The role of pregnane X receptor in 2-acetylaminofluorene-mediated induction of drug transport and -metabolizing enzymes in mice.

摘要: Activation of the pregnane X receptor (PXR) mediates induction several drug transporters and -metabolizing enzymes. In vitro studies have reported that these genes are induced after exposure to hepatocarcinogen, 2-acetylaminofluorene (2-AAF). Thus, we hypothesized PXR may play a role in vivo gene expression by 2-AAF. We examined drug-metabolizing enzymes CYP1A2 CYP3A11 breast cancer resistance protein (BCRP), MRP2, OATP2. Wild-type (PXR+/+) PXR-null (PXR–/–) C57BL/6 mice were injected daily for 7 days with 150 or 300 mg/kg 2-AAF suspended corn oil (i.p.), whereas control group received vehicle. Levels mRNA isolated from liver measured reverse transcription-polymerase chain reaction normalized β-actin. Treatment PXR+/+ resulted dose-dependent 2- 4-fold ( p < 0.001) OATP2, BCRP, CYP3A11, CYP1A2, but no was observed PXR–/– mice. Induction 2-AAF-treated Furthermore, increase CYP3A4 promoter construct activity HepG2 cells cotransfected human rat PXR, indicating does indeed activate PXR. These results suggest is responsible 2-AAF-mediated efflux biotransformation liver. Moreover, novel findings demonstrate plays regulation transporter,