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Event: 715

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Activation, Constitutive androstane receptor

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Activation, Constitutive androstane receptor

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
signaling nuclear receptor subfamily 1 group I member 3 increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
CAR activation- Hepatocellular tumors MolecularInitiatingEvent Brendan Ferreri-Hanberry (send email) Open for citation & comment EAGMST Under Review

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI
Hamster Hamster High NCBI
human Homo sapiens High NCBI
dog Canis lupus familiaris High NCBI
Monkey Monkey High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
All life stages High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Unspecific High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor that is expressed primarily in the liver (and to a lesser extent in kidneys, intestines and stomach), which can be activated by xenobiotics or by certain endogenous cellular metabolites. CAR normally is tethered in the cytoplasm via a set of specific proteins including heat shock protein 90 (HSP90) and other chaperones. Chemical ligands bind to the ligand binding site of CAR, and a conformational change frees CAR from the tethering proteins and facilitates its transport into the nucleus. In addition, indirect CAR activators (e.g. phenobarbital) can bind to the EGF receptor to initiate a series of steps that eventually dephosphorylate a critical Threonine-38 residue in CAR, allowing it to migrate into the nucleus. Inside the nucleus, CAR dimerizes with RXRα and this CAR-RXR complex binds to specific response elements on the DNA to activate transcription of specific CAR-responsive genes. CAR is unique among nuclear receptors, in that it is constitutively active when in the nucleus, i.e. it will spontaneously dimerize with RXR and alter gene expression, even without an activator bound to its ligand binding domain. When activated and translocated to the nucleus, CAR alters the transcription of multiple genes, and it is the altered levels of these gene transcripts (i.e. mRNA levels) that produce the downstream biological effects following activation of CAR (Omiecinski et al., 2011bOmiecinski et al., 2011aReschly and Krasowski, 2006Swales and Negishi, 2004).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Activation of CAR by a chemical substance is often detected in an in vitro system, using a reporter construct that is transiently transfected into a model cell line. The reporter readouts are typically luminescent (e.g. luciferase-based) (Omiecinski et al., 2011bStanley et al., 2006). Because CAR is constitutively active, many traditional reporter assay approaches can be confounded due to high background activity when the cytoplasmic tethering complex for CAR is inadequate in the cell line being used. Omiecinski et al. (2011b) were able to develop a successful reporter assay for CAR from mouse, rat, human and dogs by inserting a 5 amino acid modification into the different species' CAR, in conjunction with a luciferase reporter construct driven by a human CYP2B6 response element. This system showed strong responses to model CAR activators that were selective for each species' CAR, which is an important consideration since the ability of a particular chemical to activate the CAR receptor is very species-specific (Omiecinski et al., 2011b).  Other groups have used a similar strategy to develop sensitive reporter assays by inserting a single amino acid residue into human CAR (Chen et al., 2010).

With in vivo testing, activation of CAR by a chemical substance is most readily detected by indirect methods, considering the complex set of processes that are involved. Typically, expression of a small subset of genes in a tissue of interest (e.g. liver) that are known to be regulated by CAR can be measured via RT-PCR methods (reverse transcripase - polymerase chain reaction), or for the whole animal transcriptome by microarrays or RNAseq methodologies (Currie et al., 2014Peffer et al., 2018aPeffer et al., 2018b). In these experiments, treatment of animals for 7 or 14 days and comparison of the response in control vs. treated tissue is assessed;  CAR-responsive genes in mice might include Cyp2b10, Gadd45b, Ki67, Cyp2c55 and Gstm3 (Oshida et al., 2015aPeffer et al., 2018aTojima et al., 2012), but an appropriate set of genes for the species and strain being tested would need to be devised based on the literature. Oshida et al. (2015a) have developed a CAR signature  in mice that represents the combined change in an 83-gene signature derived from multiple CAR activating compounds given to groups of mice for 30 days. A compound's response compared to the CAR signature can be compared for both the direction and magnitude of all 83 genes, and a statistically significant match evaluated via Correlation Engine (Illumina).  When a known CAR activator (Peffer et al.Tamura et al., 2013) that was not part of the training set was tested and evaluated, it also gave a clear statistically significant confirmation as a CAR activator (Peffer et al., 2018b). 

