Phenobarbital induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane X receptors

Toxicological Sciences

Volumn 139, Issue 2, 2014, Pages 501-511

  Luisier, Raphaëlle ^a   Lempiäinen, Harri ^a   Scherbichler, Nina ^a   Braeuning, Albert ^b   Geissler, Miriam ^b   Dubost, Valerie ^a   Müller, Arne ^a   Scheer, Nico ^c   Chibout, Salah Dine ^a   Hara, Hisanori ^a   Picard, Frank ^a   Theil, Diethilde ^a   Couttet, Philippe ^a   Vitobello, Antonio ^a   Grenet, Olivier ^a   Grasl Kraupp, Bettina ^d   Ellinger Ziegelbauer, Heidrun ^e   Thomson, John P ^f   Meehan, Richard R ^f   Elcombe, Clifford R ^g   Henderson, Colin J ^h   Wolf, C Roland ^h   Schwarz, Michael ^b   Moulin, Pierre ^a   Terranova, Rémi ^a   Moggs, Jonathan G ^a   more..

^a NOVARTIS PHARMA AG   (Switzerland)

^b UNIVERSITY OF TÜBINGEN   (Germany)

^c TaconicArtemis   (Germany)

^d MEDICAL UNIVERSITY OF VIENNA   (Austria)

^e BAYER PHARMA AG   (Germany)

^f UNIVERSITY OF EDINBURGH   (United Kingdom)

^g CXR Biosciences Ltd   (United Kingdom)

^h UNIVERSITY OF DUNDEE   (United Kingdom)

Author keywords

Cancer risk assessment; CAR; Humanized mice; Liver; Nongenotoxic carcinogenesis; Phenobarbital; Proliferation; PXR; Transcription

Indexed keywords

BIOLOGICAL MARKER; CELL CYCLE PROTEIN 20; CONSTITUTIVE ANDROSTANE RECEPTOR; CYCLIN DEPENDENT KINASE 1; DLK1 DIO3 PROTEIN; ESCO2 PROTEIN; HELLS PROTEIN; KI 67 ANTIGEN; MESSENGER RNA; MICRORNA; MINICHROMOSOME MAINTENANCE PROTEIN 6; PHENOBARBITAL; PREGNANE X RECEPTOR; REAL TIME POLYMERASE CHAIN REACTIO\N; UNCLASSIFIED DRUG; UNTRANSLATED RNA; WISP1 PROTEIN; CELL RECEPTOR; STEROID RECEPTOR; TRANSCRIPTOME; XENOBIOTIC AGENT;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CARCINOGENESIS; CELL CYCLE; CONTROLLED STUDY; DNA REPLICATION; IMMUNOHISTOCHEMISTRY; LIVER; LIVER CELL; MALE; MOUSE; NONHUMAN; PROTEIN LOCALIZATION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RNA ISOLATION; UPREGULATION; WILD TYPE; XENOBIOTIC METABOLISM; ANIMAL; C57BL MOUSE; CELL PROLIFERATION; DRUG EFFECTS; ENZYMOLOGY; GENE EXPRESSION PROFILING; GENETICS; HUMAN; KNOCKOUT MOUSE; METABOLISM; PATHOLOGY; SPECIES DIFFERENCE; TOXICITY;

ANIMALS; CELL CYCLE; CELL PROLIFERATION; GENE EXPRESSION PROFILING; HUMANS; LIVER; MALE; MICE, INBRED C57BL; MICE, KNOCKOUT; PHENOBARBITAL; RECEPTORS, CYTOPLASMIC AND NUCLEAR; RECEPTORS, STEROID; SPECIES SPECIFICITY; TRANSCRIPTOME; XENOBIOTICS;

EID: 84899944047     PISSN: 10966080     EISSN: 10960929     Source Type: Journal    
DOI: 10.1093/toxsci/kfu038     Document Type: Article

References (53)

