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Vol. 61, Issue 1, 1-6, January 2002
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology (A.U., Y.Y., T.S., M.N.) and National Institute of Environmental Health Sciences (NIEHS) Microarray Center (H.K.H., C.A.A.); Laboratory of Molecular Carcinogenesis, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina; and Tularik, South San Francisco, California (H.K.W., J.M.L.)
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results and Discussion
References
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Phenobarbital (PB) induces various gene encoding drug/steroid-metabolizing enzymes such as cytochromes P450 (P450s) and transferases. Although the nuclear orphan constitutive active receptor (CAR) has been identified as a key transcription factor that regulates the induction of CYP2B, the full scope of CAR-regulated genes still remains a major question. To this end, reverse transcriptase-polymerase chain reaction and cDNA microarray techniques were employed to examine gene expression in wild-type and CAR-null mice. The results show that a total of 138 genes were detected to be either induced or repressed in response to PB treatment, of which about half were under CAR regulation. Including CYP2B10, CYP3A11, and NADPH-CYP reductase, CAR regulated a group of the PB-induced drug/steroid-metabolizing enzymes. Enzymes such as amino levulinate synthase 1 and squalene epoxidase displayed CAR-independent induction by PB. Cyp4a10 and Cyp4a14 represented the group of genes induced by PB only in CAR-null mice, indicating that CAR may be a transcription blocker that prevents these genes from being induced by PB. Additionally, the group of genes encoding enzymes and proteins involved in basic biological processes such as energy metabolism underwent the CAR-dependent repression by PB. Thus, CAR seems to have diverse roles, both as a positive and negative regulator, in the regulation of hepatic genes in response to PB beyond drug/steroid metabolism.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
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Phenobarbital (PB) elicits
pleiotropic effects on various cellular processes in liver, including
growth, apoptosis, communication, tumorigenesis, and induction of
drug/steroid-metabolizing enzymes such as cytochromes P450 (P450s) and
specific conjugation enzymes. The nuclear receptor CAR is implicated in
mediating PB responses (Zelko and Negishi, 2000
; Sueyoshi and Negishi,
2001). In response to PB exposure, CAR translocates to the nucleus,
forms a heterodimer with the retinoid X receptor (RXR), and activates
the 51-bp PB-responsive enhancer module that is conserved in the
mouse, rat, and human CYP2B genes (Trottier et al., 1995;
Park et al., 1996; Honkakoski et al., 1998a,c; Kawamoto et al., 1999;
Ramsden et al., 1999; Sueyoshi et al., 1999; Wei et al., 2000; Zelko et
al., 2001). In addition, similar CAR-regulated enhancer sequences have
been found in some other PB-inducible genes, such as CYP3A
and human bilirubin UDP-glucuronosyltransferase UGT1A1
(Sueyoshi et al., 1999; Smirlis et al., 2001; Sugatani et al., 2001).
Increased liver weight and DNA synthesis in response to PB treatment
were also reported to be CAR-mediated (Wei et al., 2000).
There are two major questions regarding the role of CAR as a regulator
of PB response. 1) How many genes are regulated by CAR? PB induces more
than 20 different genes in chicken hepatocytes (Frueh et al., 1997),
and as many as 77 differentially displayed cDNAs were detected in
PB-induced mouse liver (Garcia-Allan et al., 2000). The number of genes
under CAR regulation, however, remains unknown. 2) To what extent does
CAR coordinate multifaceted responses to PB? PB concertedly induces
various hepatic enzymes to increase the drug/steroid-metabolizing
capability, including P450s, P450 reductase (the key enzyme that
transfers electrons from NADPH to P450), and such transferases as
glucuronosyltransferases, glutathione S-transferases, and
sulfotransferases and transporters (Waxman and Azaroff, 1992;
Honkakoski and Negishi, 1998b). Moreover, PB also induces
aminolevulinate synthase 1 to increase the supply of heme to newly
synthesized P450 apoprotein, and proliferates endoplasmic reticulum to
provide additional membrane bindings for P450s and other membrane
enzymes. To shed light on these questions, we used RT-PCR and cDNA
microarrays to compare gene expression profiles derived from livers of
PB-treated wild-type and CAR-null mice. PB induced a number of
drug/steroid-metabolizing enzymes in a CAR-dependent fashion, although
not all genes induced by PB were regulated by CAR. In addition, we have
identified a large number of potential new CAR-target genes. CAR plays
diverse set of roles (e.g., activator, repressor, and blocker of gene
expression) that go beyond drug/steroid metabolism.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
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Animals and RNA Preparation.
