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Event: 1214

Key Event Title

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Altered gene expression specific to CAR activation, Hepatocytes

Short name
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Altered expression of hepatic CAR-dependent genes
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Biological Context

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The location/biological environment in which the event takes place.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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
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Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  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 signaling 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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
regulation of gene expression abnormal

Key Event Overview

AOPs Including This Key Event

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AOP Name Role of event in AOP Point of Contact Author Status OECD Status
CAR activation- Hepatocellular tumors KeyEvent Brendan Ferreri-Hanberry (send email) Open for citation & comment Under Review

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.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 NCBI
mouse Mus musculus NCBI
Hamster Hamster NCBI
human Homo sapiens NCBI
dog Canis lupus familiaris NCBI
Monkey Monkey NCBI

Life Stages

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Life stage Evidence
All life stages

Sex Applicability

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Term Evidence
Unspecific High

Key Event Description

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This key event describes the gene expression changes specific to activation of the constitutive androstane receptor transcription factor (CAR; NR1I3) in the hepatocytes of mammalian species that have been have been exposed to xenobiotics or endogenous activators. Changes in mRNA concentrations, protein concentrations, or protein activity may be used to measure CAR-dependent gene regulation.

CAR is maintained in a multiprotein complex in the cytoplasm in its inactive state. CAR may be activated by direct binding of a ligand (e.g. TCPOBOP) or by indirect mechanisms that do not involve ligand-CAR interactions (e.g., activation by phenobarbital). Activated CAR is released from the protein complex in the cytoplasm and is translocated to the nucleus, where it binds as a dimer with the retinoid X receptor alpha (RXRα) to regulatory DNA elements of target genes. CAR-RXR binding to specific target genes is achieved via a highly conserved DNA-binding domain on the CAR molecule, and results in the stimulation or suppression of target gene transcription (Omiecinski et al., 2011bTolson and Wang, 2010).

CAR is primarily expressed in the liver and small intestine and is activated by a variety of xenobiotics and by endobiotics such as bilirubin. CAR-dependent expression profiles identified in the livers of all mammalian species include genes involved in phase I and phase II xenobiotic metabolism and transport, glucose metabolism, and lipid metabolism (Omiecinski et al., 2011aTolson and Wang, 2010). In rats and mice, but not other mammalian species, additional CAR-responsive genes that regulate cell proliferation and apoptosis have been identified (Peffer et al., 2018b). Some xenobiotics will induce several transcription factors simultaneously, and these transcription factors may regulate the expression of some of the same genes. For instance, there is some overlap between the gene expression profiles of CAR-responsive genes and pregnane X receptor (PXR)-responsive genes. Both PXR and CAR can dimerize with RXRα and have been shown to influence the expression of common genes involved in functions such as xenobiotic metabolism, apoptosis, and cell signaling, although each transcription factor also independently controls the expression of genes specific to that nuclear receptor as well (Cui and Klaassen, 2016Tojima et al., 2012Tolson and Wang, 2010).

Hepatic CAR-dependent genes have been identified by comparing the transcriptional profiles of wild-type mice to those of CAR-null mice after xenobiotic stimulation. These include genes involved in functions such as apoptosis, lipid metabolism, xenobiotic metabolism and transport, cholesterol biosynthesis, and cell cycle regulation (Aleksunes and Klaassen, 2012Tojima et al., 2012).