1. Auerbach, S. S., Stoner, M. A., Su, S., and Omiecinski, C. J. (2005). Retinoid X receptor-alpha-dependent transactivation by a naturally occurring structural variant of human constitutive androstane receptor (NR1I3). Mol. Pharmacol. 68, 1239-1253.
2. Aydinlik, H., Nguyen, T. D., Moennikes, O., Buchmann, A., and Schwarz, M. (2001). Selective pressure during tumor promotion by phenobarbital leads to clonal outgrowth of beta-catenin-mutated mouse liver tumors. Oncogene 20, 7812-7816.
3. Becker, F. F. (1982). Morphological classification of mouse liver tumors based on biological characteristics. Cancer Res.42, 3918-3923.
4. Benjamini, Y., and Hochberg, Y.(1995). Controlling the false discovery rate: A practical and powerful approach to multiple testing. J. R. Stat. Soc. B (Methodological) 57, 289-300.
5. Bohm, N., and Noltemeyer, N. (1981). Excessive reversible phenobarbital induced nuclear DNA-polyploidization in the growingmouse liver. Histochemistry 72, 63-74.
6. Bolstad, B. M., Irizarry, R. A., Astrand, M., and Speed, T. P. (2003). A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19, 185-193.
7. Bursch, W., Grasl-Kraupp, B., Wastl, U., Hufnagl, K., Chabicovsky, M., Taper, H., and Schulte-Hermann, R. (2004). Role of apoptosis for mouse liver growth regulation and tumor promotion: Comparative analysis of mice with high (C3H/He) and low (C57Bl/6J) cancer susceptibility. Toxicol. Lett. 149, 25-35.
8. 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., et al. (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.
9. Gentleman, R. C., Carey, V. J., Bates, D. M., Bolstad, B., Dettling, M., Dudoit, S., Ellis, B., Gautier, L., Ge, Y., Gentry, J., et al. (2004). Bioconductor: Open software development for computational biology and bioinformatics. Genome Biol. 5, R80.
10. Gentric, G., Celton-Morizur, S., and Desdouets, C. (2012a). Polyploidy and liver proliferation. Clin. Res. Hepatol. Gastroenterol.36, 29-34.
11. Gentric, G., Desdouets, C., and Celton-Morizur, S. (2012b). Hepatocytes polyploidization and cell cycle control in liver physiopathology. Int. J. Hepatol. 2012, 282430.
12. Gonzales, A. J., Christensen, J. G., Preston, R. J., Goldsworthy, T. L., Tlsty, T. D., and Fox, T. R. (1998). Attenuation of G1 checkpoint function by the non-genotoxic carcinogen phenobarbital. Carcinogenesis 19, 1173-1183.
13. Hasmall, S. C., and Roberts, R. A. (1999). The perturbation of apoptosis and mitosis by drugs and xenobiotics. Pharmacol. Ther. 82, 63-70.
14. Holsapple, M. P., Pitot, H. C., Cohen, S. M., Boobis, A. R., Klaunig, J. E., Pastoor, T., Dellarco, V. L., and Dragan, Y. P. (2006). Mode of action in relevance of rodent liver tumors to human cancer risk. Toxicol. Sci. 89, 51-56.
15. 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, 1646-1653.
16. IARC (2001). Phenobarbital and its sodium salt. In monographs, I. (Ed.), Some thyrotropic agents, pp. 161-286.
17. Kauffmann, A., Gentleman, R., and Huber, W. (2009). arrayQualityMetrics-A bioconductor package for quality assessment of microarray data. Bioinformatics 25, 415-416.
18. Kawamoto, T., Sueyoshi, T., Zelko, I., Moore, R., Washburn, K., and Negishi, M. (1999). Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene. Mol. Cell. Biol. 19, 6318-6322.
19. Lamminpaa, A., Pukkala, E., Teppo, L., and Neuvonen, P. J. (2002). Cancer incidence among patients using antiepileptic drugs: A long-term follow-up of 28,000 patients. Eur. J. Clin. Pharmacol. 58, 137-141.
