Received for publication March 10, 2006.
Revised July 6, 2006.
Accepted for publication July 7, 2006.

Differential regulation of sinusoidal and canalicular hepatic drug transporter expression by xenobiotics activating drug-sensing receptors in primary human hepatocytes

Abstract

Sinusoidal and canalicular hepatic drug transporters constitute key-factors involved in liver drug elimination. Regulation of their expression via activation of xenosensors such as aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR) and nuclear factor E2-related factor 2 (Nrf2), remains incompletely characterized. The present study was therefore designed to carefully analyze expression of major drug transporters in primary human hepatocytes exposed to dioxin (TCDD) (an AhR activator), rifampicin (RIF) (a PXR activator), phenobarbital (PB) (a CAR activator) and oltipraz (OPZ) (a Nrf2 activator), using mainly reverse transcription-real time polymerase chain reaction assays. With a threshold corresponding to a 1.5-fold-factor change in mRNA levels, observed in at least 3 of 7 independent human hepatocyte cultures, efflux transporters such as MDR1, MRP2 and BCRP were up-regulated by PB, RIF and OPZ, whereas MRP3 was induced by OPZ and RIF. MDR1 and BCRP expression was also increased by TCDD and RIF augmented mRNA levels of the influx transporter OATP-C. Bile acid transporters, i.e. BSEP and NTCP, and the sinusoidal transporter OAT2 were down-regulated by all the tested chemicals. Influx transporters such as OCT1, OATP-B and OATP8 were repressed by PB and TCDD; PB also decreased MRP6 expression whereas mRNA levels of OCT1 and OATP8 were down-regulated by RIF and OPZ, respectively. Taken together, these data establish a complex pattern of transporter regulation by xenobiotics in human hepatocytes, in addition to inter-individual variability in responsiveness. This may deserve further attention with respect to drug-drug interactions and hepatic drug adverse effects.

Key words: ABC transporters, hepatic transport, hepatobiliary transport, hepatocytes, induction, organic anion transport, organic cation transport, regulation of gene expression, transporters

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