonionic surfactants
Subjects:	NATURAL SCIENCES > Chemistry > Analytic Chemistry NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology NATURAL SCIENCES > Interdisciplinary Natural Sciences > Environmental Science
Divisions:	Division for Marine and Enviromental Research
Projects:	Project title Project leader Project code Project type Organski spojevi kao molekulski obilježivači antropogenog utjecaja na okoliš- Marijan Ahel 098-0982934-2712 MZOS Ekotoksikološko značenje ABC transportnih proteina u vodenih organizama- Tvrtko Smital 098-0982934-2745 MZOS
Depositing User:	Marta Popović
Date Deposited:	07 Nov 2018 16:02
URI:	http://fulir.irb.hr/id/eprint/4214
DOI:	10.1021/es400334t

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