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J. Biol. Chem., Vol. 276, Issue 41, 37739-37742, October 12, 2001
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§ and¶
From the ¶ Howard Hughes Medical Institute and
Gene Expression Laboratory, The Salk Institute for
Biological Studies, La Jolla, California 92037
Orphan nuclear receptors
(NRs)1 include gene products
that are structurally related to nuclear hormone receptors but lack
known physiological ligands. It has become clear that orphan NRs
represent a unique and pivotal resource to uncover new regulatory
systems that impact both health and human diseases.
In addition to production and clearance of endogenous hormones,
mammals also confront numerous foreign chemicals (xenobiotics) such as
ingested food, environmental pollutants, and carcinogens as well as
prescription and non-prescription drugs. Such compounds may accumulate
to toxic levels unless they are metabolized and eliminated, a process
largely mediated by the supergene family of cytochrome P450 (CYP)
enzymes. Expressed mainly in the liver and capable of recognizing an
amazing diversity of xenobiotics, CYP enzymes catalyze the metabolic
conversion of xenobiotics to polar derivatives that are more readily
eliminated (for reviews, see Refs. 1 and 2). Thus, CYP enzymes,
especially members of the CYP 1-4 families, are crucial for xenobiotic
detoxification and survival of organisms (for a review, see Ref. 3).
Among CYP enzymes, the CYP3A and -2B isoenzymes are of particular
medical significance. For example, the human CYP3A4 enzyme alone is
involved in the metabolism of 50-60% of clinical drugs as well as
neutraceuticals and herbal medicines (4). An additional 25-30% of
these compounds are metabolized by the CYP2B isoenzymes. The combined
metabolic versatility of CYP3A and -2B, coupled with their inducibility by xenobiotic substrates, constitutes a molecular basis for many clinical drug-drug interactions (4). Compounds that are strong CYP
enzyme inducers such as glucocorticoids, phenobarbital (PB), or
rifampicin (RIF) can dramatically affect the clearance of any co-consumed drug that is a substrate for the enzyme. Recently, St.
Johns wort, a popular herbal remedy for depression, was found to
trigger severe adverse drug-drug interactions with oral contraceptives, the HIV protease inhibitor indinavir, and the immunosuppressant cyclosporin as a consequence of activating the CYP3A system (Ref. 5,
and references therein).
In 1992, the aryl hydrocarbon receptor was identified as a
transcriptional sensor mediating the induction of CYP1A and
-1B1 genes by dioxin and a variety of related
polycyclic aromatic hydrocarbons (6). Aryl hydrocarbon receptor is a
member of the basic helix-loop-helix family of transcription
factors, and it was presumed that other basic helix-loop-helix
proteins might control the CYP3A and -2B gene
families. This turned out to be an incorrect assumption, and the
molecular basis for induction of CYP3A and -2B
genes remained largely unknown. A major conceptual challenge in
defining the molecular mechanisms for xenobiotic response is that
CYP genes are induced by thousands of natural and synthetic
compounds, and yet the inducibility of CYP enzymes shows clear target
gene and species specificity. For example, the antibiotic RIF has been shown to be a specific CYP3A inducer in humans and rabbits,
whereas pregnenolone 16 In the past 3-4 years, emerging evidence has increasingly pointed to a
unique role for orphan NRs in the regulation of CYP genes by
functioning as atypical pleotropic receptors for a remarkable diversity
of xenobiotic compounds (Fig. 1).
In 1998, a human orphan receptor SXR (steroid and
xenobiotic receptor) and its rodent ortholog PXR (pregnane X
receptor) were isolated as candidate xenobiotic receptors
(xeno-sensors) postulated to regulate CYP3A gene expression
(8-10) (for reviews, see Refs. 3, 11, and 12). Initially isolated as a
homolog of the Xenopus BXR (benzoate X receptor)
gene and predominantly expressed in the liver and intestine,
SXR and PXR were found to be activated by a
variety of xenobiotic compounds and steroids that were known to induce
hepatic and intestinal CYP3A activity. Moreover, SXR and PXR
have been shown to bind to the IR-6 and DR-3 xenobiotic response
elements localized in the promoter regions of the human or
rodent CYP3A genes (8-10).