CAR-null and wild-type mice
were produced from a single breeding colony of multiple
CAR-heterozygous females with one CAR-heterozygous male (Webb et al.,
2001). These mice were fed Teklad 5053 autoclaved rodent chow (Harlan
Teklad, Madison, WI) ad libitum and provided with autoclaved drinking
water and housed in high-efficiency particulate air (HEPA)-filtered
caging in a temperature- and humidity-controlled environment on a
12-h/12-h light/dark cycle. Germline transmission of the disrupted
allele was detected by Northern blot analysis or by RT-PCR of liver
RNA. Six- to 9-week old CAR-null and wild-type mice were treated by
intraperitoneal injection of PB (Sigma, St. Louis, MO) in 10 mg/ml
saline solution at a dose of 100 mg/kg of body weight for 12 h
before sacrifice. For control mice, 200 µl of saline per 20 g of
body weight was injected. Total liver RNA was prepared from each mouse
using TRIzol reagent (Invitrogen, Carlsbad, CA), from which mRNA
was enriched using Oligotex mRNA kit (QIAGEN, Valencia, CA).
RT-PCR. cDNAs were prepared from total RNA using SuperScript II reverse transcriptase (Invitrogen) and were amplified using the following sets of primers: CYP2B10 mRNA, 5'-AAAGTCCCGTGGCAACTTCC-3' and 5'-CATCCCAAAGTCTCTCATGG-3'; CYP3A11 mRNA, 5'-CTCAATGGTGTGTATATCCCC-3' and 5'-CCGATGTTCTTAGACACTGCC-3'; P450 reductase mRNA, 5'-GTTTGCTGTGTTTGGTCTCG-3' and 5'-CTCTCAGTGCCTTGGTTCAG-3'. PCR was performed in total volume of 50 µl on cDNA synthesized from 0.12 µg of total RNA using Advantage 2 PCR enzyme (CLONTECH, Palo Alto, CA). The PCR protocol consisted of an initial denaturing step at 95°C for 1 min followed by 19 to 29 cycles of 95°C for 30 s and 68°C for 1 min. The expected sizes of the amplified cDNA were 340 bp, 423 bp, and 393 bp for CYP2B10, CYP3A11, and P450 reductase mRNAs, respectively.
Real time PCR was performed using ABI Prism 7700 (Applied Biosystems, Foster City, CA). The following primers and probes were constructed: CYP4A10 mRNA, 5'-GTGCTGAGGTGGACACATTCAT-3' and 5'-TGTGGCCAGAGCATAGAAGATC-3' as primers with 6FAM-CCATGACACCACAGCCAGTGGAGTCTC-TAMRA as the probe; aminolevulinate synthase 1, 5'-TTACTCTGATTCCGGGAACCA-3' and 5'-ACGTCATTGTGGCGGAAGATA-3' as primers with 6FAM-CCATGATCCAAGGGATTCGCAACAG-TAMRA as the probe; squalene epoxidase, 5'-TGACGGTCATCGAGAGAGATTTAA-3' and 5'-TGGGCATTGAGACCTTCTACTGTAT-3' as primers with 6FAM-AGCTCCTGGAGAACACGGTAGCCTCCT-TAMRA with the probe; and 7-dehydrocholesterol reductase, 5'-ACTGGATCCCCTTGCTATGGT-3' and 5'-CCCTTGATCATTGCGAACGT as primers with 6FAM-CCAACATCCTGGGCTATG- CCGTGT-TAMRA as the probe. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was amplified as an internal control using the TaqMan rodent GAPDH control reagents (Applied Biosystems). The levels of a given mRNA were normalized against the GAPDH mRNA level.Microarray Hybridization.
cDNA microarray chips
containing 8736 mouse genes/ESTs were prepared as described previously
(DeRisi et al., 1997).1
Detailed methods are available at http://dir.niehs.nih.gov/microarray. Briefly, mouse clones (gene expression microarray set 1) were purchased as bacterial stocks from Incyte (Palo Alto, CA). Routine re-sequencing of the clones is conducted in our laboratory for validation of spot identity. Updated clone lists are available at the
same web site. Purified plasmids were isolated and used as templates
for amplification of inserts by PCR. The PCR products were analyzed on
2% agarose gels to ensure quality of the reactions and purified by
ethanol precipitation. The purified cDNAs were resuspended in ArrayIt
buffer (Telechem, San Jose, CA) and spotted onto
poly(L-lysine) coated glass slides using a modified,
robotic DNA arrayer (Beecher Instruments, Bethesda, MD).
Poly(A+) RNA (2-4 µg) was labeled with Cy3 and
Cy5-conjugated dUTP (Amersham Biosciences, Piscataway, NJ) using a
reverse transcription reaction and hybridized to the mouse cDNA
microarray chip (DeRisi et al., 1997). cDNA chips were scanned using
the Axon 4000 scanner (Axon Instruments, Union City, CA), and images
were analyzed using the Array Suite Software (Scanalytics, Fairfax,
VA). The relative fluorescence intensity was measured for each labeled
RNA and a ratio of the values for the intensity of each fluor bound to
each probe (CAR-null or wild-type) was calculated. The level of
autofluorescence was measured and a minimum intensity cut-off was set
just above this value. The distribution of the ratio of all of the
genes was calculated and intensity ratio values that differed from the median with a confidence interval of greater than 95.0% (Chen et al.,
1997) were scored as significant changes. Approximately equal amounts
of the same liver RNA samples within each experimental group were
labeled and hybridized in four independent reactions to four
independent chips; each RNA sample was labeled twice with each
fluorophore to account for fluorophore incorporation bias. The data for
each array experiment were normalized using the mean of all of the
targets on the array (range, 0.8-1.2, indicating a normal
distribution). The coefficient of variance for each hybridization was
less than 0.1. A database tool, Microarray Project System (MAPS; Bushel
et al., 2001) was used to compile the overall list of consistent,
significantly changed genes across the multiple hybridizations. The
hierarchical clustering method from Eisen et al. (1998) was used to
cluster the gene expression changes for visualization.