A more generic in vivo measurement approach that may be applicable in a wider array of species, is to look for increases in  enzyme activity or protein levels for CAR-responsive enzymes, such as CYP2B or CYP3A induction (Burke et al., 1985Burke et al., 1994Sun et al., 2006). While this approach gives some evidence that the chemical tested is a CAR activator, it must be recognized that other nuclear receptors can also induce the same enzymes to varying extents, so evidence by these methods is suggestive of CAR activation but not definitive. More definitive evidence that a substance is a CAR activator, can be attained in vivo by experiments in CAR null mice or rats, which lack the gene for the CAR molecule. Absence of responses in CAR null mice or rats for the gene expression, CYP2B enzyme induction,  liver hepatocellular hypertrophy and increases in liver weight, and presence of these responses in treated wild-type animals, is a convincing proof that these effects were mediated by activation of CAR in the wild-type animals.

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

CAR (NR1I3) is evolutionarily conserved across mammalian species, but is not present in other vertebrate species (Moore et al., 2006Omiecinski et al., 2011bReschly and Krasowski, 2006). The related NR1I nuclear receptors PXR (NR1I2) and VDR (NR1I1) are found in diverse vertebrate species from fish to mammals, and evidence suggests that CAR arose from a duplication of an ancestral PXR gene (Reschly and Krasowski, 2006). CAR exhibits a low sequence conservation of amino acids between species, including the residues of amino acids within the ligand-binding pocket.  As a result, different species' CAR receptors have very different abilities to bind and become activated by CAR-activating chemicals (Omiecinski et al., 2011b). In different mammalian species, the role of CAR has been most actively studied in the liver, where it plays a central role in activation of CYP enzymes, Phase II conjugation enzymes, lipid and glucose metabolism and detoxification of bile acids. CAR is also found at lower levels in the intestine, stomach and kidneys (Moore et al., 2006). In rats and mice, CAR has been shown to also stimulate genes responsible for hepatocellular proliferation, and as a result, these species can eventually develop hepatocellular adenomas and carcinomas that do not develop in other mammalian species such as hamsters and humans (Elcombe et al., 2014Lake, 2018).

Evidence for Perturbation by Stressor

Overview for Molecular Initiating Event

When a specific MIE can be defined (i.e., the molecular target and nature of interaction is known), in addition to describing the biological state associated with the MIE, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to list stressors known to trigger the MIE and provide evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). Depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). Known stressors should be included in the MIE description, but it is not expected to include a comprehensive list. Rather initially, stressors identified will be exemplary and the stressor list will be expanded over time. For more information on MIE, please see pages 32-33 in the User Handbook.

Stressors of CAR (i.e. chemicals that activate CAR) can be quite species-specific, due to the heterogeneity of the amino acid sequence of CAR, particularly in the ligand binding domain. TCPOBOP (1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene, 3,3′,5,5′-tetrachloro-1,4-bis(pyridyloxy)benzene) is a very potent direct CAR activator in the mouse (Huang et al., 2005Omiecinski et al., 2011b). In reporter assays for CAR from mouse, rat, human and dog, TCPOBOP was shown to be a strong activator of mouse CAR (28-fold), but it showed no activation of rat and dog CAR, and only a minimal activation of human CAR (3-fold) (Omiecinski et al., 2011b). Consistent with this potent activation in mice,  studies in wild-type and CAR-null mice showed that absence of the CAR receptor effectively blocked CAR-mediated downstream effects including gene activation (Tojima et al., 2012), cell proliferation (Huang et al., 2005Wei et al., 2000) and  formation of liver tumors (Diwan et al., 1992Huang et al., 2005).

Metofluthrin is a potent activator of CAR in rats, and produces liver tumors in chronic toxicity studies in male and female Wistar rats, but no liver tumors in male and female CD-1 mice (Yamada et al., 2009). In rats, metofluthrin produced significant increases in gene expression of CAR-responsive genes Cyp2b1/2 and Cyp3a1, increased cell proliferation and increased indirect markers of CAR activation such as CYP2B protein levels and hepatocellular hypertrophy. While metofluthrin was not tested in CAR-null rats, isolated rat hepatocyte cultures treated with metofluthrin and siRNA for CAR (a gene silencing technique) caused a knockdown of Car mRNA expression and resulting suppression of the response to metofluthrin in terms of Cyp2b1 mRNA and Car mRNA levels (Deguchi et al., 2009). This suppression indicates that metofluthrin produces its in vivo effects in rats via activation of CAR.

Phenobarbital is an indirect activator of CAR, in that it does not bind directly to the ligand binding domain, but instead binds to an EGF receptor to initiate a series of steps that eventually dephosphorylate a critical Threonine-38 residue in CAR, allowing it to migrate into the nucleus and alter gene expression (Mutoh et al., 2009Mutoh et al., 2013Swales and Negishi, 2004). Downstream events following CAR activation by phenobarbital have been shown to be essentially the same as with direct CAR activators, and include Cyp2b10 gene expression, cell proliferation and increases in mouse liver tumors (Huang et al., 2005), which are prevented by treatment of CAR-null mice lacking the CAR receptor (Huang et al., 2005Wei et al., 2000Yamamoto et al., 2004). Thus, lack of these downstream key events in CAR-null mice, including an initiation-promotion study, has been used to demonstrate that phenobarbital activates the CAR receptor in mice.

