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Vol. 62, Issue 3, 638-646, September 2002
Nuclear Receptor Discovery Research (J.M.M., C.M.S., B.G., J.T.M., S.A.K.) and Bioscience Support (D.H.-B.), GlaxoSmithKline, Research Triangle Park, North Carolina
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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The nuclear pregnane X receptor (PXR) and constitutive androstane receptor (CAR) play central roles in protecting the body against environmental chemicals (xenobiotics). PXR and CAR are activated by a wide range of xenobiotics and regulate cytochrome P450 and other genes whose products are involved in the detoxification of these chemicals. In this report, we have used receptor-selective agonists together with receptor-null mice to identify PXR and CAR target genes in the liver and small intestine. Our results demonstrate that PXR and CAR regulate overlapping but distinct sets of genes involved in all phases of xenobiotic metabolism, including oxidative metabolism, conjugation, and transport. Among the murine genes regulated by PXR were those encoding PXR and CAR. We provide evidence that PXR regulates a similar program of genes involved in xenobiotic metabolism in human liver. Among the genes regulated by PXR in primary human hepatocytes were the aryl hydrocarbon receptor and its target genes CYP1A1 and CYP1A2. These findings underscore the importance of these two nuclear receptors in defending the body against a broad array of potentially harmful xenobiotics.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The
body must protect itself against myriad xenobiotics, including those
ingested in the diet or absorbed through the skin or lungs. Two members
of the nuclear receptor family of ligand-activated transcription
factors, termed the pregnane X receptor (PXR; NR1I2) and constitutive
androstane receptor (CAR; NR1I4), are expressed in the liver,
intestine, lung, and other tissues, where they have important roles in
detecting xenobiotics and stimulating genes encoding cytochrome P450
enzymes (P450s) and other proteins involved in their
detoxification and elimination from the body (Waxman, 1999
; Honkakoski
and Negishi, 2000). Mice lacking either of these receptors are
hypersensitive to treatment with various xenobiotics, including the
anesthetic tribromoethanol and the muscle relaxant zoxazolamine (Wei et
al., 2000; Xie et al., 2000a).
PXR is activated by a structurally diverse collection of xenobiotics,
including both prescription drugs (e.g., macrocyclic antibiotics,
antimycotics, glucocorticoids) and herbs (e.g., St. John's wort)
(Bertilsson et al., 1998; Blumberg et al., 1998; Kliewer et al., 1998;
Lehmann et al., 1998; Moore et al., 2000a). PXR was originally shown to
regulate the expression of CYP3A isozymes by binding as a heterodimer
with the 9-cis retinoic acid receptor (NR2B1) to xenobiotic
response elements located in the regulatory regions of these genes
(Bertilsson et al., 1998; Blumberg et al., 1998; Kliewer et al., 1998;
Lehmann et al., 1998). PXR is now known to regulate the expression of
several additional genes encoding proteins involved in xenobiotic
metabolism, including multidrug resistance protein 1 (MDR1) (Geick et
al., 2001; Synold et al., 2001), multidrug resistance-associated
protein 2 (MRP2) (Dussault et al., 2001; Kast et al., 2002), and
organic anion transporter polypeptide 2 (Staudinger et al., 2001). PXR
ligands, including the synthetic steroid pregnenolone
16
-carbonitrile (PCN) and the macrocyclic antibiotic rifampicin,
have been shown to regulate other classes of genes, including those
encoding glutathione S-transferases (GSTs),
UDP-glucuronosyltransferases (UGTs), and sulfotransferases (SULTs)
(Madhu and Klaassen, 1991; Liu and Klaassen, 1996; Dunn et al., 1999;
Runge-Morris et al., 1999; Falkner et al., 2001), which suggests a
broad role for PXR in detoxification of xenobiotics. Although PXR
evolved to protect the body, its activation by drugs represents the
basis for a common class of potentially life-threatening drug
interactions in which one drug accelerates the metabolism of another
(Moore and Kliewer, 2000). Thus, understanding the processes regulated
by PXR has important pharmaceutical ramifications.
CAR seems to be activated by a more restricted set of chemicals,
including phenobarbital (PB) and the planar hydrocarbon
1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) (Sueyoshi et
al., 1999; Moore et al., 2000b; Tzameli et al., 2000). Like PXR, CAR
regulates the expression of target genes by binding to xenobiotic
response elements as a heterodimer with 9-cis retinoic acid
receptor. CAR was originally demonstrated to regulate CYP2B
gene expression (Honkakoski et al., 1998). CAR has since been shown to
regulate a number of genes involved in a variety of biological
processes (Sugatani et al., 2001; Kast et al., 2002; Ueda et al.,
2002). Recent studies have also demonstrated overlap in the genes
regulated by PXR and CAR. For instance, PXR can regulate
CYP2B genes and CAR can regulate CYP3A genes (Xie
et al., 2000b; Goodwin et al., 2001; Smirlis et al., 2001; Wei et al.,
2002). This cross talk provides a mechanism for amplifying the body's
detoxification response to a broad range of chemicals.
In the current study, we have exploited PXR- and CAR-selective ligands as well as PXR- and CAR-null mice to examine systematically whether PXR and CAR regulate genes involved in the different phases of xenobiotic metabolism in murine liver and small intestine and in human hepatocytes.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Chemicals. PCN was purchased from Biomol Research Labs (Plymouth Meeting, PA), PB and rifampicin were purchased from Sigma-Aldrich Chemical Co. (St. Louis, MO), and TCPOBOP was purchased from Maybridge plc (Tintagel, England).
Human Hepatocytes. Human hepatocytes were purchased from BioWhittaker, Inc. (Walkersville, MD). They were maintained in Williams' Medium E (Invitrogen, Carlsbad, CA) supplemented with 100 nM dexamethasone (Invitrogen), 2 mM L-glutamine (Invitrogen) and insulin-transferrin-selenium (Invitrogen) and were treated with either rifampicin (10 µM) or PB (1 mM). Rifampicin was added to the culture medium as a 1000× stock in DMSO; PB was added directly into the medium. Control cultures received DMSO alone. Cells were harvested after 48 h.
Experimental Animals and Protocols.
All procedures performed
were in compliance with the Animal Welfare Act and Unites States
Department of Agriculture regulations and were approved by the
GlaxoSmithKline Institutional Animal Care and Use Committee. CAR-null
mice were generated by Deltagen, Inc. (Redwood City, CA) by homologous
recombination using a targeting vector that deletes nucleotides 38 to
159 of the CAR open reading frame. This targeting event removes the
first zinc finger of the DNA binding domain and results in a frame
shift. PXR-null mice were generated as described previously (Staudinger
et al., 2001). Mice were maintained on standard laboratory chow and
were allowed food and water ad libitum. Six- to eight- week old
PXR-null, CAR-null, and wild-type mice (three per group) were treated
for 28 h with either vehicle (corn oil plus 5% DMSO), PCN (100 mg/kg), or TCPOBOP (0.3 mg/kg) in corn oil plus 5% DMSO. Two
intraperitoneal injections were administered at 0 h and 24 h
and the mice were sacrificed 4 h after the last injection. Livers
and epithelial cells derived by scraping the small intestine were
frozen in liquid nitrogen.
RNA Preparation and Real Time Quantitative PCR Analysis.
Total RNA from mouse tissues or human hepatocytes were isolated using
TRIzol reagent (Invitrogen) according to the manufacturer's instructions. Real-time quantitative PCR (RTQ-PCR) was performed using
an ABI PRISM 7700 Sequence Detection System instrument and software
(Applied Biosystems, Inc., Foster City, CA). RNA samples were diluted
to 100 µg/ml and treated with 40 U/ml RNA-free deoxyribonuclease I
for 30 min at 37° C followed by inactivation at 75° C for 5 min.
