Abstract
Diesel exhaust particles (DEPs) are common environmental air pollutants primarily affecting the lung. DEPs or chemicals adsorbed on DEPs also exert extra-pulmonary effects, including alteration of hepatic drug detoxifying enzyme expression. The present study was designed to determine whether organic DEP extract (DEPe) may target hepatic drug transporters that contribute in a major way to drug detoxification. Using primary human hepatocytes and transporter-overexpressing cells, DEPe was first shown to strongly inhibit activities of the sinusoidal solute carrier (SLC) uptake transporters organic anion-transporting polypeptides (OATP) 1B1, 1B3 and 2B1 and of the canalicular ATP-binding cassette (ABC) efflux pump multidrug resistance-associated protein 2, with IC50 values ranging from approximately 1 to 20 μg/mL and relevant to environmental exposure situations. By contrast, 25 μg/mL DEPe failed to alter activities of the SLC transporter organic cation transporter (OCT) 1 and of the ABC efflux pumps P-glycoprotein and bile salt export pump (BSEP), whereas it only moderately inhibited those of sodium taurocholate co-transporting polypeptide and of breast cancer resistance protein (BCRP). Treatment by 25 μg/mL DEPe was next demonstrated to induce expression of BCRP at both mRNA and protein level in cultured human hepatic cells, whereas it concomitantly repressed mRNA expression of various transporters, including OATP1B3, OATP2B1, OCT1 and BSEP. Such changes in transporter expression were found to be highly correlated to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a reference activator of the aryl hydrocarbon receptor (AhR) pathway. This suggests that DEPe, which is enriched in known ligands of AhR like polycyclic aromatic hydrocarbons, alters drug transporter expression via activation of the AhR cascade. Taken together, these data established human hepatic transporters as targets of organic chemicals containing in DEPs, which may contribute to their systemic effects through impairing hepatic transport of endogenous compound or drug substrates of these transporters.
Highlights
Diesel exhaust particles (DEPs) are major and widely-distributed environmental air pollutants, originating from diesel engines [1]
DEP extract (DEPe) was added at a 25 μg/mL concentration, that likely corresponds to a 4.92 μg/cm2 equivalent DEP dose according to previous conversions of in vitro DEPe/DEP dose to DEP dose/unit surface area [56] and that is in the range of DEPe/DEP concentrations commonly retained for in vitro studies [57,58,59]
The data reported in the present work demonstrated that DEPe can alter both activity and expression of human hepatic drug transporters, confirming that detoxifying proteins constitute molecular targets for DEPs
Summary
Diesel exhaust particles (DEPs) are major and widely-distributed environmental air pollutants, originating from diesel engines [1] They are usually composed of a center core of elemental carbon and adsorbed organic compounds, including polycyclic aromatic hydrocarbons (PAHs) and nitro-PAHs, and small amounts of sulfate, nitrate, metals, and other trace elements. Even if toxic effects of DEPs primarily target the lung, reflecting that the major, if not exclusive, way of exposure to these pollutants is inhalation, systemic effects, including vascular and inflammatory effects, occur [7,8,9] This may be consistent with the passage across the pulmonary alveolar-capillary barrier of ultrafine DEPs [10] and/or of some organic or inorganic compounds primarily adsorbed on DEPs such as PAHs [11]. Such data indicate that these pollutants, like other inhaled deleterious contaminants such as cigarette smoke [17, 18], may alter hepatic detoxification pathways, probably through activation of the aryl hydrocarbon receptor (AhR) pathway [19]
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