The induced expression of several genes have been used as indicators of hepatic CAR activation in mice and rats, but not all of these genes are specific to CAR activation. In particular, CAR activation leads to the induction of xenobiotic-metabolizing enzymes belonging to the cytochrome P450 CYP2B and CYP3A subfamilies, namely the increased expression of Cyp2b10 and Cyp3a11 in mice, Cyp2b1/2 and Cyp3a1 in rats, and CYP2B6 and CYP3A4 in humans (Cui and Klaassen, 2016Deguchi et al., 2009Geter et al., 2014Oshida et al., 2015aPeffer et al., 2018b). Cross-talk can occur between xenobiotics, and PXR activation can also induce CYP2B and CYP3A isoforms; however, unlike prototypical CAR activators, PXR activators will generally induce expression of CYP3A isoforms to a greater extent than CYP2B isoforms. Other metabolizing and transporter genes that are upregulated by CAR activation include UGT1A1, MRP2, SLC1A6, GSTA1 and GSTA2, and sulfotransferase enzymes have been found to be activated or suppressed by CAR activation with extensive variations based upon the species and sex of the animals (Tolson and Wang, 2010). This induction may be assayed at the mRNA level or the enzyme activity level (Elcombe et al., 2014Felter et al., 2018Peffer et al., 2018b). The induction of Ki67 and Gadd45b, genes that are implicated in cell proliferation, have also been used as indicators of CAR activation in mice and rats, although the expression of these genes is not strictly CAR-dependent (Columbano et al., 2005Peffer et al., 2018aPeffer et al., 2018b). Gadd45b can play an anti-apoptotic role, and its induction coincides with entry into an active cell cycle. It has been classified as a marker of immediate early phase of hepatocyte cell proliferation (Columbano et al., 2005). Ki67 is one of several cell cycle control genes that are transcriptionally altered in response to CAR activation to ultimately result in a pro-proliferative, anti-apoptotic environment (Peffer et al., 2018b).

A gene expression biomarker signature of CAR activation has been developed based on the genomic responses of livers of wild-type and CAR-null mice after exposure to three structurally-diverse CAR activators, namely phenobarbital, TCPOBOP, or CITCO, for three days. This resulted in a gene expression signature containing 83 genes (76 upregulated, 7 downregulated) that can be used to reliably predict CAR activation  in the mouse liver using a Running Fisher’s algorithm (Oshida et al., 2015a). This signature was shown to exhibit a prediction accuracy of 97% when tested against chemicals that are known to be positive and negative for CAR activation in the mouse.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.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). Do not provide detailed protocols. More help

Changes in CAR-dependent gene expression is most directly determined by quantitating mRNA levels of the genes of interest isolated from chemical-exposed cultured hepatocytes or the livers of chemically-treated animals. Changes in mRNA levels are then statistically compared to levels detected in the appropriate controls, such as the livers of vehicle-treated animals, chemical-treated CAR-null animals, or vehicle-treated hepatocytes, to determine if there is a statistically significant change in CAR-dependent gene expression.

Recognizing that not all mRNAs are translated into protein, CAR-dependent gene expression changes may also be determined at the protein level or by quantitating changes in protein (e.g., enzyme) activity. The appropriateness of the method used to query for CAR-dependent gene expression is dependent on the design and goals of a particular experiment. For instance, high-throughput chemical screening for CAR activation may be best accomplished by evaluating the transcriptional response of query chemicals against a CAR mRNA expression signature (Oshida et al., 2015a), whereas protein level/activity determinations may be more appropriate in experiments in which a small number of proteins are of particular interest, such as experiments where the mode of action for a specific adverse effect in the liver are being investigated.

The measurement of mRNA levels of genes of interest can be accomplished using one of several well-established methods that are widely accepted by the scientific community. Methods such as quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), microarray expression profiling, and next generation sequencing methods (whole transcriptome RNA sequencing, e.g., RNA-seq) are highly specific, sensitive, and generate reproducible results. Microarrays and RNA-seq technologies in particular allow for the rapid and simultaneous quantitation of many transcripts. Advances in several of these techniques have enabled the reliable analysis of differential gene expression in a variety of sample types including cell lysates, frozen tissues, and formalin-fixed, paraffin-embedded (FFPE) tissues.  