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Results and Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
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First, we performed RT-PCR on liver RNA samples from control and
PB-treated wild-type and CAR-null mice to confirm that CAR, in fact,
regulates the Cyp2b10 gene. The CYP2B10 mRNA was measured individually for the four wild-type and six null mice. The mRNA was
greatly increased in all wild-type mice treated with PB, whereas no
change in message was observed in the null mice (Fig.
1). Thus, the PB induction of
Cyp2b10 gene was tightly regulated by CAR in the mice.
Although CYP3A11 and P450 reductase showed high levels of the
constitutive expression of their mRNA, PB treatment caused a further
increase in the wild-type but not in CAR-null mice (Fig. 1). These
findings suggested a general role of CAR in regulating a number of
drug/steroid-metabolizing enzymes. In particular, the coordinated
regulation by CAR of P450 reductase with the P450 induction is
particularly important because the reductase is an essential component
of P450-dependent metabolic activity.
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To further investigate to what extent CAR regulates hepatic genes, we
performed microarray experiments using liver mRNA samples obtained and
pooled from three control and three PB-treated wild-type mice and two
each of control and PB-treated CAR-null mice. After scanning,
microarray images were analyzed to determine relative intensity ratios
between the control and treated mice. Subsequently, genes that were
determined to be induced or repressed at a 95% confidence interval in
three or four of four hybridizations were used to compile a list of 144 significant changes. This list of genes was then used for hierarchical
cluster analysis that reiteratively joins the two closest clusters
starting from singletons (Fig. 2). The
final output revealed relatively high correlation (r > 0.8) in
the expression of sets of genes across either of PB-treated wild-type
or CAR-null mice. Genes were grouped into six major categories: group A
includes genes induced by PB in wild-type but not in CAR-null mice;
group B, genes induced by PB in both wild-type and CAR-null mice; group
C, genes induced by PB in CAR-null but not in wild-type mice; group D,
genes repressed by PB in wild-type but not in CAR-null mice; group E,
genes repressed by PB in CAR-null but not in wild-type mice; and group
F, genes repressed by PB in both wild-type and CAR-null mice.
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CAR-Dependent PB-Inducible Genes. cDNA microarray analyses revealed a total of 22 genes that were induced by PB in only the wild-type mice (group A). In addition to PB-inducible Cyp2b10 and Cyp3a11, six other Cyp genes (Cyp2b9, -2d10, -2j5, -2f2, -4a10, and -4a14) were contained on the chip, but only Cyp2b10 was identified as being induced by PB in a CAR-dependent fashion. The degree of induction was very low (Fig. 1) and/or high constitutive levels of CYP3A11 mRNA may have masked differential detection of this gene on the chip. A cDNA probe for P450 reductase mRNA was not on the chips. Ten known genes were identified as those regulated by CAR, eight of which encode enzymes involved in xenochemical metabolism (Fig. 2). The other two genes are cAMP-regulated phosphoprotein and semaphorin 3. The 12 remaining genes are ESTs. Together with P450 reductase and CYP3A11, these results indicate that drug/steroid-metabolizing enzymes constitute a majority of PB-inducible genes that are regulated by CAR and the present number of CAR-regulated enzymes could have been underestimated because probes, such as for glucuronosyltransferases, were not on the chip.
CAR-Dependent PB-Repressed Genes.
A total of 30 genes were
found to be down-regulated in response to PB treatment in wild-type but
not CAR-null mice (group D). Of the 30 genes, 11 are ESTs.
Interestingly, the majority of repressed genes encode enzymes and
proteins that are involved in basic liver function. Carnitine
palmitoyltransferase and enoyl-CoA isomerase are key enzymes in fatty
acid oxidation. Phosphoenolpyruvate carboxykinase is involved in
glucose synthesis and catalyzes the formation of phosphoenolpyruvate
from oxaloacetate in the presence of GTP. Fibronectin promotes cell
adhesion and angiogenin regulates neovascularization required for
normal physiology such as embryonic development, reproduction, and
wound repair. Angiogenin is also up-regulated in various tumor tissues.