Recently, proof of the function identity of SXR/PXR has been
established by targeted disruption of the mouse PXR locus,
which abolishes the CYP3A xenobiotic response (13, 14). More
importantly, replacement of PXR with its human homolog
SXR fully restores the xenobiotic response within the mouse
liver but now with a humanized response profile (Fig.
2) (13). Therefore, SXR and PXR function as species-specific xeno-sensors mediating the classic "adaptive hepatic response." It has long been postulated that evolutionary selection for the xenobiotic response was in part driven by the ability
of one toxin to confer "metabolic immunity" to both itself and
other co-consumed toxins by virtue of induction of common metabolic
enzymes. If this hypothesis is correct, PXR null mice would
fail to mount a hepatic response and thus remain sensitive to multidrug
response. One common test of this idea is the ability of PCN
pretreatment to protect mice from subsequent exposure to a second drug.
Indeed, this key role for SXR/PXR in xenoprotection is confirmed by the
failure of PCN-treated PXR null mice to protect against
sedative xenotoxicants such as zoxazolamine and tribromoethanol (15) or
the hepatotoxic bile acid lithocholic acid (14, 15). In contrast,
hepatic expression of a constitutively activated SXR
(VPSXR) transgene results in sustained up-regulation of
CYP3A gene expression and consequent protection against
xenotoxicants (Fig. 3) (13).
INTRODUCTION
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INTRODUCTION
Molecular Basis of the...
SXR and PXR as...
A Xenobiotic CAR
Receptor Cross-talk and a...
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Molecular Basis of the Xenobiotic Response
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-carbonitrile (PCN), an anti-glucocorticoid,
is a rodent-specific CYP3A inducer (Ref. 7, and references
therein). Pharmacologic studies in cultured primary hepatocytes suggest that it is not the structure of CYP3A genes but rather
species-specific cellular factor(s) that dictates the profile of
CYP3A inducibility (7).
View larger version (20K):
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Fig. 1.
Nuclear receptor-mediated CYP
gene induction. XenoR, xenobiotic receptor;
XRE, xenobiotic response element; MDR, multiple
drug resistance.
SXR and PXR as Xeno-sensors
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View larger version (23K):
[in a new window]
Fig. 2.
Establishment of a humanized xenobiotic
mouse. wt, wild type.
View larger version (45K):
[in a new window]
Fig. 3.
Activation of SXR confers protection against
xenobiotic toxicants. The zoxazolamine paralysis test in
wild-type (WT) and VPSXR mice (the left and
right mouse in B, respectively) is shown. The
VPSXR mice, engineered to express an activated form of SXR
transgene in the liver, exhibit enhanced protection against paralytic
zoxazolamine.
In addition to its ability to mediate CYP3A induction, SXR
has been shown to induce the expression of the multiple drug resistance (MDR1) gene in response to several SXR agonists such as the
chemotherapeutic agent Taxol (16). MDR1 encodes a transporter that
protects cells from toxicity by rapidly effluxing drugs. Therefore, SXR
is implicated in both drug metabolism and clearance (Fig. 1).
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A Xenobiotic CAR |
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Constitutive androstane receptor (CAR) was initially
isolated and shown to activate a DR-5 type of retinoid acid response element (
RARE) in a ligand-independent manner (17). The identity of
CAR as a xenobiotic receptor was first hinted by the ability of
selective androstane metabolites to inhibit its constitutive activity
(18). Its role in positive xenobiotic regulation was suggested when CAR
was shown to activate the phenobarbital response element found in
promoters of PB-inducible CYP2B genes (Ref. 19, and
references therein). Subsequently, this activation was found to be
potentiated by PB and its derivatives such as TCPOBOP (19). Moreover,
disruption of the mouse CAR locus by homologous
recombination resulted in loss of PB and TCPOBOP activation of the
CYP2B10 gene (20). Oddly, loss of CAR increases
sensitivity to zoxazolamine-induced paralysis while decreasing
sensitivity to cocaine-induced acute hepatic response (20), furthering
the complexity of the xenobiotic response. Similar to SXR and PXR, CAR
also exhibits clear species-dependent ligand specificity.