The quantitation of proteins of interest from cell lysates can be performed using immunostaining techniques such as enzyme-linked immunosorbent assays (ELISAs) or denaturing gel electrophoresis followed by Western blot analysis. These techniques are well-established and well-accepted in the scientific community. Changes in specific protein activity may also be conducted if suitable assays are available. For instance, changes in activity level of enzymes can be determined using biochemical fluorometric assays. For CYP2B isoforms, the formation of resorufin from pentoxyresorufin (pentoxyresorufin-O-depentylation; PROD) or from benzyloxyresorufin (benzyloxyresorufin-O-debenzylation; BROD) can be assayed, although there is some contribution from other Cyps, including those in the CYP3A family (Burke et al., 1985Burke et al., 1994Gervot et al., 1999Lake, 2009reviewed by Peffer et al., 2018bSun et al., 2006). Benzyloxyquinolone metabolism (BQ = benzyloxyquinoline-O-debenzylation) and testosterone 6-β-hydroxylase activity can also be used to measure CYP3A activity (Chovan et al., 2007Renwick et al., 2001Stresser et al., 2002).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Gene expression can be modulated by nuclear receptor activation in all living systems, but the CAR nuclear receptor is only found in mammalian cells (Moore et al., 2006Omiecinski et al., 2011b), so therefore, the altered expression of CAR-responsive genes is specific to mammals. Evidence of CAR activation and altered gene expression has been studies in humans, as well as in rats, mice, hamsters, dogs and monkeys (Diwan et al., 1986Hasmall and Roberts, 1999Lake, 2018Lake, 2009Omiecinski et al., 2011bPeffer et al., 2018bReschly and Krasowski, 2006). As discussed in prior sections, the specific genes and the processes controlled by them are somewhat common following CAR activation across the mammalian species, but individual species differences are clearly observed. For example, cell proliferation and apoptosis control genes have been shown to be altered by CAR activation in mice and rats, but not in humans or hamsters (Peffer et al., 2018b).


List of the literature that was cited for this KE description. More help

Aleksunes, L. M. and Klaassen, C. D. (2012), Coordinated regulation of hepatic phase I and II drug-metabolizing genes and transporters using AhR-, CAR-, PXR-, PPARalpha-, and Nrf2-null mice. Drug Metab Dispos 40, 1366-79, 10.1124/dmd.112.045112.

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.

Chovan, J. P., Ring, S. C., Yu, E. and Baldino, J. P. (2007), Cytochrome P450 probe substrate metabolism kinetics in Sprague Dawley rats. Xenobiotica 37, 459-73, 10.1080/00498250701245250.

Chua, S. and Moore, D. (2012), Analysis of constitutive androstane receptor (CAR/Nr1i3) ligand-dependent transcriptomes in wild type, CAR/Nr1i3 null mutant and human CAR/NR1I3 knockin mouse liver., v1.0, NURSA Datasets.

Columbano, A., Ledda-Columbano, G. M., Pibiri, M., Cossu, C., Menegazzi, M., Moore, D. D., Huang, W., Tian, J. and Locker, J. (2005), Gadd45beta is induced through a CAR-dependent, TNF-independent pathway in murine liver hyperplasia. Hepatology 42, 1118-26, 10.1002/hep.20883.

Cui, J. Y. and Klaassen, C. D. (2016), RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome. Biochim Biophys Acta 1859, 1198-1217, 10.1016/j.bbagrm.2016.04.010.

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., Ward, J. M., Anderson, L. M., Hagiwara, A. and Rice, J. M. (1986), Lack of effect of phenobarbital on hepatocellular carcinogenesis initiated by N-nitrosodiethylamine or methylazoxymethanol acetate in male Syrian golden hamsters. Toxicol Appl Pharmacol 86, 298-307.

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.

Felter, S. P., Foreman, J. E., Boobis, A., Corton, J. C., Doi, A. M., Flowers, L., Goodman, J., Haber, L. T., Jacobs, A., Klaunig, J. E., Lynch, A. M., Moggs, J. and Pandiri, A. (2018), Human relevance of rodent liver tumors: Key insights from a Toxicology Forum workshop on nongenotoxic modes of action. Regul Toxicol Pharmacol 92, 1-7, 10.1016/j.yrtph.2017.11.003.

Forbes, K. P., Kouranova, E., Tinker, D., Janowski, K., Cortner, D., McCoy, A. and Cui, X. (2017), Creation and Preliminary Characterization of Pregnane X Receptor and Constitutive Androstane Receptor Knockout Rats. Drug Metab Dispos 45, 1068-1076, 10.1124/dmd.117.075788.

Gervot, L., Rochat, B., Gautier, J. C., Bohnenstengel, F., Kroemer, H., de Berardinis, V., Martin, H., Beaune, P. and de Waziers, I. (1999), Human CYP2B6: expression, inducibility and catalytic activities. Pharmacogenetics 9, 295-306.

Geter, D. R., Bhat, V. S., Gollapudi, B. B., Sura, R. and Hester, S. D. (2014), Dose-response modeling of early molecular and cellular key events in the CAR-mediated hepatocarcinogenesis pathway. Toxicol Sci 138, 425-45, 10.1093/toxsci/kfu014.