In addition, our present microarray experiments showed that peptidyl
isomerase, keratins, metallothionein, translocator of inner
mitochondrial membrane 4, liposaccharide binding protein, myoglobin,
DNase inhibitor inhibited by DNA fragment factor, lipocalin,
inter-
-trypsin inhibitor, fibrinogen 1, histone H1, and pleiotropic
regulator 1 were all in this group. These enzymes and proteins are
involved in signal transduction, fatty acid oxidation, energy
metabolism, and/or cell surface communication, indicating that CAR may
mediate PB effects on many critical processes in liver physiology.
Genes under CAR-Dependent Blocking.
Interestingly, this group
contains genes that are either induced or repressed by PB in only the
CAR-null mice, not in wild-type mice (Fig. 2). Apparently, the presence
of CAR blocked these genes from being either induced or repressed by
PB. Among the 24 genes that fall into these two categories, only nine
genes are known. Including Cyp4a10 and Cyp4a14,
four genes are induced only in the CAR-null mice. Consistent with the
results for the CYP4A10 mRNA obtained from real-time PCR (Fig.
3A), these Cyp genes were clearly induced by PB in only the CAR-null mice, whereas these were
slightly repressed in the PB-treated wild-type mice. Both Cyp4a genes are highly inducible by the peroxisome
proliferator methylclofenapate in normal mouse liver (Heng et al.,
1997). CYP4A10 and CYP4A14, major microsomal lipid peroxidases, are
up-regulated in Cyp2e1-null mice with nonalcoholic
steatohepatitis, thus identified as possible initiators of oxidative
stress in the liver (Leclercq et al., 2000). Intriguingly, CAR is
absent in the fatty liver of the obese Zucker rat (K. Yoshinari
and M. Negishi, unpublished observations), in which lipid peroxidation
products were increased (Koneru et al., 1995). Thus, CAR can be viewed
as an endogenous determinant suppressing oxidative stress by preventing
the induction of Cyp4a genes by xenochemical exposures. This
function of CAR as a repressor for oxidative stress is consistent with
the CAR-mediated induction of superoxide dismutase 3 by PB (Sugatani et
al., 2001). Eight genes, of which three are ESTs, are repressed only in
the CAR-null mice.
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CAR-Independent PB-Inducible or -Repressed Genes. A total of 37 genes were induced in both wild-type and CAR-null mice (group B), whereas 23 genes were repressed (group F) (Fig. 2). Several known genes were induced by PB in a CAR-independent manner, and aminolevulinate synthase 1 (ALAS-1) was one of the 14 known genes that was induced by PB. ALAS-1, the key enzyme in regulating heme biosynthesis was clearly induced by PB both in the wild-type and CAR-null mice. In addition, real time PCR confirmed the induction of ALAS-1 mRNA in both types of mice (Fig. 3B). The concerted induction of the enzymes is considered as a way to effectively supply heme to newly synthesized P450 apoenzyme. The mechanism by which liver cells coordinate the induction of both P450 and ALAS has been an unsolved question. The present results clearly indicate that CAR does not play a role in the coordinated induction of the two enzymes systems.
Our microarray experiments showed that PB induces two enzymes in cholesterol biosynthesis (i.e., squalene epoxidase and 7-dehydroxycholesterol reductase) in a CAR-independent fashion (Fig. 2). Phenobarbital treatment is known to increase the plasma level of cholesterol in human (Eiris et al., 1995; Aynaci et al., 2001). We also
performed real time RT-PCR for these two enzymes (Fig. 3B). Their mRNAs were, in fact, induced in both PB-treated wild-type and CAR-null mice,
consistent with the induction pattern obtained from the present cDNA
microarray experiments. Although the direction of induction agreed, the
actual folds of induction varied between the PCR and array experiments.
Squalene epoxidase mRNA was increased by PB slightly higher than 2-fold
in the wild-type mice, whereas the increase was more than 20-fold in
the PB-treated CAR-null mice. Northern hybridization revealed that the
level of this mRNA was low in the control CAR-null mice compared with
that in the control wild-type mice, whereas the induced levels were
similar in both wild-type and null mice treated with PB (data not
shown). The extremely high fold induction in the CAR-null mice
apparently occurred because of the low constitutive level of the mRNA
in the control mice. Nevertheless, our present experiments have shown clearly that the genes such as ALAS-1 and squalene
epoxidase are induced by PB in a CAR-independent mechanism.
The profile of gene expressions obtained from our microarray
experiments was confirmed by subsequent RT-PCR, real time PCR and/or
Northern hybridization. The results of microarray technology are
accurate in a qualitative fashion; although more quantitative in the
2-fold range, microarray technology will most often compress the
quantitation of data in the higher range. Actual folds of alteration in
the array experiments should be taken arbitrarily until they are
verified by more quantitative methods. For example, the microarray data
displayed a 6.75-fold induction of the Cyp2b10 gene,
although both RT-PCR (Fig. 1) and real time PCR (not shown) indicated
an indefinite fold of the induction. A similar discrepancy was also
observed in the case of squalene epoxidase. High background hybridization to a low level of target signal and/or earlier saturation of hybridization to a high level of target may interfere in the estimate of an accurate fold of mRNA alteration in some cases of cDNA
microarray hybridization. However, this should not be a discouraging
factor for the technique because it simultaneously provides us with
extensive information about the relative expression of a large number
of genes in a short period of time.