Samples were quantitated by spectrophotometry and diluted to a
concentration of 10 ng/µl. Samples were then assayed in duplicate or
triplicate 25-µl reactions using 25 ng of RNA per reaction. Gene-specific primers were used at 7.5 or 23 pmol per reaction and the
gene-specific probe was used at 5 pmol per reaction. Primers and probes
were designed using Primer Express Version 2.0.0 (Applied Biosystems)
and synthesized by Keystone Laboratories (Camarillo, CA). All primers
and probes were entered into the NCBI Blast program to ensure
specificity. Fold induction values were calculated by subtracting the
mean threshold cycle number for each treatment group from the mean
threshold cycle number for the vehicle group and raising 2 to the power
of this difference. The expression levels of selected mouse genes
(Table 1) and human genes (Table 2) were compared between vehicle and
chemical treatment. For animal studies, the average of each treatment
group (3 animals per group) was used.
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Northern Blot Analysis.
Total RNA (10 µg) was resolved on
a 1% agarose/2.2 M formaldehyde denaturing gel and transferred to a
nylon membrane (Hybond N+; Amersham Bioscience, Piscataway, NJ). Blots
were hybridized with 32P-labeled cDNAs
corresponding to mALAS1 (bases 599-1037 of the published cDNA; GenBank
accession number M63245), mouse UGT1a1 (bases 561-845 of the published
cDNA; GenBank accession number L27122), human CYP1A1 (bases 82-1620 of
the published cDNA; GenBank accession number BC023019), human CYP1A2
(bases 65-1612 of the published cDNA; GenBank accession number
NM_000761), or human UGT1A1 (bases 75-766 of the published cDNA;
Genbank accession number NM000463). The blots were subsequently
reprobed with a radiolabeled 
-actin cDNA (BD Clontech Laboratories
Inc., Palo Alto, CA). The intensity of signals was quantified using
ImageQuant software (Molecular Dynamics, Sunnyvale, CA).
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Wild-type or PXR-null mice were treated with the PXR-selective
ligand PCN or vehicle alone. In parallel, wild-type or CAR-null mice
were treated with the CAR-selective ligand TCPOBOP. RNA was prepared
from the livers and small intestines of the mice, and the expression of
36 candidate genes involved in xenobiotic metabolism was evaluated by
RTQ-PCR. The complete list of mouse genes that were analyzed is shown
in Table 1. Data for genes whose expression was changed 
1.5-fold in
one or both tissues are shown in Table 3.
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Genes Encoding Phase I (Oxidative Metabolism) Enzymes. As expected, Cyp3a11 was induced by PCN treatment in both liver and small intestine (Table 3, line 6). No regulation of Cyp3a11 was observed in PXR-null mice. Cyp3a11 expression was also induced by TCPOBOP in the liver but not the small intestine of wild-type mice (Table 3, line 6). This induction was not seen in the CAR-null mice. These data demonstrate that both PXR and CAR regulate Cyp3a11 expression in vivo. Expression of Cyp2b10, the prototypical CAR target gene, was dramatically induced in the liver and modestly induced in the small intestine of wild-type mice treated with TCPOBOP (Table 3, line 5). These effects were not seen in CAR-null mice. PCN also induced Cyp2b10 expression in the liver and small intestine, albeit to a much lesser extent than TCPOBOP (Table 3, line 5), indicating that CAR has more robust effects on Cyp2b10 expression than PXR.
We examined whether PXR and CAR regulate other P450s. TCPOBOP had a modest inductive effect on Cyp1a1 in liver and no effect in small intestine in wild-type mice (Table 3, line 3). Notably, TCPOBOP decreased Cyp1a1 expression in the small intestine of CAR-null mice, suggesting that this chemical may have CAR-independent effects on gene expression. PCN did not affect Cyp1a1 expression in liver but strongly suppressed its expression in small intestine in a PXR-dependent manner (Table 3, line 3). Similarly, PXR has previously been shown to repress expression of Cyp7a1 (Staudinger et al., 2001). Thus, PXR can either stimulate or suppress
gene expression. Cyp1a1 is known to be highly inducible by
2,3,7,8-tetrachlorodibenzo-p-dioxin and polycyclic aromatic
hydrocarbon carcinogens. This induction is mediated by the aryl
hydrocarbon receptor (AhR), a member of the
helix-loop-helix/PER/ARNT/SIM (periodicity/AhR nuclear
translocator/single-minded) family of transcription factors (Honkakoski
and Negishi, 2000). Ahr expression was modestly induced by
TCPOBOP in liver in a CAR-dependent manner (Table 3, line 20),
suggesting that CAR may regulate Cyp1a1 indirectly though
effects on AhR.
As reported previously (Smith et al., 1993; Wei et al., 2002), TCPOBOP
induced the expression of Cyp2a4 in the liver of wild-type mice (Table 3, line 4). Consistent with the results of others, this
effect was not seen in CAR-null mice (Wei et al., 2002). TCPOBOP did
not affect Cyp2a4 expression in the small intestine. PCN had
no effect on Cyp2a4 in either tissue. CYP2A4 hydroxylates a
variety of steroid hormones, including androgens and estrogens, at the
15 position, and also metabolizes xenobiotics (Fernandez-Salguero and
Gonzalez, 1995). The regulation of Cyp2a4 by CAR but not PXR suggests that these two receptors may have distinct roles in
metabolizing endogenous steroids.
P450s require a heme prosthetic group to oxidize substrates.
Aminolevulinic acid synthase 1 (ALAS1) catalyzes the first and rate-limiting step in heme biosynthesis and is up-regulated in response
to various xenobiotics, including the CAR activator PB (May et al.,
1995). Alas1 expression was increased 2.9- and 3.4-fold in
the liver and small intestine, respectively, of wild-type mice treated
with PCN (Table 3, line 19). This induction was reduced to 1.7-fold in
the liver and was completely absent in the small intestine of PXR-null
mice, indicating a role for PXR in the induction of Alas1
expression. The regulation of Alas1 by TCPOBOP was notable in two respects (Table 3, line 19). First Alas1 was induced
by TCPOBOP in liver but not small intestine. Second, the induction of
Alas1 expression was not diminished in the CAR-null mice,
indicating that the effect of TCPOBOP on Alas1 expression
does not require CAR. Similar data were obtained via Northern blot
analysis (Figure 1). PCN treatment
increased liver Alas1 expression 4.2-fold in wild-type mice
and 2.1-fold in PXR-null mice, whereas TCPOBOP increased
Alas1 expression by 2-fold in the wild-type mice and 3.6-fold in the CAR-null mice. The basis for TCPOBOP-mediated induction
of Alas1 remains unclear. A similar, CAR-independent induction of Alas1 by PB was recently reported (Ueda et al.,
2002). PXR and CAR also regulated the expression of the gene encoding P450 oxidoreductase, which is an essential component of the P450 monooxygenase complex and binds FMN, FAD, and NADPH cofactors. PCN
induced Por in the liver and intestine (Table 3, line 21); these effects were either reduced or eliminated in PXR-null mice. TCPOBOP up-regulated Por in liver via a mechanism that was
partially dependent on CAR (Table 3, line 21). Similar results have
been reported using PB (Ueda et al., 2002).
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).
PCN treatment induced the expression of Aldh1a7 in mouse
liver and small intestine in a PXR-dependent fashion (Table 3, line 2).
PCN also induced the expression of the gene encoding ALDH1A1 (Table 3,
line 1), a closely related protein involved in retinoic acid metabolism
(Vasiliou et al., 2000). TCPOBOP induced the expression of
Aldh1a1 and Aldh1a7 in the liver in a
CAR-dependent manner but did not increase their expression in the small
intestine (Table 3, lines 1 and 2).
Genes Encoding Phase II (Conjugation) Enzymes.