20. Lehmann, J. M., McKee, D. D., Watson, M. A., Willson, T. M., Moore, J. T., and Kliewer, S. A. (1998). The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Invest. 102, 1016-1023.
21. Lempiainen, H., Couttet, P., Bolognani, F., Muller, A., Dubost, V., Luisier, R., Espinola Adel, R., Vitry, V., Unterberger, E. B., Thomson, J. P., et al. (2013). Identification of Dlk1-Dio3 imprinted gene cluster noncoding RNAs as novel candidate biomarkers for liver tumor promotion. Toxicol. Sci. 131, 375-386.
22. Lempiainen, H., Muller, A., Brasa, S., Teo, S. S., Roloff, T. C., Morawiec, L., Zamurovic, N., Vicart, A., Funhoff, E., Couttet, P., et al. (2011). Phenobarbital mediates an epigenetic switch at the constitutive androstane receptor (CAR) target gene Cyp2b10 in the liver of B6C3F1 mice. PLoS One 6, e18216.
23. Moore, L. B., Maglich, J. M., McKee, D. D., Wisely, B., Willson, T. M., Kliewer, S. A., Lambert, M. H., and Moore, J. T. (2002). Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors. Mol. Endocrinol. 16, 977-986.
24. Moore, L. B., Parks, D. J., Jones, S. A., Bledsoe, R. K., Consler, T. G., Stimmel, J. B., Goodwin, B., Liddle, C., Blanchard, S. G., Willson, T. M., et al. (2000). Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J. Biol. Chem. 275, 15122-15127.
25. 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.
26. Nims, R.W., Sinclair, P. R., Sinclair, J. F., Dragnev, K. H., Jones, C. R.,Mellini, D. W., Thomas, P. E., and Lubet, R. A. (1993). Dose-response relationships for the induction of P450 2B by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzne (TCPOBOP) in rat and cultured rat hepatocytes. Xenobiotica 23, 1411-1426.
27. Pandit, S. K., Westendorp, B., and de Bruin, A.(2013). Physiological significance of polyploidization in mammalian cells. Trends Cell Biol. 23, 556-566
28. Pandit, S K., Westendorp, B., Nantasanti, S., van Liere, E., Tooten, P. C., Cornelissen, P. W., Toussaint, M. J., Lamers, W. H., and de Bruin, A. (2012). E2F8 is essential for polyploidization in mammalian cells. Nat. Cell Biol. 14, 1181-1191.
29. Parzefall, W., Erber, E., Sedivy, R., and Schulte-Hermann, R. (1991). Testing for induction of DNA synthesis in human hepatocyte primary cultures by rat liver tumor promoters. Cancer Res. 51, 1143-1147.
30. Pfaffl, M. W. (2001). A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45.
31. Phillips, J. M., Burgoon, L. D., and Goodman, J. I. (2009a). The constitutive active/androstane receptor facilitates unique phenobarbital-induced expression changes of genes involved in key pathways in precancerous liver and liver tumors. Toxicol. Sci. 110, 319-333.
32. Phillips, J. M., Burgoon, L. D., andGoodman, J. I. (2009b). Phenobarbital elicits unique, early changes in the expression of hepatic genes that affect critical pathways in tumor-prone B6C3F1 mice. Toxicol. Sci. 109, 193-205.
33. Phillips, J. M., and Goodman, J. I. (2009).Multiple genes exhibit phenobarbitalinduced constitutive active/androstane receptor-mediated DNA methylation changes during liver tumorigenesis and in liver tumors. Toxicol. Sci. 108, 273-289.
34. Pirttiaho, H. I., Sotaniemi, E. A., Pelkonen, R. O., and Pitkanen, U. (1982). Hepatic blood flow and drug metabolism in patients on enzyme-inducing anticonvulsants. Eur. J. Clin. Pharmacol. 22, 441-445.
35. R Core Team (2013). R: A language and environment for statistical computing. R Foundation for Statistical Computing. Vienna, Autria. Available at: http://www.R-project.org/.Accessed March 18, 2014.