PB treatment altered expression of a large number of hepatic genes, and
approximately half of those genes are regulated by the nuclear receptor
CAR. CAR plays diverse roles in regulating hepatic genes in response to
PB treatment. Importantly, each group of genes that is differently
modulated by PB and CAR seems to be, in part, characterized by
functional basis of the gene products (Fig.
4). CAR mediates coordinate induction of
drug/steroid-metabolizing enzymes (P450s and transferases), conferring
higher metabolic capability to liver cells. Considering that high
metabolic activity is to protect cells from xenochemical toxicity
and/or carcinogenicity, a biological role of CAR is to sense
xenochemicals to induce metabolic enzymes. In addition, CAR may play a
role in protecting liver cells by blocking genes being induced in some
cases, such as Cyp4a genes. Because the induction of
Cyp4a genes may increase the risk of developing certain
types of hepatitis (Leclercq et al., 2000), the blocking of the
induction may protect liver cells from developing hepatitis.
Understanding the molecular mechanism by which CAR blocks the PB
induction of Cyp4a genes remains an interesting question for
future research.
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Acknowledgments |
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We would like to acknowledge the efforts of all of the staff of the NIEHS Microarray Center, especially Karla Martin, Rupesh Amin, Pierre Bushel, Jeff Tucker, Lee Bennett, and Stella Sieber. In addition, we would like to thank Loretta Moore and Jennifer Collins for preparation of the manuscript.
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Footnotes |
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Received July 31, 2001; Accepted October 5, 2001
1 The complete microarray data set and chip clone list is available at http://dir.niehs.nih.gov/microarray/datasets/
Dr. Masahiko Negishi, Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institutes of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709. E-mail: negishi{at}niehs.nih.gov
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Abbreviations |
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PB, phenobarbital; P450, cytochrome P450; CAR, constitutive active receptor; RXR, retinoid X receptor; RT-PCR, reverse transcriptase-polymerase chain reaction; bp, base pair(s); GAPDH, glyceraldehyde-3-phosphate dehydrogenase; EST, expression sequence tag; ALAS, aminolevulinate synthase.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
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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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 T. Sueyoshi, R. Moore, J. Sugatani, Y. Matsumura, and M. Negishi PPP1R16A, The Membrane Subunit of Protein Phosphatase 1{beta}, Signals Nuclear Translocation of the Nuclear Receptor Constitutive Active/Androstane Receptor Mol. Pharmacol., April 1, 2008; 73(4): 1113 - 1121. [Abstract] [Full Text] [PDF]
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L. D. Beilke, D. G. Besselsen, Q. Cheng, S. Kulkarni, A. L. Slitt, and N. J. Cherrington Minimal Role of Hepatic Transporters in the Hepatoprotection against LCA-Induced Intrahepatic Cholestasis Toxicol. Sci., March 1, 2008; 102(1): 196 - 204. [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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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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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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 Y. Yamazaki, S. Kakizaki, N. Horiguchi, N. Sohara, K. Sato, H. Takagi, M. Mori, and M. Negishi The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitis Gut, April 1, 2007; 56(4): 565 - 574. [Abstract] [Full Text] [PDF]
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K. Nakamura, R. Moore, M. Negishi, and T. Sueyoshi Nuclear Pregnane X Receptor Cross-talk with FoxA2 to Mediate Drug-induced Regulation of Lipid Metabolism in Fasting Mouse Liver J. Biol. Chem., March 30, 2007; 282(13): 9768 - 9776. [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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J. M. Phillips, Y. Yamamoto, M. Negishi, R. R. Maronpot, and J. I. Goodman Orphan Nuclear Receptor Constitutive Active/Androstane Receptor-Mediated Alterations in DNA Methylation during Phenobarbital Promotion of Liver Tumorigenesis Toxicol. Sci., March 1, 2007; 96(1): 72 - 82. [Abstract] [Full Text] [PDF]
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 S. M. Blattler, F. Rencurel, M. R. Kaufmann, and U. A. Meyer In the regulation of cytochrome P450 genes, phenobarbital targets LKB1 for necessary activation of AMP-activated protein kinase PNAS, January 16, 2007; 104(3): 1045 - 1050. [Abstract] [Full Text] [PDF]