We examined the
expression of a number of genes encoding different classes of phase II
enzymes including GSTs, UGTs, and SULTs (Mulder and Jakoby, 1990). GSTs
catalyze the conjugation of glutathione to electrophilic substrates,
which are often the products of phase I metabolism. These substrates
include xenobiotics. Thus, GST conjugation is a major pathway for the
detoxification of a variety of different substances. The mammalian GSTs
are divided into several families of cytosolic enzymes including GSTs
(GSTA), µ (GSTM), and, 
(GSTT). Several GST genes were
regulated by PXR and/or CAR including Gsta1,
Gstm1, Gstm2, and Gstt1 (Table 3,
lines 7-10). Gsta1 was markedly induced by PCN (16-fold)
and TCPOBOP (15-fold) in liver (Table 3, line 7). This induction was
absent in PXR-null and CAR-null mice. A more modest induction of
Gsta1 (4.3-fold) was observed in the small intestine of
PCN-treated mice; in contrast, no induction of Gsta1 was
observed in the small intestine of TCPOBOP-treated animals (Table 3,
line 7). PCN induced the expression of the Gstm1 and
Gstm2 isoforms in the liver and small intestine in a
PXR-dependent manner (Table 3, lines 8 and 9). Whereas TCPOBOP induced
expression of both Gstm1 and Gstm2 in the liver,
only Gstm1 was induced in the small intestine (Table 3,
lines 8 and 9). No induction of Gstm1 was seen in the livers of TCPOBOP-treated CAR-null mice; in fact, TCPOBOP decreased
Gstm1 expression in these animals (Table 3, line 8).
However, Gstm2 was still induced by TCPOBOP in the livers of
CAR-null animals. Taken together, these data reveal a complex pattern
of GST regulation by PCN and TCPOBOP in the liver and small intestine
of mice, including PXR- and CAR-dependent and independent effects.
).
TCPOBOP induced expression of the sulfotransferase gene
Sultn in liver but not small intestine (Table 3, line 11);
this regulation was lost in CAR-null mice. PCN had no effect on
Sultn in either tissue. TCPOBOP did not regulate Ugt1a1 1.5-fold in the liver as assessed by RTQ-PCR. This
was unexpected because a previous study showed that PB induces UGT1A1 in human hepatocytes via CAR (Sugatani et al., 2001). This
apparent disparity may reflect either differences in the chemicals used or the species studied. Conversely, PCN up-regulated Ugt1a1
2.8-fold in liver in a PXR-dependent manner but had a lesser effect
(1.6-fold) in the small intestine (Table 3, line 12). Similar data were obtained by Northern blot analysis (Figure
2). PCN treatment increased liver
Ugt1a1 expression by only 1.7-fold in the wild-type mouse but had little or no effect in the PXR knock-out strain. TCPOBOP had
only very modest effects on Ugt1a1 expression in wild-type and CAR-null mice (~1.5- and 1.2-fold, respectively) as measured by
Northern blot analysis. Overall, the data demonstrate that PXR and CAR
regulate a program of genes whose products conjugate xenobiotics.
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Genes Encoding Transporters.
We examined the expression of
several proteins that transport xenobiotics and other lipophilic
substances in enterohepatic tissues including MDR1a and MDR1b, which
function as broad-specificity efflux pumps in the intestine and apical
transporters in the liver, and MRP2 and MRP3 (Stieger and Meier, 1998).
MDR1 has been shown to be regulated by PXR in human
intestinal cell lines (Geick et al., 2001; Synold et al., 2001);
MRP2 is regulated by CAR and PXR in vitro (Dussault et al.,
2001; Kast et al., 2002); MRP3 is regulated by both CAR and
PXR activators (Ogawa et al., 2000; Schrenk et al., 2001). Both
Mdr1a and Mdr1b were up-regulated by PCN in the
liver and intestine in a PXR-dependent manner (Table 3, lines 13 and
14). Mdr1a was regulated 1.7-fold by TCPOBOP in the liver
and intestine of wild-type mice (Table 3, line 13). TCPOBOP-mediated
regulation of Mdr1a was absent in the small intestine of
CAR-null mice but was intact in the livers of TCPOBOP-treated CAR-null
mice. TCPOBOP did not regulate Mdr1b expression (Table 3,
line 14). Expression of MRP2, a basolateral protein that transports glutathione and sulfate conjugates of xenobiotics and various natural
compounds, was modestly increased in the small intestine of PCN-treated
mice and the liver of TCPOBOP-treated mice (Table 3, line 16). These
effects were absent in the corresponding receptor-null mice. Expression
of MRP3, which mediates the sinusoidal efflux of organic anions, was
induced 3.0-fold and 1.9-fold in the livers of PCN and TCPOBOP-treated
mice, respectively (Table 3, line 17). These effects were not observed
in the PXR- and CAR-null mice. Thus, PXR and CAR regulate distinct but
overlapping sets of genes encoding xenobiotic transporters in the liver
and small intestine.
Human Hepatocytes.
We next examined whether PXR and CAR
activators regulated a similar program of genes in human hepatocytes.
Primary cultures of human hepatocytes derived from two different donors
were treated with either rifampicin or PB, and the expression of
fourteen genes involved in xenobiotic metabolism was evaluated by
RTQ-PCR. Rifampicin is a selective ligand for human PXR; PB activates
both human CAR and human PXR (Lehmann et al., 1998; Pascussi et al.,
2000). No selective activators of human CAR have been reported to date. The complete list of human genes analyzed is shown in Table 2.
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). This effect may be mediated through CAR because
rifampicin had little or no effect on UGT1A1 expression
(Figure 4). Taken together, our data support a role for PXR and perhaps
CAR in the regulation of genes involved in different phases of
xenobiotic metabolism in human hepatoctyes.
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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It is well established that PXR and CAR regulate the expression of
P450 family members, including CYP2B, CYP2C, CYP2H, and CYP3A isozymes,
in various species (Waxman, 1999; Honkakoski and Negishi, 2000). In
this report, we have exploited receptor-selective agonists to identify
additional genes regulated by PXR in murine liver and intestine and in
primary cultures of human hepatocytes. Our results demonstrate that PXR
and CAR coordinately regulate programs of genes involved in all phases
of xenobiotic metabolism, including oxidative metabolism, conjugation,
and transport in mouse liver and small intestine. Moreover, our data
provide evidence that PXR has a similarly broad regulatory role in
human hepatocytes. Many of the genes regulated by PXR and/or CAR are
also implicated in the metabolism and excretion of bilirubin and bile
acids and other steroids. Because both CAR and PXR can be regulated by
endogenous substances, such as steroids (Forman et al., 1998; Kliewer
et al., 1998; Moore et al., 2000b; Staudinger et al., 2001; Xie et al.,
2001), these nuclear receptors may also be important components in the
body's defenses against chemicals that are produced during periods of
stress or disease.
Although there is a high degree of overlap in the genes regulated by PXR and CAR, there are many genes that are differentially regulated by these two receptors in mice. Two interesting trends emerged in our mouse studies. First, PXR regulated a number of genes in small intestine that were not regulated by CAR, including Aldh1a1, Aldh1a7, Cyp3a11, Gsta1, Gstm2, Mdr1b, and Mrp2 (Table 3). Second, CAR stimulated the expression of several genes in liver that were not regulated by PXR, including Cyp1a1, Cyp2a4, Sultn, Mrp1, and Mrp2 (Table 3). These data suggest that PXR and CAR have overlapping but distinct biological functions and, furthermore, suggest that PXR and CAR may play more dominant roles in xenobiotic metabolism in small intestine and liver, respectively.
Among the genes regulated by PXR in murine liver were those encoding PXR and CAR (Table 3, lines 22 and 23). These data demonstrate that PXR is under autoregulation and reveal an additional level of cross-talk between PXR and CAR. This cross talk is asymmetric in that CAR did not regulate Pxr expression. PXR also weakly regulated its own expression in human hepatocytes derived from one of the two donors but did not seem to regulate CAR (Table 4, lines 14 and 15). Thus, PXR may be weakly autoregulatory in the human liver.
