RT Journal Article
SR Electronic
T1 INDUCTION OF ABCC3 (MRP3) BY PREGNANE X RECEPTOR ACTIVATORS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1296
OP 1299
DO 10.1124/dmd.31.11.1296
VO 31
IS 11
A1 Shirley Teng
A1 Veronika Jekerle
A1 Micheline Piquette-Miller
YR 2003
UL http://dmd.aspetjournals.org/content/31/11/1296.abstract
AB The pregnane X receptor (PXR) mediates the induction of various genes by xenobiotics, including several ATP-binding cassette transporters. PXR is also activated by bile acids likely to prevent their accumulation to toxic levels; however, the role of PXR in the regulation of MRP3, an important bile acid efflux transporter, has not been elucidated. The impact of PXR activators on the hepatic expression of MRP3 was examined in vivo and in vitro. The human hepatoma cell lines HuH7 and HepG2 were treated with PXR activators including clotrimazole, rifampicin, 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU486), metyrapone, nifedipine, lithocholic acid, and 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN). Levels of MRP3 mRNA, as determined by reverse transcription-polymerase chain reaction, were induced 1.6- to 8-fold in a dose-dependent manner (p < 0.05). Corresponding decreases in the multidrug resistance-associated protein-dependent cellular retention of 5-carboxyfluorescein were also seen in the treated HuH7 cells. In vivo studies demonstrated increased PXR mRNA and induction of MRP3 mRNA in the livers of wild-type mice treated with the PXR activator RU486. On the other hand, MRP3 induction was not seen in the RU486-treated PXR-null mice. These results suggest that PXR activation may play a role in the regulation of MRP3 expression. The American Society for Pharmacology and Experimental Therapeutics