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S. R. Faucette, T.-C. Zhang, R. Moore, T. Sueyoshi, C. J. Omiecinski, E. L. LeCluyse, M. Negishi, and H. Wang Relative Activation of Human Pregnane X Receptor versus Constitutive Androstane Receptor Defines Distinct Classes of CYP2B6 and CYP3A4 Inducers J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 72 - 80. [Abstract] [Full Text] [PDF]
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E. S. Tien, K. Matsui, R. Moore, and M. Negishi The Nuclear Receptor Constitutively Active/Androstane Receptor Regulates Type 1 Deiodinase and Thyroid Hormone Activity in the Regenerating Mouse Liver J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 307 - 313. [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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D. M. Nelson, V. Bhaskaran, W. R. Foster, and L. D. Lehman-McKeeman p53-Independent Induction of Rat Hepatic Mdm2 following Administration of Phenobarbital and Pregnenolone 16{alpha}-Carbonitrile Toxicol. Sci., December 1, 2006; 94(2): 272 - 280. [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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 I. Meijerman, J. H. Beijnen, and J. H.M. Schellens Herb-Drug Interactions in Oncology: Focus on Mechanisms of Induction Oncologist, July 1, 2006; 11(7): 742 - 752. [Abstract] [Full Text] [PDF]
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Y. Yamamoto, R. Moore, H. A. Hess, G. L. Guo, F. J. Gonzalez, K. S. Korach, R. R. Maronpot, and M. Negishi Estrogen Receptor {alpha} Mediates 17{alpha}-Ethynylestradiol Causing Hepatotoxicity J. Biol. Chem., June 16, 2006; 281(24): 16625 - 16631. [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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J. Miao, S. Fang, Y. Bae, and J. K. Kemper Functional Inhibitory Cross-talk between Constitutive Androstane Receptor and Hepatic Nuclear Factor-4 in Hepatic Lipid/Glucose Metabolism Is Mediated by Competition for Binding to the DR1 Motif and to the Common Coactivators, GRIP-1 and PGC-1{alpha} J. Biol. Chem., May 26, 2006; 281(21): 14537 - 14546. [Abstract] [Full Text] [PDF]
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F. Hosseinpour, R. Moore, M. Negishi, and T. Sueyoshi Serine 202 Regulates the Nuclear Translocation of Constitutive Active/Androstane Receptor Mol. Pharmacol., April 1, 2006; 69(4): 1095 - 1102. [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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M. P. Holsapple, H. C. Pitot, S. H. Cohen, A. R. Boobis, J. E. Klaunig, T. Pastoor, V. L. Dellarco, and Y. P. Dragan Mode of Action in Relevance of Rodent Liver Tumors to Human Cancer Risk Toxicol. Sci., January 1, 2006; 89(1): 51 - 56. [Abstract] [Full Text] [PDF]
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 J. C. Corton and H. M. Brown-Borg Peroxisome Proliferator-Activated Receptor {gamma} Coactivator 1 in Caloric Restriction and Other Models of Longevity J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2005; 60(12): 1494 - 1509. [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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C. Gnerre, G. U. Schuster, A. Roth, C. Handschin, L. Johansson, R. Looser, P. Parini, M. Podvinec, K. Robertsson, J.-A. Gustafsson, et al. LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver J. Lipid Res., August 1, 2005; 46(8): 1633 - 1642. [Abstract] [Full Text] [PDF]
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Y. Mu, C. R. J. Stephenson, C. Kendall, S. P. S. Saini, D. Toma, S. Ren, H. Cai, S. C. Strom, B. W. Day, P. Wipf, et al. A Pregnane X Receptor Agonist with Unique Species-Dependent Stereoselectivity and Its Implications in Drug Development Mol. Pharmacol., August 1, 2005; 68(2): 403 - 413. [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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 D. Desaulniers, G. M. Cooke, K. Leingartner, K. Soumano, J. Cole, J. Yang, M. Wade, and A. Yagminas Effects of Postnatal Exposure to a Mixture of Polychlorinated Biphenyls, p,p'-dichlorodiphenyltrichloroethane, and p-p'-dichlorodiphenyldichloroethene in Prepubertal and Adult Female Sprague-Dawley Rats International Journal of Toxicology, March 1, 2005; 24(2): 111 - 127. [Abstract] [Full Text] [PDF]
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S. Ekins, E. Kirillov, E. A. Rakhmatulin, and T. Nikolskaya A NOVEL METHOD FOR VISUALIZING NUCLEAR HORMONE RECEPTOR NETWORKS RELEVANT TO DRUG METABOLISM Drug Metab. Dispos., March 1, 2005; 33(3): 474 - 481. [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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K. Swales, S. Kakizaki, Y. Yamamoto, K. Inoue, K. Kobayashi, and M. Negishi Novel CAR-mediated Mechanism for Synergistic Activation of Two Distinct Elements within the Human Cytochrome P450 2B6 Gene in HepG2 Cells J. Biol. Chem., February 4, 2005; 280(5): 3458 - 3466. [Abstract] [Full Text] [PDF]