Hasmall, S. C. and Roberts, R. A. (1999), The perturbation of apoptosis and mitosis by drugs and xenobiotics. Pharmacol Ther 82, 63-70.

Kandel, B. A., Thomas, M., Winter, S., Damm, G., Seehofer, D., Burk, O., Schwab, M. and Zanger, U. M. (2016), Genomewide comparison of the inducible transcriptomes of nuclear receptors CAR, PXR and PPARalpha in primary human hepatocytes. Biochim Biophys Acta 1859, 1218-1227, 10.1016/j.bbagrm.2016.03.007.

Lake, B. G. (2009), Species differences in the hepatic effects of inducers of CYP2B and CYP4A subfamily forms: relationship to rodent liver tumour formation. Xenobiotica 39, 582-96, 10.1080/00498250903098184.

Lake, B. G. (2018), Human relevance of rodent liver tumour formation by constitutive androstane receptor (CAR) activators. Toxicol Res (Camb) 7, 697-717, 10.1039/c8tx00008e.

Li, D., Mackowiak, B., Brayman, T. G., Mitchell, M., Zhang, L., Huang, S. M. and Wang, H. (2015), Genome-wide analysis of human constitutive androstane receptor (CAR) transcriptome in wild-type and CAR-knockout HepaRG cells. Biochem Pharmacol 98, 190-202, 10.1016/j.bcp.2015.08.087.

Maglich, J. M., Parks, D. J., Moore, L. B., Collins, J. L., Goodwin, B., Billin, A. N., Stoltz, C. A., Kliewer, S. A., Lambert, M. H., Willson, T. M. and Moore, J. T. (2003), Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes. J Biol Chem 278, 17277-83, 10.1074/jbc.M300138200.

Marmugi, A., Lukowicz, C., Lasserre, F., Montagner, A., Polizzi, A., Ducheix, S., Goron, A., Gamet-Payrastre, L., Gerbal-Chaloin, S., Pascussi, J. M., Moldes, M., Pineau, T., Guillou, H. and Mselli-Lakhal, L. (2016), Activation of the Constitutive Androstane Receptor induces hepatic lipogenesis and regulates Pnpla3 gene expression in a LXR-independent way. Toxicol Appl Pharmacol 303, 90-100, 10.1016/j.taap.2016.05.006.

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.

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.

Renwick, A. B., Lavignette, G., Worboy, P. D., Williams, B., Surry, D., Lewis, D. F., Price, R. J., Lake, B. G. and Evans, D. C. (2001), Evaluation of 7-benzyloxy-4-trifluoromethylcoumarin, some other 7-hydroxy-4-trifluoromethylcoumarin derivatives and 7-benzyloxyquinoline as fluorescent substrates for rat hepatic cytochrome P450 enzymes. Xenobiotica 31, 861-78, 10.1080/00498250110074063.

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.

Stresser, D. M., Turner, S. D., Blanchard, A. P., Miller, V. P. and Crespi, C. L. (2002), Cytochrome P450 fluorometric substrates: identification of isoform-selective probes for rat CYP2D2 and human CYP3A4. Drug Metab Dispos 30, 845-52.

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.

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.

Tolson, A. H. and Wang, H. (2010), Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. Adv Drug Deliv Rev 62, 1238-49, 10.1016/j.addr.2010.08.006.

Ueda, A., Hamadeh, H. K., Webb, H. K., Yamamoto, Y., Sueyoshi, T., Afshari, C. A., Lehmann, J. M. and Negishi, M. (2002), Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol Pharmacol 61, 1-6.

Whysner, J., Ross, P. M. and Williams, G. M. (1996), Phenobarbital mechanistic data and risk assessment: enzyme induction, enhanced cell proliferation, and tumor promotion. Pharmacol Ther 71, 153-91.

Yamada, T., Okuda, Y., Kushida, M., Sumida, K., Takeuchi, H., Nagahori, H., Fukuda, T., Lake, B. G., Cohen, S. M. and Kawamura, S. (2014), Human hepatocytes support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogen sodium phenobarbital in an in vivo study using a chimeric mouse with humanized liver. Toxicol Sci 142, 137-57, 10.1093/toxsci/kfu173.

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.