36. Rignall, B., Braeuning, A., Buchmann, A., and Schwarz, M. (2011). Tumor formation in liver of conditional beta-catenin-deficient mice exposed to a diethylnitrosamine/phenobarbital tumor promotion regimen. Carcinogenesis 32, 52-57.
37. Ross, J., Plummer, S. M., Rode, A., Scheer, N., Bower, C. C., Vogel, O., Henderson, C. J., Wolf, C. R., and Elcombe, C. R. (2010). Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogens phenobarbital and chlordane in vivo. Toxicol. Sci. 116, 452-466.
38. Saito, K., Morre, R., and Negishi,M. (2013) Nuclear receptor CAR specifically activates the two-pore K+ channel Kcnk1 gene in male mouse livers, which attenuates phenobarbital-induced hepatic hyperplasia. Toxicol Sci., 132, 151-161.
39. Scheer, N., and Wolf, C. R.(2013). Genetically humanized mouse models of drug metabolizing enzymes and transporters and their applications. Xenobiotica. 44, 96-108.
40. Scheer, N., Ross, J., Kapelyukh, Y., Rode, A., and Wolf, C. R. (2010). In vivo responses of the human and murine pregnane X receptor to dexamethasone in mice. Drug Metab. Dispos. 38, 1046-1053.
41. Scheer, N., Ross, J., Rode, A., Zevnik, B., Niehaves, S., Faust, N., and Wolf, C. R. (2008). A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response. J. Clin. Invest. 118, 3228-3239.
42. Scheer, N., Snaith,M., Wolf, C. R., and Seibler, J. (2013).Generation and utility of genetically humanized mousemodels. Drug Discov. Today 18, 1200-1211.
43. Shizu, R., Benoki, S., Numakura, Y., Kodama, S., Miyata, M., Yamazoe, Y., and Yoshinari, K. (2013). Xenobiotic-induced hepatocyte proliferation associated with constitutive active/androstane receptor (CAR) or peroxisome proliferator-activated receptor alpha (PPARalpha) is enhanced by pregnane X receptor (PXR) activation in mice. PLoS One 8, e61802.
44. Soccio, R. E., Tuteja, G., Everett, L. J., Li, Z., Lazar, M. A., and Kaestner, K. H. (2011). Species-specific strategies underlying conserved functions of metabolic transcription factors. Mol. Endocrinol. 25, 694-706.
45. Stadtfeld, M., Apostolou, E., Akutsu, H., Fukuda, A., Follett, P., Natesan, S., Kono, T., Shioda, T., and Hochedlinger, K. (2010). Aberrant silencing of imprinted genes on chromosome 12qF1 inmouse induced pluripotent stem cells. Nature 465, 175-181.
46. Styles, J. A. (1993). Measurement of ploidy and cell proliferation in the rodent liver. Environ. Health Perspect. 101(Suppl. 5), 67-71.
47. Thomson, J. P., Hunter, J. M., Lempiainen, H., Muller, A., Terranova, R., Moggs, J. G., and Meehan, R. R. (2013). Dynamic changes in 5-hydroxymethylation signatures underpin early and late events in drug exposed liver. Nucleic Acids Res. 41, 5639-5654.
48. Thomson, J. P., Lempiainen, H., Hackett, J. A., Nestor, C. E., Muller, A., Bolognani, F., Oakeley, E. J., Schubeler, D., Terranova, R., Reinhardt, D., et al. (2012). Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome. Genome Biol. 13, R93.
49. Tolson, A. H., andWang, H. (2010). Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. Adv. Drug Deliv. Rev. 62, 1238-1249.
50. 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.
51. La Vecchia, C., and Negri, E.(2013). A review of epidemiological data on epilepsy, phenobarbital, and risk of liver cancer. Eur. J. Cancer Prev. 23, 1-7.
52. 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, 153-191.
53. 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, 7197-7200.