For example, TCPOBOP is an activating ligand for rodent CAR but fails
to affect human CAR
(21).2
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Receptor Cross-talk and a Metabolic Safety Net |
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SXR/PXR and CAR were originally shown to regulate CYP3A
and -2B genes, respectively, presumably through distinct
classes of drugs. Because the xenobiotic response elements in these two
classes of CYP genes are different, it seemed reasonable to
speculate that they were independently regulated. Surprisingly, several groups have recently demonstrated the existence of cross-talks between
these receptors and their target CYP genes. Such reciprocal regulation is accomplished via adaptive recognition of each other's DNA response elements as diagrammed in Fig.
4. The phenobarbital response element of
the CYP2B promoter contains two imperfect DR-4 type NR
binding sites that display measurable affinity for SXR, and
subsequently SXR was found to regulate CYP2B both in cultured cells and in transgenic mice (22). In a type of functional symmetry, CAR can activate CYP3A through previously defined
SXR/PXR response elements (19, 21-23). The in vivo
cross-talk between PXR and CAR could be more thoroughly explored via
the generation of mice deficient in both PXR and
CAR genes. Nevertheless, the cross-regulation of
CYP gene classes provides an explanation for the dual
activation property of certain xenobiotics (24). However, not all drugs
appear to be dual activators, which might correlate to their relative
affinity for the receptors or reflect other more complex factors.
Despite some limitations, this reciprocal regulation of CYP
genes by multiple xenobiotic receptors reveals the existence of a
fail-safe metabolic safety net to protect against xenotoxicants and at
the same time to increase the propensity for drug-drug interactions.
Moreover, the overlap in their response element recognition establishes
a molecular basis for a regulatory network of CYP gene
expression that expands the function of an individual orphan
receptor.
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Nuclear Xenobiology, an Emerging Field |
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The summarized work represents the beginning of an undoubtedly long road to understand the molecular complexity of the xenobiotic response. The identification and characterization of xenobiotic receptors such as SXR/PXR and CAR have created many future research opportunities described in the following paragraphs.
Systematic Identification of Xenobiotic Target Genes-- Having demonstrated that SXR and PXR mediate CYP3A response, the presence of candidate DR-3 or IR-6 response elements in genes encoding additional phase I and phase II xenobiotic enzymes such as CYP2A, CYP2C, CYP2E, and UDP-glucuronosyltransferase raised the potential for a broader physiologic function (8). In addition, recent identification of MDR-1 (also known as P-glycoprotein) as a direct target of SXR implicates this receptor in drug efflux, which adds a new dimension to the action of these receptors (16).
Identification of Additional Orphan Receptors Mediating the
Xenobiotic Response--
It has become clear that many genes belonging
to CYP 1-4 families can be transcriptionally activated by foreign
chemicals through one or more NRs. Table
I summarizes a list of P450
inducers, their responsive CYPs, the mediating NR, and the
cognate response elements. Of note, many of the xenobiotic receptors
also have endogenous ligands, indicating a broader physiologic role for these receptors. Interestingly, as a common heterodimerization partner
for xenobiotic receptors, RXR seems to function as a master regulator
for CYP gene expression because a liver-specific disruption of mouse RXR gene causes decreased basal expression of
CYP3A, -2B, -4A, and -7A
(25). Accordingly, both CYP2B1/2 and CYP3A isoenzymes become elevated
in rats treated with RXR-selective agonists (26).
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Identification of Atypical Ligands for Xenobiotic Receptors with Implications in Physiologic and Pathologic Processes-- For example, certain types of bile acids, known as potent ligands for farnesoid X receptor, have recently been shown to activate SXR and PXR in both cultured cells and mice (14, 15). A combination of knockout and transgenic mouse studies revealed that activation of SXR/PXR is necessary and sufficient to both induce CYP3A enzymes and confer a resistance to toxic cholestatic bile acid lithocholic acid (14, 15). These observations not only establish a unique role for SXR/PXR-mediated xenobiotic response in the detoxification of bile acids but also provide a molecular mechanism for the clinical relief of cholestasis-associated pruritus by RIF or other CYP3A inducers.