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Burke, M. D., Thompson, S., Elcombe, C. R., Halpert, J., Haaparanta, T. and Mayer, R. T. (1985), Ethoxy-, pentoxy- and benzyloxyphenoxazones and homologues: a series of substrates to distinguish between different induced cytochromes P-450. Biochem Pharmacol 34, 3337-45.

Burke, M. D., Thompson, S., Weaver, R. J., Wolf, C. R. and Mayer, R. T. (1994), Cytochrome P450 specificities of alkoxyresorufin O-dealkylation in human and rat liver. Biochem Pharmacol 48, 923-36.

Chen, T., Tompkins, L. M., Li, L., Li, H., Kim, G., Zheng, Y. and Wang, H. (2010), A single amino acid controls the functional switch of human constitutive androstane receptor (CAR) 1 to the xenobiotic-sensitive splicing variant CAR3. J Pharmacol Exp Ther 332, 106-15, 10.1124/jpet.109.159210.

Currie, R. A., Peffer, R. C., Goetz, A. K., Omiecinski, C. J. and Goodman, J. I. (2014), Phenobarbital and propiconazole toxicogenomic profiles in mice show major similarities consistent with the key role that constitutive androstane receptor (CAR) activation plays in their mode of action. Toxicology 321, 80-8, 10.1016/j.tox.2014.03.003.

Deguchi, Y., Yamada, T., Hirose, Y., Nagahori, H., Kushida, M., Sumida, K., Sukata, T., Tomigahara, Y., Nishioka, K., Uwagawa, S., Kawamura, S. and Okuno, Y. (2009), Mode of action analysis for the synthetic pyrethroid metofluthrin-induced rat liver tumors: evidence for hepatic CYP2B induction and hepatocyte proliferation. Toxicol Sci 108, 69-80, 10.1093/toxsci/kfp006.

Diwan, B. A., Lubet, R. A., Ward, J. M., Hrabie, J. A. and Rice, J. M. (1992), Tumor-promoting and hepatocarcinogenic effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in DBA/2NCr and C57BL/6NCr mice and an apparent promoting effect on nasal cavity tumors but not on hepatocellular tumors in F344/NCr rats initiated with N-nitrosodiethylamine. Carcinogenesis 13, 1893-901.

Elcombe, C. R., Peffer, R. C., Wolf, D. C., Bailey, J., Bars, R., Bell, D., Cattley, R. C., Ferguson, S. S., Geter, D., Goetz, A., Goodman, J. I., Hester, S., Jacobs, A., Omiecinski, C. J., Schoeny, R., Xie, W. and Lake, B. G. (2014), Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator. Crit Rev Toxicol 44, 64-82, 10.3109/10408444.2013.835786.

Huang, W., Zhang, J., Washington, M., Liu, J., Parant, J. M., Lozano, G. and Moore, D. D. (2005), Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol Endocrinol 19, 1646-53, 10.1210/me.2004-0520.

Lake, B. G. (2018), Human relevance of rodent liver tumour formation by constitutive androstane receptor (CAR) activators. Toxicology Research, 10.1039/c8tx00008e. http://dx.doi.org/10.1039/C8TX00008E

Moore, D. D., Kato, S., Xie, W., Mangelsdorf, D. J., Schmidt, D. R., Xiao, R. and Kliewer, S. A. (2006), International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor. Pharmacol Rev 58, 742-59, 10.1124/pr.58.4.6.

Mutoh, S., Osabe, M., Inoue, K., Moore, R., Pedersen, L., Perera, L., Rebolloso, Y., Sueyoshi, T. and Negishi, M. (2009), Dephosphorylation of threonine 38 is required for nuclear translocation and activation of human xenobiotic receptor CAR (NR1I3). J Biol Chem 284, 34785-92, 10.1074/jbc.M109.048108.

Mutoh, S., Sobhany, M., Moore, R., Perera, L., Pedersen, L., Sueyoshi, T. and Negishi, M. (2013), Phenobarbital indirectly activates the constitutive active androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling. Sci Signal 6, ra31, 10.1126/scisignal.2003705.

Omiecinski, C. J., Coslo, D. M., Chen, T., Laurenzana, E. M. and Peffer, R. C. (2011b), Multi-species analyses of direct activators of the constitutive androstane receptor. Toxicol Sci 123, 550-62, 10.1093/toxsci/kfr191.

