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.