Regulation of human hepatic drug transporter activity and expression by diesel exhaust particle extract

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...

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Bibliographic Details
Published in:PloS one 2015-03, Vol.10 (3), p.e0121232
Main Authors: Le Vee, Marc, Jouan, Elodie, Stieger, Bruno, Lecureur, Valérie, Fardel, Olivier
Format: Article
Language:English
Subjects:
Air pollution
Aromatic compounds
Asthma
ATP-Binding Cassette Transporters - metabolism
Bile
Blood-brain barrier
Breast cancer
Cells, Cultured
Chemical contaminants
Chemicals
Cytokines
Detoxification
Diesel
Diesel emissions
Diesel engines
Dioxin
Dioxins
Efflux
Enzymes
Gene expression
Glycoproteins
Hepatocytes
Hepatocytes - drug effects
Hepatocytes - metabolism
Humans
Hydrocarbons
Inactivation, Metabolic
Life Sciences
Liver
Liver - drug effects
Liver - metabolism
Lung cancer
Multidrug resistance
Multidrug Resistance-Associated Proteins - metabolism
Organic Anion Transporters - metabolism
Organic Anion Transporters, Sodium-Dependent - metabolism
Organic anion transporting polypeptide
Organic cation transporter
Organic Cation Transporter 1 - metabolism
Organic chemistry
P-Glycoprotein
Pollutants
Polycyclic aromatic hydrocarbons
Polypeptides
Primary Cell Culture
Proteins
RNA
Rodents
Sodium
Substrates
Symporters - metabolism
Taurocholic Acid - pharmacology
TCDD
Transportation
Transporter
Vehicle Emissions
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0121232