Omiecinski, C. J., Vanden Heuvel, J. P., Perdew, G. H. and Peters, J. M. (2011a), Xenobiotic metabolism, disposition, and regulation by receptors: from biochemical phenomenon to predictors of major toxicities. Toxicol Sci 120 Suppl 1, S49-75, 10.1093/toxsci/kfq338.

Oshida, K., Vasani, N., Jones, C., Moore, T., Hester, S., Nesnow, S., Auerbach, S., Geter, D. R., Aleksunes, L. M., Thomas, R. S., Applegate, D., Klaassen, C. D. and Corton, J. C. (2015a), Identification of chemical modulators of the constitutive activated receptor (CAR) in a gene expression compendium. Nucl Recept Signal 13, e002, 10.1621/nrs.13002.

Peffer, R. C., Cowie, D. E., Currie, R. A. and Minnema, D. J. (2018a), Sedaxane-Use of Nuclear Receptor Transactivation Assays, Toxicogenomics, and Toxicokinetics as Part of a Mode of Action Framework for Rodent Liver Tumors. Toxicol Sci 162, 582-598, 10.1093/toxsci/kfx281.

Peffer, R. C., LeBaron, M. J., Battalora, M., Bomann, W. H., Werner, C., Aggarwal, M., Rowe, R. R. and Tinwell, H. (2018b), Minimum datasets to establish a CAR-mediated mode of action for rodent liver tumors. Regul Toxicol Pharmacol 96, 106-120, 10.1016/j.yrtph.2018.04.001.

Peffer, R. C., Moggs, J. G., Pastoor, T., Currie, R. A., Wright, J., Milburn, G., Waechter, F. and Rusyn, I. (2007), Mouse liver effects of cyproconazole, a triazole fungicide: role of the constitutive androstane receptor. Toxicol Sci 99, 315-25, 10.1093/toxsci/kfm154.

Reschly, E. J. and Krasowski, M. D. (2006), Evolution and function of the NR1I nuclear hormone receptor subfamily (VDR, PXR, and CAR) with respect to metabolism of xenobiotics and endogenous compounds. Curr Drug Metab 7, 349-65.

Stanley, L. A., Horsburgh, B. C., Ross, J., Scheer, N. and Wolf, C. R. (2006), PXR and CAR: nuclear receptors which play a pivotal role in drug disposition and chemical toxicity. Drug Metab Rev 38, 515-97, 10.1080/03602530600786232.

Sun, G., Thai, S. F., Lambert, G. R., Wolf, D. C., Tully, D. B., Goetz, A. K., George, M. H., Grindstaff, R. D., Dix, D. J. and Nesnow, S. (2006), Fluconazole-induced hepatic cytochrome P450 gene expression and enzymatic activities in rats and mice. Toxicol Lett 164, 44-53, 10.1016/j.toxlet.2005.11.015.

Swales, K. and Negishi, M. (2004), CAR, driving into the future. Mol Endocrinol 18, 1589-98, 10.1210/me.2003-0397.

Tamura, K., Inoue, K., Takahashi, M., Matsuo, S., Irie, K., Kodama, Y., Ozawa, S., Nishikawa, A. and Yoshida, M. (2013), Dose-response involvement of constitutive androstane receptor in mouse liver hypertrophy induced by triazole fungicides. Toxicol Lett 221, 47-56, 10.1016/j.toxlet.2013.05.011.

Tojima, H., Kakizaki, S., Yamazaki, Y., Takizawa, D., Horiguchi, N., Sato, K. and Mori, M. (2012), Ligand dependent hepatic gene expression profiles of nuclear receptors CAR and PXR. Toxicol Lett 212, 288-97, 10.1016/j.toxlet.2012.06.001.

Wei, P., Zhang, J., Egan-Hafley, M., Liang, S. and Moore, D. D. (2000), The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature 407, 920-3, 10.1038/35038112.

Yamada, T., Uwagawa, S., Okuno, Y., Cohen, S. M. and Kaneko, H. (2009), Case study: an evaluation of the human relevance of the synthetic pyrethroid metofluthrin-induced liver tumors in rats based on mode of action. Toxicol Sci 108, 59-68, 10.1093/toxsci/kfp007.

Yamamoto, Y., Moore, R., Goldsworthy, T. L., Negishi, M. and Maronpot, R. R. (2004), The orphan nuclear receptor constitutive active/androstane receptor is essential for liver tumor promotion by phenobarbital in mice. Cancer Res 64, 7197-200, 10.1158/0008-5472.can-04-1459.