We note that several genes, including Alas1,
Gstm2, and Por, seem to be regulated by TCPOBOP
in a CAR-independent fashion (Table 3, lines 9, 19, 21). Similar
CAR-independent effects on Alas1 expression in liver were
recently described for PB (Ueda et al., 2002). It also seems that there
may be a PXR-independent component to PCN regulation of
Alas1 in mouse liver (Table 3, line 19). These data suggest
that these chemicals mediate at least some of their effects through
other signaling pathways. Moreover, they underscore the importance of
using genetic models such as receptor-null mice to validate the
pharmacologic data derived with receptor-selective ligands.
Our data indicate that PXR regulates a similar program of genes involved in the solubilization and excretion of xenobiotics in mouse and human hepatocytes. However, there seem to be species-specific effects. One of the most interesting of these differences relates to AhR and its target genes CYP1A1 and CYP1A2. In human hepatocytes, activation of PXR by rifampicin results in a modest induction of AhR and a marked induction of its target genes CYP1A1 and CYP1A2 (Table 4, lines 2, 3, and 12). These data raise the intriguing possibility that in human liver, PXR activation effectively primes hepatocytes to respond to challenges by other classes of xenobiotics such as aryl hydrocarbons that might otherwise escape detection by PXR. Thus, there seems to be cross-talk between different structural classes of xenobiotic-sensing transcription factors. We do not know at this point whether PXR regulates AhR, CYP1A1, and CYP1A2 directly or indirectly. In contrast, activation of PXR by PCN in mouse liver did not induce either AhR or Cyp1a1 (Table 3, lines 3 and 20). Expression of both AhR and Cyp1a1 was induced modestly in mouse liver by activation of CAR (Table 3, lines 3 and 20).
In summary, we have shown that PXR and CAR regulate overlapping but distinct programs of genes involved in the detoxification of xenobiotics and endogenous lipophilic chemicals in mice. Moreover, we show that PXR regulates a similar program of genes in human hepatocytes. Our data provide evidence for a broad role for these nuclear receptors in defending the body against potentially harmful chemicals.
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Acknowledgments |
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We are indebted to Mary Cameron, Jennifer Dew, Joe Watson, and Jo Sledge for their technical assistance and Dr. Curtis Klaasen for comments on the manuscript.
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Footnotes |
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Received February 1, 2001; Accepted May 20, 2001
J.M.M. and C.M.S. contributed equally to this work.
Address correspondence to: Dr. Steven A. Kliewer, Department of Molecular Biology, University of Texas Southwestern Medical Center, Building NC7.214, 5323 Harry Hines Blvd., Dallas, TX 75390-8594. E-mail: steven.kliewer{at}utsouthwestern.edu
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Abbreviations |
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PXR, pregnane X receptor;
CAR, constitutive
androstane receptor;
P450, cytochrome P450;
MDR, multidrug resistance
protein;
MRP, multidrug resistance-associated protein;
PCN, pregnenolone 16-carbonitrile;
GST, glutathione
S-transferase;
UGT, UDP glucuronosyltransferase;
SULT, sulfotransferase;
PB, phenobarbital;
TCPOBOP, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene;
DMSO, dimethyl sulfoxide;
RTQ-PCR, real time quantitative polymerase chain reaction;
AhR, aryl
hydrocarbon receptor.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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.
Nature (Lond)
395:
612-615[CrossRef][Medline].-carbonitrile on acetaminophen-induced hepatotoxicity in hamsters.
Toxicol Appl Pharmacol
109:
305-313[CrossRef][Medline].This article has been cited by other articles:
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  C. Xu, X. Wang, and J. L. Staudinger Regulation of Tissue-Specific Carboxylesterase Expression by Pregnane X Receptor and Constitutive Androstane Receptor Drug Metab. Dispos., July 1, 2009; 37(7): 1539 - 1547. [Abstract] [Full Text] [PDF]
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V. Chu, H. J. Einolf, R. Evers, G. Kumar, D. Moore, S. Ripp, J. Silva, V. Sinha, M. Sinz, and A. Skerjanec In Vitro and in Vivo Induction of Cytochrome P450: A Survey of the Current Practices and Recommendations: A Pharmaceutical Research and Manufacturers of America Perspective Drug Metab. Dispos., July 1, 2009; 37(7): 1339 - 1354. [Abstract] [Full Text] [PDF]
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 M. Ott, G. Fricker, and B. Bauer Pregnane X Receptor (PXR) Regulates P-Glycoprotein at the Blood-Brain Barrier: Functional Similarities between Pig and Human PXR J. Pharmacol. Exp. Ther., April 1, 2009; 329(1): 141 - 149. [Abstract] [Full Text] [PDF]
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 K. Lichti-Kaiser, C. Xu, and J. L. Staudinger Cyclic AMP-dependent Protein Kinase Signaling Modulates Pregnane x Receptor Activity in a Species-specific Manner J. Biol. Chem., March 13, 2009; 284(11): 6639 - 6649. [Abstract] [Full Text] [PDF]
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 N. Hariparsad, X. Chu, J. Yabut, P. Labhart, D. P. Hartley, X. Dai, and R. Evers Identification of pregnane-X receptor target genes and coactivator and corepressor binding to promoter elements in human hepatocytes Nucleic Acids Res., March 1, 2009; 37(4): 1160 - 1173. [Abstract] [Full Text] [PDF]
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D. T. Szabo, V. M. Richardson, D. G. Ross, J. J. Diliberto, P. R. S. Kodavanti, and L. S. Birnbaum Effects of Perinatal PBDE Exposure on Hepatic Phase I, Phase II, Phase III, and Deiodinase 1 Gene Expression Involved in Thyroid Hormone Metabolism in Male Rat Pups Toxicol. Sci., January 1, 2009; 107(1): 27 - 39. [Abstract] [Full Text] [PDF]
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K. Lichti-Kaiser and J. L. Staudinger The Traditional Chinese Herbal Remedy Tian Xian Activates Pregnane X Receptor and Induces CYP3A Gene Expression in Hepatocytes Drug Metab. Dispos., August 1, 2008; 36(8): 1538 - 1545. [Abstract] [Full Text] [PDF]
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C. Naspinski, X. Gu, G.-D. Zhou, S. U. Mertens-Talcott, K. C. Donnelly, and Y. Tian Pregnane X Receptor Protects HepG2 Cells from BaP-Induced DNA Damage Toxicol. Sci., July 1, 2008; 104(1): 67 - 73. [Abstract] [Full Text] [PDF]
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 M. B. Rosen, B. D. Abbott, D. C. Wolf, J. C. Corton, C. R. Wood, J. E. Schmid, K. P. Das, R. D. Zehr, E. T. Blair, and C. Lau Gene Profiling in the Livers of Wild-type and PPAR{alpha}-Null Mice Exposed to Perfluorooctanoic Acid Toxicol Pathol, June 1, 2008; 36(4): 592 - 607. [Abstract] [Full Text] [PDF]
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R. S. Sane, D. J. Buckley, A. R. Buckley, S. C. Nallani, and P. B. Desai Role of Human Pregnane X Receptor in Tamoxifen- and 4-Hydroxytamoxifen-Mediated CYP3A4 Induction in Primary Human Hepatocytes and LS174T Cells Drug Metab. Dispos., May 1, 2008; 36(5): 946 - 954. [Abstract] [Full Text] [PDF]
