engleski

Inhibitors of the ABC transport proteins as emerging pollutants— Determination and ecotoxicological relevance

One of the most intriguing defense strategies evolutionary developed in aquatic organisms is the activity of the MultiXenobiotic Resistance (MXR) mechanism, first described in early 1990-ties by Kurelec and coworkers. As in the case of the multidrug resistance (MDR) phenomenon expressed in various mammalian tissues, it has been shown that specific transmembrane ABC (ATP Binding Cassette) transport proteins are key mediators of the MXR activity. Among them, the P-glycoprotein (P-gp, ABCB1) and the multidrug resistance-associated proteins (MRPs, ABCCs) are the best known and most studied efflux transporters. With remarkable substrate (non)specificity these proteins actively export a diverse group of natural products, chemotherapeutic drugs and hydrophobic peptides across the plasma membrane, contributing to the selective pharmacological and toxicological barrier and providing resistance to aquatic organisms living in polluted environments. However, the main disadvantage of the MXR defense is its sensitivity to the presence of specific compounds, so-called chemosensitizers or MXR inhibitors. By blocking the P-gp and/or MRPs transport activity they can cause an increase in intracellular accumulation and toxic effects of other xenobiotics normally effluxed by the ABC transport proteins. Enhancement of MXR inhibition with concomitant detrimental effects has been shown in several studies with aquatic organisms exposed to both model MXR inhibitors and environmental pollutants. Furthermore, the presence of MXR inhibitors has been demonstrated in environmental samples from polluted locations at concentrations that could completely abolish P-gp and/or MRPs transport activity. Ecotoxicological significance of MXR inhibition is being additionally highlighted by their presence among both conventional and emerging man-made pollutants – in addition to pharmaceuticals some pesticides and synthetic musk fragrances show extremely high MXR inhibitory potential at environmentally relevant concentrations. Consequently, the MXR-inhibitors might have important implications on key environmental parameters (exposure, uptake, internal dose, bioaccumulation, response, synergism, toxicity) and within this presentation I will try to illustrate why the property to inhibit MXR defense classifies these substances among top-hazardous environmental pollutants.

ABC transport proteins; MultiDrug Resistance (MDR); MultiXenobiotic Resistance (MXR); aquatic organisms; MXR inhibitors; emerging contaminants

doi:10.1016/j.toxlet.2006.06.092