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

被引:38
作者
Anapolsky, A
Teng, S
Dixit, S
Piquette-Miller, M
机构
[1] Univ Toronto, Leslie Dan Fac Pharm, Dept Pharmaceut Sci, Toronto, ON M5S 2S2, Canada
[2] Vanderbilt Univ, Sch Med, Div Clin Pharmacol, Nashville, TN 37212 USA
关键词
D O I
10.1124/dmd.105.006197
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 beta-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.
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页码:405 / 409
页数:5
相关论文
共 41 条
[1]   Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction [J].
Bertilsson, G ;
Heidrich, J ;
Svensson, K ;
Åsman, M ;
Jendeberg, L ;
Sydow-Bäckman, M ;
Ohlsson, R ;
Postlind, H ;
Blomquist, P ;
Berkenstam, A .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (21) :12208-12213
[2]   COINDUCTION OF MDR-1 MULTIDRUG-RESISTANCE AND CYTOCHROME-P-450 GENES IN RAT-LIVER BY XENOBIOTICS [J].
BURT, RK ;
THORGEIRSSON, SS .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1988, 80 (17) :1383-1386
[3]   COMPETITIVE-BINDING AFFINITY OF CARCINOGENIC AROMATIC-AMINES TO THE RAT HEPATIC AROMATIC HYDROCARBON (AH) RECEPTOR INVITRO AND POTENCY TO INDUCE MONOOXYGENASE ACTIVITY INVIVO [J].
CIKRYT, P ;
GOTTLICHER, M ;
NEUMANN, HG .
CARCINOGENESIS, 1990, 11 (08) :1359-1366
[4]  
Drocourt L, 2001, DRUG METAB DISPOS, V29, P1325
[5]   Peptide mimetic HIV protease inhibitors are ligands for the orphan receptor SXR [J].
Dussault, I ;
Lin, M ;
Hollister, K ;
Wang, EH ;
Synold, TW ;
Forman, BM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (36) :33309-33312
[6]   Identification of a novel estrogen response element in the breast cancer resistance protein (ABCG2) gene [J].
Ee, PLR ;
Kamalakaran, S ;
Tonetti, D ;
He, XL ;
Ross, DD ;
Beck, WT .
CANCER RESEARCH, 2004, 64 (04) :1247-1251
[7]   The effect of rifampin treatment on intestinal expression of human MRP transporters [J].
Fromm, MF ;
Kauffmann, HM ;
Fritz, P ;
Burk, O ;
Kroemer, HK ;
Warzok, RW ;
Eichelbaum, M ;
Siegmund, W ;
Schrenk, D .
AMERICAN JOURNAL OF PATHOLOGY, 2000, 157 (05) :1575-1580
[8]   REGULATION OF 2-ACETYLAMINOFLUORENE MEDIATED AND 3-METHYLCHOLANTHRENE MEDIATED INDUCTION OF MULTIDRUG RESISTANCE AND CYTOCHROME-P450IA GENE FAMILY EXPRESSION IN PRIMARY HEPATOCYTE CULTURES AND RAT-LIVER [J].
GANT, TW ;
SILVERMAN, JA ;
BISGAARD, HC ;
BURT, RK ;
MARINO, PA ;
THORGEIRSSON, SS .
MOLECULAR CARCINOGENESIS, 1991, 4 (06) :499-509
[9]  
GEICK A, 2001, J BIOL CHEM, V277, P2908
[10]  
GONZALEZ FJ, 1984, MOL PHARMACOL, V26, P117