RT Journal Article
SR Electronic
T1 Differential Regulation of Sinusoidal and Canalicular Hepatic Drug Transporter Expression by Xenobiotics Activating Drug-Sensing Receptors in Primary Human Hepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1756
OP 1763
DO 10.1124/dmd.106.010033
VO 34
IS 10
A1 Emilie Jigorel
A1 Marc Le Vee
A1 Claire Boursier-Neyret
A1 Yannick Parmentier
A1 Olivier Fardel
YR 2006
UL http://dmd.aspetjournals.org/content/34/10/1756.abstract
AB Sinusoidal and canalicular hepatic drug transporters constitute key factors involved in drug elimination from liver. 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 (2,3,7,8-tetrachlorodibenzo-p-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 three of seven 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., bile salt export pump and Na+-taurocholate cotransporting polypeptide, 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 interindividual variability in responsiveness. This may deserve further attention with respect to drug-drug interactions and adverse effects of hepatic drugs. The American Society for Pharmacology and Experimental Therapeutics