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M. B. Rosen, J. S. Lee, H. Ren, B. Vallanat, J. Liu, M. P. Waalkes, B. D. Abbott, C. Lau, and J. C. Corton Toxicogenomic Dissection of the Perfluorooctanoic Acid Transcript Profile in Mouse Liver: Evidence for the Involvement of Nuclear Receptors PPAR{alpha} and CAR Toxicol. Sci., May 1, 2008; 103(1): 46 - 56. [Abstract] [Full Text] [PDF]
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 H. Wang, H. Li, L. B. Moore, M. D. L. Johnson, J. M. Maglich, B. Goodwin, O. R. R. Ittoop, B. Wisely, K. Creech, D. J. Parks, et al. The Phytoestrogen Coumestrol Is a Naturally Occurring Antagonist of the Human Pregnane X Receptor Mol. Endocrinol., April 1, 2008; 22(4): 838 - 857. [Abstract] [Full Text] [PDF]
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J. B. Silkworth, E. A. Carlson, C. McCulloch, K. Illouz, S. Goodwin, and T. R. Sutter Toxicogenomic Analysis of Gender, Chemical, and Dose Effects in Livers of TCDD- or Aroclor 1254-Exposed Rats Using a Multifactor Linear Model Toxicol. Sci., April 1, 2008; 102(2): 291 - 309. [Abstract] [Full Text] [PDF]
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 A. Roth, R. Looser, M. Kaufmann, S. M. Blattler, F. Rencurel, W. Huang, D. D. Moore, and U. A. Meyer Regulatory Cross-Talk between Drug Metabolism and Lipid Homeostasis: Constitutive Androstane Receptor and Pregnane X Receptor Increase Insig-1 Expression Mol. Pharmacol., April 1, 2008; 73(4): 1282 - 1289. [Abstract] [Full Text] [PDF]
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 R. Callaghan, E. Crowley, S. Potter, and I. D. Kerr P-glycoprotein: So Many Ways to Turn It On J. Clin. Pharmacol., March 1, 2008; 48(3): 365 - 378. [Abstract] [Full Text] [PDF]
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Y. Alnouti and C. D. Klaassen Regulation of Sulfotransferase Enzymes by Prototypical Microsomal Enzyme Inducers in Mice J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 612 - 621. [Abstract] [Full Text] [PDF]
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V. Dixit, N. Hariparsad, F. Li, P. Desai, K. E. Thummel, and J. D. Unadkat Cytochrome P450 Enzymes and Transporters Induced by Anti-Human Immunodeficiency Virus Protease Inhibitors in Human Hepatocytes: Implications for Predicting Clinical Drug Interactions Drug Metab. Dispos., October 1, 2007; 35(10): 1853 - 1859. [Abstract] [Full Text] [PDF]
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M. Wortham, M. Czerwinski, L. He, A. Parkinson, and Y.-J. Y. Wan Expression of Constitutive Androstane Receptor, Hepatic Nuclear Factor 4{alpha}, and P450 Oxidoreductase Genes Determines Interindividual Variability in Basal Expression and Activity of a Broad Scope of Xenobiotic Metabolism Genes in the Human Liver Drug Metab. Dispos., September 1, 2007; 35(9): 1700 - 1710. [Abstract] [Full Text] [PDF]
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M. B. Dail, S. C. Burgess, E. C. Meek, J. Wagner, J. Baravik, and J. E. Chambers Spatial Distribution of CYP2B1/2 Messenger RNA within the Rat Liver Acinus following Exposure to the Inducers Phenobarbital and Dieldrin Toxicol. Sci., September 1, 2007; 99(1): 35 - 42. [Abstract] [Full Text] [PDF]
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R. C. Peffer, J. G. Moggs, T. Pastoor, R. A. Currie, J. Wright, G. Milburn, F. Waechter, and I. Rusyn Mouse Liver Effects of Cyproconazole, a Triazole Fungicide: Role of the Constitutive Androstane Receptor Toxicol. Sci., September 1, 2007; 99(1): 315 - 325. [Abstract] [Full Text] [PDF]
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J. P. Hernandez, W. Huang, L. M. Chapman, S. Chua, D. D. Moore, and W. S. Baldwin The Environmental Estrogen, Nonylphenol, Activates the Constitutive Androstane Receptor Toxicol. Sci., August 1, 2007; 98(2): 416 - 426. [Abstract] [Full Text] [PDF]
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M.-L. Ricketts, M. V. Boekschoten, A. J. Kreeft, G. J. E. J. Hooiveld, C. J. A. Moen, M. Muller, R. R. Frants, S. Kasanmoentalib, S. M. Post, H. M. G. Princen, et al. The Cholesterol-Raising Factor from Coffee Beans, Cafestol, as an Agonist Ligand for the Farnesoid and Pregnane X Receptors Mol. Endocrinol., July 1, 2007; 21(7): 1603 - 1616. [Abstract] [Full Text] [PDF]
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C. G. Woods, J. P. Vanden Heuvel, and I. Rusyn Genomic Profiling in Nuclear Receptor-Mediated Toxicity Toxicol Pathol, June 1, 2007; 35(4): 474 - 494. [Abstract] [Full Text] [PDF]
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S. S. Auerbach, J. G. DeKeyser, M. A. Stoner, and C. J. Omiecinski CAR2 Displays Unique Ligand Binding and RXR{alpha} Heterodimerization Characteristics Drug Metab. Dispos., March 1, 2007; 35(3): 428 - 439. [Abstract] [Full Text] [PDF]
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A. Kawase, Y. Tsunokuni, and M. Iwaki Effects of Alterations in CAR on Bilirubin Detoxification in Mouse Collagen-Induced Arthritis Drug Metab. Dispos., February 1, 2007; 35(2): 256 - 261. [Abstract] [Full Text] [PDF]
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 M. G Traber Heart disease and single-vitamin supplementation Am. J. Clinical Nutrition, January 1, 2007; 85(1): 293S - 299S. [Abstract] [Full Text] [PDF]
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J. Yang and B. Yan Photochemotherapeutic Agent 8-Methoxypsoralen Induces Cytochrome P450 3A4 and Carboxylesterase HCE2: Evidence on an Involvement of the Pregnane X Receptor Toxicol. Sci., January 1, 2007; 95(1): 13 - 22. [Abstract] [Full Text] [PDF]
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J. W. Allen, D. C. Wolf, M. H. George, S. D. Hester, G. Sun, S.-F. Thai, D. A. Delker, T. Moore, C. Jones, G. Nelson, et al. Toxicity Profiles in Mice Treated with Hepatotumorigenic and Non-Hepatotumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil Toxicol Pathol, December 1, 2006; 34(7): 853 - 862. [Abstract] [Full Text] [PDF]
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W. O. Ward, D. A. Delker, S. D. Hester, S.-F. Thai, D. C. Wolf, J. W. Allen, and S. Nesnow Transcriptional Profiles in Liver from Mice Treated with Hepatotumorigenic and Nonhepatotumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil Toxicol Pathol, December 1, 2006; 34(7): 863 - 878. [Abstract] [Full Text] [PDF]
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S. D. Hester, D. C. Wolf, S. Nesnow, and S.-F. Thai Transcriptional Profiles in Liver from Rats Treated with Tumorigenic and Non-tumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil Toxicol Pathol, December 1, 2006; 34(7): 879 - 894. [Abstract] [Full Text] [PDF]
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J. P. Jackson, S. S. Ferguson, M. Negishi, and J. A. Goldstein Phenytoin Induction of the Cyp2c37 Gene Is Mediated by the Constitutive Androstane Receptor Drug Metab. Dispos., December 1, 2006; 34(12): 2003 - 2010. [Abstract] [Full Text] [PDF]
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J. Guzelian, J. L. Barwick, L. Hunter, T. L. Phang, L. C. Quattrochi, and P. S. Guzelian Identification of Genes Controlled by the Pregnane X Receptor by Microarray Analysis of mRNAs from Pregnenolone 16{alpha}-Carbonitrile-Treated Rats Toxicol. Sci., December 1, 2006; 94(2): 379 - 387. [Abstract] [Full Text] [PDF]
