Abstract
Activation of the pregnane X receptor (PXR) mediates the induction of several drug transporters and -metabolizing enzymes. In vitro studies have reported that several of these genes are induced after exposure to the hepatocarcinogen, 2-acetylaminofluorene (2-AAF). Thus, we hypothesized that PXR may play a role in the in vivo induction of gene expression by 2-AAF. We examined the expression of the drug-metabolizing enzymes CYP1A2 and CYP3A11 and the drug transporters breast cancer resistance protein (BCRP), MRP2, and OATP2. Wild-type (PXR+/+) and PXR-null (PXR–/–) C57BL/6 mice were injected daily for 7 days with 150 or 300 mg/kg 2-AAF suspended in corn oil (i.p.), whereas the control group received corn oil vehicle. Levels of mRNA isolated from liver were measured by reverse transcription-polymerase chain reaction and normalized to β-actin. Treatment of PXR+/+ mice resulted in a dose-dependent 2- to 4-fold induction (p < 0.001) of MRP2, OATP2, BCRP, CYP3A11, and CYP1A2, but no induction was observed in PXR–/– mice. Induction of PXR mRNA was observed in the 2-AAF-treated PXR+/+ mice. Furthermore, a dose-dependent increase in CYP3A4 promoter construct activity was observed in HepG2 cells cotransfected with human or rat PXR, indicating that 2-AAF does indeed activate PXR. These results suggest that PXR is responsible for 2-AAF-mediated induction of drug efflux transporters and biotransformation enzymes in the liver. Moreover, novel findings demonstrate that PXR plays a role in regulation of the drug efflux transporter, BCRP, in mice.
Footnotes
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Funding for this study was provided by a grant from the Canadian Institutes of Health Research (CIHR).
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.006197.
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ABBREVIATIONS: 2-AAF, 2-acetylaminofluorene; PXR, pregnane X receptor; MRP, multidrug resistance-associated protein; PCR, polymerase chain reaction; OATP, organic anion transporting peptide; BCRP, breast cancer resistance protein; RU486, 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one; P450, cytochrome P450; ABC, ATP-binding cassette transporter; AhR, aryl hydrocarbon receptor.
- Received June 22, 2005.
- Accepted December 14, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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