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 Y. Yamamoto, R. Moore, T. L. Goldsworthy, M. Negishi, and R. R. Maronpot The Orphan Nuclear Receptor Constitutive Active/Androstane Receptor Is Essential for Liver Tumor Promotion by Phenobarbital in Mice Cancer Res., October 15, 2004; 64(20): 7197 - 7200. [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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H. Wang, S. Faucette, R. Moore, T. Sueyoshi, M. Negishi, and E. LeCluyse Human Constitutive Androstane Receptor Mediates Induction of CYP2B6 Gene Expression by Phenytoin J. Biol. Chem., July 9, 2004; 279(28): 29295 - 29301. [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. P. Jackson, S. S. Ferguson, R. Moore, M. Negishi, and J. A. Goldstein The Constitutive Active/Androstane Receptor Regulates Phenytoin Induction of Cyp2c29 Mol. Pharmacol., June 1, 2004; 65(6): 1397 - 1404. [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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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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K. Matsumura, T. Saito, Y. Takahashi, T. Ozeki, K. Kiyotani, M. Fujieda, H. Yamazaki, H. Kunitoh, and T. Kamataki Identification of a Novel Polymorphic Enhancer of the Human CYP3A4 Gene Mol. Pharmacol., February 1, 2004; 65(2): 326 - 334. [Abstract] [Full Text] [PDF]
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S. D. Shenoy, T. A. Spencer, N. A. Mercer-Haines, M. Alipour, M. D. Gargano, M. Runge-Morris, and T. A. Kocarek CYP3A INDUCTION BY LIVER X RECEPTOR LIGANDS IN PRIMARY CULTURED RAT AND MOUSE HEPATOCYTES IS MEDIATED BY THE PREGNANE X RECEPTOR Drug Metab. Dispos., January 1, 2004; 32(1): 66 - 71. [Abstract] [Full Text] [PDF]
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D. Bauer, N. Wolfram, G. F. Kahl, and K. I. Hirsch-Ernst Transcriptional Regulation of CYP2B1 Induction in Primary Rat Hepatocyte Cultures: Repression by Epidermal Growth Factor Is Mediated via a Distal Enhancer Region Mol. Pharmacol., January 1, 2004; 65(1): 172 - 180. [Abstract] [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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K. Kobayashi, T. Sueyoshi, K. Inoue, R. Moore, and M. Negishi Cytoplasmic Accumulation of the Nuclear Receptor CAR by a Tetratricopeptide Repeat Protein in HepG2 Cells Mol. Pharmacol., November 1, 2003; 64(5): 1069 - 1075. [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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D. Desaulniers, K. Leingartner, B. Musicki, A. Yagminas, G.-H. Xiao, J. Cole, L. Marro, M. Charbonneau, and B. K. Tsang Effects of Postnatal Exposure to Mixtures of Non-ortho-PCBs, PCDDs, and PCDFs in Prepubertal Female Rats Toxicol. Sci., October 1, 2003; 75(2): 468 - 480. [Abstract] [Full Text] [PDF]
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Y. Chen, S. S. Ferguson, M. Negishi, and J. A. Goldstein Identification of Constitutive Androstane Receptor and Glucocorticoid Receptor Binding Sites in the CYP2C19 Promoter Mol. Pharmacol., August 1, 2003; 64(2): 316 - 324. [Abstract] [Full Text] [PDF]
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 A. Kinoshita, H. Wanibuchi, K. Morimura, M. Wei, J. Shen, S. Imaoka, Y. Funae, and S. Fukushima Phenobarbital at low dose exerts hormesis in rat hepatocarcinogenesis by reducing oxidative DNA damage, altering cell proliferation, apoptosis and gene expression Carcinogenesis, August 1, 2003; 24(8): 1389 - 1399. [Abstract] [Full Text] [PDF]
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J. Gu, Y. Weng, Q.-Y. Zhang, H. Cui, M. Behr, L. Wu, W. Yang, L. Zhang, and X. Ding Liver-specific Deletion of the NADPH-Cytochrome P450 Reductase Gene: IMPACT ON PLASMA CHOLESTEROL HOMEOSTASIS AND THE FUNCTION AND REGULATION OF MICROSOMAL CYTOCHROME P450 AND HEME OXYGENASE J. Biol. Chem., July 3, 2003; 278(28): 25895 - 25901. [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. 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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S.-W. Kim, K. Park, E. Kwak, E. Choi, S. Lee, J. Ham, H. Kang, J. M. Kim, S. Y. Hwang, Y.-Y. Kong, et al. Activating Signal Cointegrator 2 Required for Liver Lipid Metabolism Mediated by Liver X Receptors in Mice Mol. Cell. Biol., May 15, 2003; 23(10): 3583 - 3592. [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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H. Wang, S. R. Faucette, D. Gilbert, S. L. Jolley, T. Sueyoshi, M. Negishi, and E. L. LeCluyse Glucocorticoid Receptor Enhancement of Pregnane X Receptor-Mediated CYP2B6 Regulation in Primary Human Hepatocytes Drug Metab. Dispos., May 1, 2003; 31(5): 620 - 630. [Abstract] [Full Text] [PDF]