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H. Sakai, H. Iwata, E.-Y. Kim, O. Tsydenova, N. Miyazaki, E. A. Petrov, V. B. Batoev, and S. Tanabe Constitutive Androstane Receptor (CAR) as a Potential Sensing Biomarker of Persistent Organic Pollutants (POPs) in Aquatic Mammal: Molecular Characterization, Expression Level, and Ligand Profiling in Baikal Seal (Pusa sibirica) Toxicol. Sci., November 1, 2006; 94(1): 57 - 70. [Abstract] [Full Text] [PDF]
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 F. N. C. Gropp, D. L. Greger, C. Morel, S. Sauter, and J. W. Blum Nuclear receptor and nuclear receptor target gene messenger ribonucleic acid levels at different sites of the gastrointestinal tract and in liver of healthy dogs J Anim Sci, October 1, 2006; 84(10): 2684 - 2691. [Abstract] [Full Text] [PDF]
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X. Ding, K. Lichti, I. Kim, F. J. Gonzalez, and J. L. Staudinger Regulation of Constitutive Androstane Receptor and Its Target Genes by Fasting, cAMP, Hepatocyte Nuclear Factor {alpha}, and the Coactivator Peroxisome Proliferator-activated Receptor {gamma} Coactivator-1{alpha} J. Biol. Chem., September 8, 2006; 281(36): 26540 - 26551. [Abstract] [Full Text] [PDF]
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 K. Chu, M. Miyazaki, W. C. Man, and J. M. Ntambi Stearoyl-Coenzyme A Desaturase 1 Deficiency Protects against Hypertriglyceridemia and Increases Plasma High-Density Lipoprotein Cholesterol Induced by Liver X Receptor Activation. Mol. Cell. Biol., September 1, 2006; 26(18): 6786 - 6798. [Abstract] [Full Text] [PDF]
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A. L. Slitt, N. J. Cherrington, C. D. Fisher, M. Negishi, and C. D. Klaassen INDUCTION OF GENES FOR METABOLISM AND TRANSPORT BY TRANS-STILBENE OXIDE IN LIVERS OF SPRAGUE-DAWLEY AND WISTAR-KYOTO RATS Drug Metab. Dispos., July 1, 2006; 34(7): 1190 - 1197. [Abstract] [Full Text] [PDF]
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S. R. Faucette, T. Sueyoshi, C. M. Smith, M. Negishi, E. L. LeCluyse, and H. Wang Differential Regulation of Hepatic CYP2B6 and CYP3A4 Genes by Constitutive Androstane Receptor but Not Pregnane X Receptor J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1200 - 1209. [Abstract] [Full Text] [PDF]
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X. Ding, K. Lichti, and J. L. Staudinger The Mycoestrogen Zearalenone Induces CYP3A through Activation of the Pregnane X Receptor Toxicol. Sci., June 1, 2006; 91(2): 448 - 455. [Abstract] [Full Text] [PDF]
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G. Lemaire, W. Mnif, J.-M. Pascussi, A. Pillon, F. Rabenoelina, H. Fenet, E. Gomez, C. Casellas, J.-C. Nicolas, V. Cavailles, et al. Identification of New Human Pregnane X Receptor Ligands among Pesticides Using a Stable Reporter Cell System Toxicol. Sci., June 1, 2006; 91(2): 501 - 509. [Abstract] [Full Text] [PDF]
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A. L. Slitt, N. J. Cherrington, M. Z. Dieter, L. M. Aleksunes, G. L. Scheffer, W. Huang, D. D. Moore, and C. D. Klaassen trans-Stilbene Oxide Induces Expression of Genes Involved in Metabolism and Transport in Mouse Liver via CAR and Nrf2 Transcription Factors Mol. Pharmacol., May 1, 2006; 69(5): 1554 - 1563. [Abstract] [Full Text] [PDF]
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H. Gong, S. V. Singh, S. P. Singh, Y. Mu, J. H. Lee, S. P. S. Saini, D. Toma, S. Ren, V. E. Kagan, B. W. Day, et al. Orphan Nuclear Receptor Pregnane X Receptor Sensitizes Oxidative Stress Responses in Transgenic Mice and Cancerous Cells Mol. Endocrinol., February 1, 2006; 20(2): 279 - 290. [Abstract] [Full Text] [PDF]
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 Y. Miki, T. Suzuki, K. Kitada, N. Yabuki, R. Shibuya, T. Moriya, T. Ishida, N. Ohuchi, B. Blumberg, and H. Sasano Expression of the Steroid and Xenobiotic Receptor and Its Possible Target Gene, Organic Anion Transporting Polypeptide-A, in Human Breast Carcinoma Cancer Res., January 1, 2006; 66(1): 535 - 542. [Abstract] [Full Text] [PDF]
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S. Aouabdi, G. Gibson, and N. Plant TRANSCRIPTIONAL REGULATION OF THE PXR GENE: IDENTIFICATION AND CHARACTERIZATION OF A FUNCTIONAL PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR {alpha} BINDING SITE WITHIN THE PROXIMAL PROMOTER OF PXR Drug Metab. Dispos., January 1, 2006; 34(1): 138 - 144. [Abstract] [Full Text] [PDF]
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 Genetically Modified Animals in Endocrinology Endocr. Rev., December 1, 2005; 26(7): 985 - 993. [Abstract] [Full Text] [PDF]
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K. K. Wolf, S. G. Wood, J. A. Hunt, B. W. Walton-Strong, K. Yasuda, L. Lan, S. X. Duan, Q. Hao, S. A. Wrighton, E. H. Jeffery, et al. ROLE OF THE NUCLEAR RECEPTOR PREGNANE X RECEPTOR IN ACETAMINOPHEN HEPATOTOXICITY Drug Metab. Dispos., December 1, 2005; 33(12): 1827 - 1836. [Abstract] [Full Text] [PDF]
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G. Dai, N. Chou, L. He, M. A. Gyamfi, A. J. Mendy, A. L. Slitt, C. D. Klaassen, and Y.-J. Y. Wan Retinoid X Receptor {alpha} Regulates the Expression of Glutathione S-transferase Genes and Modulates Acetaminophen-Glutathione Conjugation in Mouse Liver Mol. Pharmacol., December 1, 2005; 68(6): 1590 - 1596. [Abstract] [Full Text] [PDF]
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 K. A. Kruger, J. W. Blum, and D. L. Greger Expression of Nuclear Receptor and Target Genes in Liver and Intestine of Neonatal Calves Fed Colostrum and Vitamin A J Dairy Sci, November 1, 2005; 88(11): 3971 - 3981. [Abstract] [Full Text] [PDF]
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S. S. Auerbach, M. A. Stoner, S. Su, and C. J. Omiecinski Retinoid X Receptor-{alpha}-Dependent Transactivation by a Naturally Occurring Structural Variant of Human Constitutive Androstane Receptor (NR1I3) Mol. Pharmacol., November 1, 2005; 68(5): 1239 - 1253. [Abstract] [Full Text] [PDF]
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 A. A. Mathias, J. Hitti, and J. D. Unadkat P-glycoprotein and breast cancer resistance protein expression in human placentae of various gestational ages Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2005; 289(4): R963 - R969. [Abstract] [Full Text] [PDF]
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Y. Weng, C. C. DiRusso, A. A. Reilly, P. N. Black, and X. Ding Hepatic Gene Expression Changes in Mouse Models with Liver-specific Deletion or Global Suppression of the NADPH-Cytochrome P450 Reductase Gene: MECHANISTIC IMPLICATIONS FOR THE REGULATION OF MICROSOMAL CYTOCHROME P450 AND THE FATTY LIVER PHENOTYPE J. Biol. Chem., September 9, 2005; 280(36): 31686 - 31698. [Abstract] [Full Text] [PDF]
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M. E. Wyde, S. E. Kirwan, F. Zhang, A. Laughter, H. B. Hoffman, E. Bartolucci-Page, K. W. Gaido, B. Yan, and L. You Di-n-Butyl Phthalate Activates Constitutive Androstane Receptor and Pregnane X Receptor and Enhances the Expression of Steroid-Metabolizing Enzymes in the Liver of Rat Fetuses Toxicol. Sci., August 1, 2005; 86(2): 281 - 290. [Abstract] [Full Text] [PDF]