As ligand-dependent transcription factors, these receptors
can be used in conjunction with DNA array-based studies to characterize the network of target genes that comprise the genetic foundation of the
xenobiotic response.
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External Chemicals and the Human Genome; a Perspective |
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Although long studied, the molecular basis of the interaction
between external chemicals and the mammalian genome has not been well
understood. NR-mediated xenobiotic regulation may represent the
critical biochemical interface of man with his chemical environment. The combination of loss (gene knockout) and gain (transgene) of function provides a unique strategy to dissect the xenobiotic response
through molecular, genomic, pharmacologic, and proteomic approaches.
The humanized mouse system represents a major step toward generating a
humanized rodent toxicologic model and thus provides an advanced way to
explore the interface between the environment and the human genome.
These xenobiotic receptors and genetically engineered animals, in
conjunction with the completion of the human genome project, should
greatly facilitate our understanding of the complexity of the
xenobiotic response and its implication in pharmaceutical development
including drug profiling, toxicity analysis, and drug-drug interaction.
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ACKNOWLEDGEMENTS |
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We thank our colleagues for their contribution to our studies described in this review. We thank Dr. Yanhong Shi for comments on the manuscript.
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FOOTNOTES |
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* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001. This is the fifth article of five in the "Nuclear Receptor Minireview Series."
§ Supported by the Susan G. Komen Breast Cancer Foundation. To whom correspondence may be addressed. E-mail: wxie@ems.salk.edu.
To whom correspondence may be addressed. E-mail: evans@salk.edu. Investigator of the Howard Hughes Medical Institute at the Salk Institute for Biological Studies and March of Dimes Chair in
Molecular and Developmental Biology.
Published, JBC Papers in Press, July 17, 2001, DOI 10.1074/jbc.R100033200
2 W. Xie and R. M. Evans, unpublished observations.
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ABBREVIATIONS |
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The abbreviations used are:
NR, nuclear
receptor;
CAR, constitutive androstane receptor;
CYP, cytochrome P450;
PB, phenobarbital;
PCN, pregnenolone 16-carbonitrile;
PXR, pregnane
X receptor;
RIF, rifampicin;
SXR, steroid and xenobiotic receptor;
TCPOBOP, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene;
RXR, retinoid X
receptor.
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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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 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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M. M. Tabb, A. Sun, C. Zhou, F. Grun, J. Errandi, K. Romero, H. Pham, S. Inoue, S. Mallick, M. Lin, et al. Vitamin K2 Regulation of Bone Homeostasis Is Mediated by the Steroid and Xenobiotic Receptor SXR J. Biol. Chem., November 7, 2003; 278(45): 43919 - 43927. [Abstract] [Full Text] [PDF]
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 S. Hata, P. Wang, N. Eftychiou, M. Ananthanarayanan, A. Batta, G. Salen, K. S. Pang, and A. W. Wolkoff Substrate specificities of rat oatp1 and ntcp: implications for hepatic organic anion uptake Am J Physiol Gastrointest Liver Physiol, November 1, 2003; 285(5): G829 - G839. [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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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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A. L. M. Sutton and P. N. MacDonald Vitamin D: More Than a "Bone-a-Fide" Hormone Mol. Endocrinol., May 1, 2003; 17(5): 777 - 791. [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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A. Madan, R. A. Graham, K. M. Carroll, D. R. Mudra, L. A. Burton, L. A. Krueger, A. D. Downey, M. Czerwinski, J. Forster, M. D. Ribadeneira, et al. Effects of Prototypical Microsomal Enzyme Inducers on Cytochrome P450 Expression in Cultured Human Hepatocytes Drug Metab. Dispos., April 1, 2003; 31(4): 421 - 431. [Abstract] [Full Text] [PDF]
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 M. Trauner and J. L. Boyer Bile Salt Transporters: Molecular Characterization, Function, and Regulation Physiol Rev, April 1, 2003; 83(2): 633 - 671. [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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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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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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A. C. Ross Advances in Retinoid Research: Mechanisms of Cancer Chemoprevention Symposium Introduction J. Nutr., January 1, 2003; 133(1): 271S - 272. [Full Text] [PDF]
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