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 H. Daniel and I. Rubio-Aliaga An update on renal peptide transporters Am J Physiol Renal Physiol, May 1, 2003; 284(5): F885 - F892. [Abstract] [Full Text] [PDF]
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 J. R. A. Wooltorton, V. I. Pidoplichko, R. S. Broide, and J. A. Dani Differential Desensitization and Distribution of Nicotinic Acetylcholine Receptor Subtypes in Midbrain Dopamine Areas J. Neurosci., April 15, 2003; 23(8): 3176 - 3185. [Abstract] [Full Text] [PDF]
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H. Wang, S. Faucette, T. Sueyoshi, R. Moore, S. Ferguson, M. Negishi, and E. L. LeCluyse A Novel Distal Enhancer Module Regulated by Pregnane X Receptor/Constitutive Androstane Receptor Is Essential for the Maximal Induction of CYP2B6 Gene Expression J. Biol. Chem., April 11, 2003; 278(16): 14146 - 14152. [Abstract] [Full Text] [PDF]
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T. Shiraki, N. Sakai, E. Kanaya, and H. Jingami Activation of Orphan Nuclear Constitutive Androstane Receptor Requires Subnuclear Targeting by Peroxisome Proliferator-activated Receptor gamma Coactivator-1alpha . A POSSIBLE LINK BETWEEN XENOBIOTIC RESPONSE AND NUTRITIONAL STATE J. Biol. Chem., March 21, 2003; 278(13): 11344 - 11350. [Abstract] [Full Text] [PDF]
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J. M. Pascussi, M. Busson-Le Coniat, P. Maurel, and M.-J. Vilarem Transcriptional Analysis of the Orphan Nuclear Receptor Constitutive Androstane Receptor (NR1I3) Gene Promoter: Identification of a Distal Glucocorticoid Response Element Mol. Endocrinol., January 1, 2003; 17(1): 42 - 55. [Abstract] [Full Text] [PDF]
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S. C. Dogra, D. Tremethick, and B. K. May Evidence That the Coactivator CBP/p300 Is Important for Phenobarbital-Induced but Not Basal Expression of the CYP2H1 Gene Mol. Pharmacol., January 1, 2003; 63(1): 73 - 80. [Abstract] [Full Text] [PDF]
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 L. Cartee, S. C. Maggio, R. Smith, H. M. Sankala, P. Dent, and S. Grant Protein Kinase C-dependent Activation of the Tumor Necrosis Factor Receptor-mediated Extrinsic Cell Death Pathway Underlies Enhanced Apoptosis in Human Myeloid Leukemia Cells Exposed to Bryostatin 1 and Flavopiridol Mol. Cancer Ther., January 1, 2003; 2(1): 83 - 93. [Abstract] [Full Text] [PDF]
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T. M. Stulnig, K. R. Steffensen, H. Gao, M. Reimers, K. Dahlman-Wright, G. U. Schuster, and J.-A. Gustafsson Novel Roles of Liver X Receptors Exposed by Gene Expression Profiling in Liver and Adipose Tissue Mol. Pharmacol., December 1, 2002; 62(6): 1299 - 1305. [Abstract] [Full Text] [PDF]
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L. Xiao, X. Cui, V. Madison, R. E. White, and K.-C. Cheng Insights from a Three-Dimensional Model into Ligand Binding to Constitutive Active Receptor Drug Metab. Dispos., September 1, 2002; 30(9): 951 - 956. [Abstract] [Full Text] [PDF]
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J. M. Maglich, C. M. Stoltz, B. Goodwin, D. Hawkins-Brown, J. T. Moore, and S. A. Kliewer Nuclear Pregnane X Receptor and Constitutive Androstane Receptor Regulate Overlapping but Distinct Sets of Genes Involved in Xenobiotic Detoxification Mol. Pharmacol., September 1, 2002; 62(3): 638 - 646. [Abstract] [Full Text] [PDF]
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S. S. Ferguson, E. L. LeCluyse, M. Negishi, and J. A. Goldstein Regulation of Human CYP2C9 by the Constitutive Androstane Receptor: Discovery of a New Distal Binding Site Mol. Pharmacol., September 1, 2002; 62(3): 737 - 746. [Abstract] [Full Text] [PDF]
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T. M. Willson and J. T. Moore Minireview: Genomics Versus Orphan Nuclear Receptors--A Half-Time Report Mol. Endocrinol., June 1, 2002; 16(6): 1135 - 1144. [Abstract] [Full Text] [PDF]
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A. Ueda, S. Kakizaki, M. Negishi, and T. Sueyoshi Residue Threonine 350 Confers Steroid Hormone Responsiveness to the Mouse Nuclear Orphan Receptor CAR Mol. Pharmacol., June 1, 2002; 61(6): 1284 - 1288. [Abstract] [Full Text] [PDF]
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J. D. Clyne, L.-F. Wang, and R. I. Hume Mutational Analysis of the Conserved Cysteines of the Rat P2X2 Purinoceptor J. Neurosci., May 15, 2002; 22(10): 3873 - 3880. [Abstract] [Full Text] [PDF]
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