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M. A. Mohutsky, D. M. Petullo, and S. A. Wrighton THE USE OF A SUBSTRATE CASSETTE STRATEGY TO IMPROVE THE CAPACITY AND THROUGHPUT OF CYTOCHROME P450 INDUCTION STUDIES IN HUMAN HEPATOCYTES Drug Metab. Dispos., July 1, 2005; 33(7): 920 - 923. [Abstract] [Full Text] [PDF]
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J. M. Maher, X. Cheng, A. L. Slitt, M. Z. Dieter, and C. D. Klaassen INDUCTION OF THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN FAMILY OF TRANSPORTERS BY CHEMICAL ACTIVATORS OF RECEPTOR-MEDIATED PATHWAYS IN MOUSE LIVER Drug Metab. Dispos., July 1, 2005; 33(7): 956 - 962. [Abstract] [Full Text] [PDF]
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X. Ding and J. L. Staudinger The Ratio of Constitutive Androstane Receptor to Pregnane X Receptor Determines the Activity of Guggulsterone against the Cyp2b10 Promoter J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 120 - 127. [Abstract] [Full Text] [PDF]
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M. D. Krasowski, K. Yasuda, L. R. Hagey, and E. G. Schuetz Evolution of the Pregnane X Receptor: Adaptation to Cross-Species Differences in Biliary Bile Salts Mol. Endocrinol., July 1, 2005; 19(7): 1720 - 1739. [Abstract] [Full Text] [PDF]
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G. Hartmann, V. Vassileva, and M. Piquette-Miller IMPACT OF ENDOTOXIN-INDUCED CHANGES IN P-GLYCOPROTEIN EXPRESSION ON DISPOSITION OF DOXORUBICIN IN MICE Drug Metab. Dispos., June 1, 2005; 33(6): 820 - 828. [Abstract] [Full Text] [PDF]
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W. Huang, J. Zhang, M. Washington, J. Liu, J. M. Parant, G. Lozano, and D. D. Moore Xenobiotic Stress Induces Hepatomegaly and Liver Tumors via the Nuclear Receptor Constitutive Androstane Receptor Mol. Endocrinol., June 1, 2005; 19(6): 1646 - 1653. [Abstract] [Full Text] [PDF]
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S. Fiorucci, C. Clerici, E. Antonelli, S. Orlandi, B. Goodwin, B. M. Sadeghpour, G. Sabatino, G. Russo, D. Castellani, T. M. Willson, et al. Protective Effects of 6-Ethyl Chenodeoxycholic Acid, a Farnesoid X Receptor Ligand, in Estrogen-Induced Cholestasis J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 604 - 612. [Abstract] [Full Text] [PDF]
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 A. M. Zavacki and P. R. Larsen CARs and Drugs: A Risky Combination Endocrinology, March 1, 2005; 146(3): 992 - 994. [Full Text] [PDF]
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M. Qatanani, J. Zhang, and D. D. Moore Role of the Constitutive Androstane Receptor in Xenobiotic-Induced Thyroid Hormone Metabolism Endocrinology, March 1, 2005; 146(3): 995 - 1002. [Abstract] [Full Text] [PDF]
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J. Jyrkkarinne, B. Windshugel, J. Makinen, M. Ylisirnio, M. Perakyla, A. Poso, W. Sippl, and P. Honkakoski Amino Acids Important for Ligand Specificity of the Human Constitutive Androstane Receptor J. Biol. Chem., February 18, 2005; 280(7): 5960 - 5971. [Abstract] [Full Text] [PDF]
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 C. A. M. Stedman, C. Liddle, S. A. Coulter, J. Sonoda, J. G. A. Alvarez, D. D. Moore, R. M. Evans, and M. Downes Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury PNAS, February 8, 2005; 102(6): 2063 - 2068. [Abstract] [Full Text] [PDF]
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J. Sonoda, L. W. Chong, M. Downes, G. D. Barish, S. Coulter, C. Liddle, C.-H. Lee, and R. M. Evans Pregnane X receptor prevents hepatorenal toxicity from cholesterol metabolites PNAS, February 8, 2005; 102(6): 2198 - 2203. [Abstract] [Full Text] [PDF]
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X. Ding and J. L. Staudinger Induction of Drug Metabolism by Forskolin: The Role of the Pregnane X Receptor and the Protein Kinase A Signal Transduction Pathway J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 849 - 856. [Abstract] [Full Text] [PDF]
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M. V. St-Pierre, T. Stallmach, A. Freimoser Grundschober, J.-F. Dufour, M. A. Serrano, J. J. G. Marin, Y. Sugiyama, and P. J. Meier Temporal expression profiles of organic anion transport proteins in placenta and fetal liver of the rat Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2004; 287(6): R1505 - R1516. [Abstract] [Full Text] [PDF]
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J. Zhang, W. Huang, M. Qatanani, R. M. Evans, and D. D. Moore The Constitutive Androstane Receptor and Pregnane X Receptor Function Coordinately to Prevent Bile Acid-induced Hepatotoxicity J. Biol. Chem., November 19, 2004; 279(47): 49517 - 49522. [Abstract] [Full Text] [PDF]
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C. A. Vyhlidal, P. K. Rogan, and J. S. Leeder Development and Refinement of Pregnane X Receptor (PXR) DNA Binding Site Model Using Information Theory: INSIGHTS INTO PXR-MEDIATED GENE REGULATION J. Biol. Chem., November 5, 2004; 279(45): 46779 - 46786. [Abstract] [Full Text] [PDF]
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M. L. Schrag, D. Cui, T. H. Rushmore, M. Shou, B. Ma, and A. D. Rodrigues SULFOTRANSFERASE 1E1 IS A LOW KM ISOFORM MEDIATING THE 3-O-SULFATION OF ETHINYL ESTRADIOL Drug Metab. Dispos., November 1, 2004; 32(11): 1299 - 1303. [Abstract] [Full Text] [PDF]
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W. Huang, J. Zhang, P. Wei, W. T. Schrader, and D. D. Moore Meclizine Is an Agonist Ligand for Mouse Constitutive Androstane Receptor (CAR) and an Inverse Agonist for Human CAR Mol. Endocrinol., October 1, 2004; 18(10): 2402 - 2408. [Abstract] [Full Text] [PDF]
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S. Kodama, C. Koike, M. Negishi, and Y. Yamamoto Nuclear Receptors CAR and PXR Cross Talk with FOXO1 To Regulate Genes That Encode Drug-Metabolizing and Gluconeogenic Enzymes Mol. Cell. Biol., September 15, 2004; 24(18): 7931 - 7940. [Abstract] [Full Text] [PDF]
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C. J. Matheny, R. Y. Ali, X. Yang, and G. M. Pollack EFFECT OF PROTOTYPICAL INDUCING AGENTS ON P-GLYCOPROTEIN AND CYP3A EXPRESSION IN MOUSE TISSUES Drug Metab. Dispos., September 1, 2004; 32(9): 1008 - 1014. [Abstract] [Full Text] [PDF]
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K. Swales and M. Negishi CAR, Driving into the Future Mol. Endocrinol., July 1, 2004; 18(7): 1589 - 1598. [Abstract] [Full Text] [PDF]
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M. Podvinec, C. Handschin, R. Looser, and U. A. Meyer Identification of the xenosensors regulating human 5-aminolevulinate synthase PNAS, June 15, 2004; 101(24): 9127 - 9132. [Abstract] [Full Text] [PDF]
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J. M. Maglich, J. Watson, P. J. McMillen, B. Goodwin, T. M. Willson, and J. T. Moore The Nuclear Receptor CAR Is a Regulator of Thyroid Hormone Metabolism during Caloric Restriction J. Biol. Chem., May 7, 2004; 279(19): 19832 - 19838. [Abstract] [Full Text] [PDF]
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V. Bombail, K. Taylor, G. G. Gibson, and N. Plant ROLE OF Sp1, C/EBP{alpha}, HNF3, AND PXR IN THE BASAL- AND XENOBIOTIC-MEDIATED REGULATION OF THE CYP3A4 GENE Drug Metab. Dispos., May 1, 2004; 32(5): 525 - 535. [Abstract] [Full Text] [PDF]
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D. P. Hartley, X. Dai, Y. D. He, E. J. Carlini, B. Wang, S.-e. W. Huskey, R. G. Ulrich, T. H. Rushmore, R. Evers, and D. C. Evans Activators of the Rat Pregnane X Receptor Differentially Modulate Hepatic and Intestinal Gene Expression Mol. Pharmacol., May 1, 2004; 65(5): 1159 - 1171. [Abstract] [Full Text]
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S. D. Shenoy, T. A. Spencer, N. A. Mercer-Haines, M. Abdolalipour, W. L. Wurster, M. Runge-Morris, and T. A. Kocarek Induction of CYP3A by 2,3-Oxidosqualene:Lanosterol Cyclase Inhibitors Is Mediated by an Endogenous Squalene Metabolite in Primary Cultured Rat Hepatocytes Mol. Pharmacol., May 1, 2004; 65(5): 1302 - 1312. [Abstract] [Full Text]
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 Z. Zhang, P. E. Burch, A. J. Cooney, R. B. Lanz, F. A. Pereira, J. Wu, R. A. Gibbs, G. Weinstock, and D. A. Wheeler Genomic Analysis of the Nuclear Receptor Family: New Insights Into Structure, Regulation, and Evolution From the Rat Genome Genome Res., April 1, 2004; 14(4): 580 - 590. [Abstract] [Full Text] [PDF]
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C. Stedman, G. Robertson, S. Coulter, and C. Liddle Feed-forward Regulation of Bile Acid Detoxification by CYP3A4: STUDIES IN HUMANIZED TRANSGENIC MICE J. Biol. Chem., March 19, 2004; 279(12): 11336 - 11343. [Abstract] [Full Text] [PDF]
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S. P. S. Saini, J. Sonoda, L. Xu, D. Toma, H. Uppal, Y. Mu, S. Ren, D. D. Moore, R. M. Evans, and W. Xie A Novel Constitutive Androstane Receptor-Mediated and CYP3A-Independent Pathway of Bile Acid Detoxification Mol. Pharmacol., February 1, 2004; 65(2): 292 - 300. [Abstract] [Full Text] [PDF]
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 C G Dietrich, A Geier, and R P J Oude Elferink ABC of oral bioavailability: transporters as gatekeepers in the gut Gut, December 1, 2003; 52(12): 1788 - 1795. [Full Text] [PDF]
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 C. Handschin and U. A. Meyer Induction of Drug Metabolism: The Role of Nuclear Receptors Pharmacol. Rev., December 1, 2003; 55(4): 649 - 673. [Abstract] [Full Text] [PDF]
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G. L. Guo, G. Lambert, M. Negishi, J. M. Ward, H. B. Brewer Jr., S. A. Kliewer, F. J. Gonzalez, and C. J. Sinal Complementary Roles of Farnesoid X Receptor, Pregnane X Receptor, and Constitutive Androstane Receptor in Protection against Bile Acid Toxicity J. Biol. Chem., November 14, 2003; 278(46): 45062 - 45071. [Abstract] [Full Text] [PDF]
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S. Teng, V. Jekerle, and M. Piquette-Miller INDUCTION OF ABCC3 (MRP3) BY PREGNANE X RECEPTOR ACTIVATORS Drug Metab. Dispos., November 1, 2003; 31(11): 1296 - 1299. [Abstract] [Full Text] [PDF]
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N. J. Cherrington, A. L. Slitt, J. M. Maher, X.-X. Zhang, J. Zhang, W. Huang, Y.-J. Y. Wan, D. D. Moore, and C. D. Klaassen INDUCTION OF MULTIDRUG RESISTANCE PROTEIN 3 (MRP3) IN VIVO IS INDEPENDENT OF CONSTITUTIVE ANDROSTANE RECEPTOR Drug Metab. Dispos., November 1, 2003; 31(11): 1315 - 1319. [Abstract] [Full Text] [PDF]
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D. J. Fraser, A. Zumsteg, and U. A. Meyer Nuclear Receptors Constitutive Androstane Receptor and Pregnane X Receptor Activate a Drug-responsive Enhancer of the Murine 5-Aminolevulinic Acid Synthase Gene J. Biol. Chem., October 10, 2003; 278(41): 39392 - 39401. [Abstract] [Full Text] [PDF]
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C. Chen, J. L. Staudinger, and C. D. Klaassen NUCLEAR RECEPTOR, PREGNANE X RECEPTOR, IS REQUIRED FOR INDUCTION OF UDP-GLUCURONOSYLTRANSFERASES IN MOUSE LIVER BY PREGNENOLONE-16{alpha}-CARBONITRILE Drug Metab. Dispos., July 1, 2003; 31(7): 908 - 915. [Abstract] [Full Text] [PDF]
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J. M. Rosenfeld, R. Vargas Jr., W. Xie, and R. M. Evans Genetic Profiling Defines the Xenobiotic Gene Network Controlled by the Nuclear Receptor Pregnane X Receptor Mol. Endocrinol., July 1, 2003; 17(7): 1268 - 1282. [Abstract] [Full Text] [PDF]
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 S. A. Kliewer The Nuclear Pregnane X Receptor Regulates Xenobiotic Detoxification J. Nutr., July 1, 2003; 133(7): 2444S - 2447. [Abstract] [Full Text] [PDF]
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S. S. Auerbach, R. Ramsden, M. A. Stoner, C. Verlinde, C. Hassett, and C. J. Omiecinski Alternatively spliced isoforms of the human constitutive androstane receptor Nucleic Acids Res., June 15, 2003; 31(12): 3194 - 3207. [Abstract] [Full Text] [PDF]
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J. M. Maglich, D. J. Parks, L. B. Moore, J. L. Collins, B. Goodwin, A. N. Billin, C. A. Stoltz, S. A. Kliewer, M. H. Lambert, T. M. Willson, et al. Identification of a Novel Human Constitutive Androstane Receptor (CAR) Agonist and Its Use in the Identification of CAR Target Genes J. Biol. Chem., May 2, 2003; 278(19): 17277 - 17283. [Abstract] [Full Text] [PDF]
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J. L. Staudinger, A. Madan, K. M. Carol, and A. Parkinson Regulation of Drug Transporter Gene Expression by Nuclear Receptors Drug Metab. Dispos., May 1, 2003; 31(5): 523 - 527. [Abstract] [Full Text] [PDF]
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W. Xie, M.-F. Yeuh, A. Radominska-Pandya, S. P. S. Saini, Y. Negishi, B. S. Bottroff, G. Y. Cabrera, R. H. Tukey, and R. M. Evans Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor PNAS, April 1, 2003; 100(7): 4150 - 4155. [Abstract] [Full Text] [PDF]
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W. Huang, J. Zhang, S. S. Chua, M. Qatanani, Y. Han, R. Granata, and D. D. Moore Induction of bilirubin clearance by the constitutive androstane receptor (CAR) PNAS, April 1, 2003; 100(7): 4156 - 4161. [Abstract] [Full Text] [PDF]
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I. Dussault, H.-D. Yoo, M. Lin, E. Wang, M. Fan, A. K. Batta, G. Salen, S. K. Erickson, and B. M. Forman Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance PNAS, February 4, 2003; 100(3): 833 - 838. [Abstract] [Full Text] [PDF]
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B. Goodwin, K. C. Gauthier, M. Umetani, M. A. Watson, M. I. Lochansky, J. L. Collins, E. Leitersdorf, D. J. Mangelsdorf, S. A. Kliewer, and J. J. Repa Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor PNAS, January 7, 2003; 100(1): 223 - 228. [Abstract] [Full Text] [PDF]
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S. A. Kliewer, B. Goodwin, and T. M. Willson The Nuclear Pregnane X Receptor: A Key Regulator of Xenobiotic Metabolism Endocr. Rev., October 1, 2002; 23(5): 687 - 702. [Abstract] [Full Text] [PDF]
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