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

References

• Aiges HW, Daum F, Olson M, et al. (1980). The effects of phenobarbital and diphenylhydantoin on liver function and morphology. J Pediatr, 97, 22–6
   PubMedGoogle Scholar
• Andersen ME, et al. (2013). Dose-response approaches for nuclear receptor-mediated modes of action for liver carcinogenicity: results of a workshop. Crit Rev Toxicol. In press
   Google Scholar
• Bachman AN, Kamendulis LM, Goodman JI. (2006). Diethanolamine and Phenobarbital produce an altered pattern of methylation in GC-rich regions of DNA in B6C3F1 mouse hepatocytes similar to that resulting from choline deficiency. Toxicol Sci, 90, 317–25
   PubMedGoogle Scholar
• Baker TK, Bachowski S, Stevenson DE, et al. (1995). Modulation of gap junctional intercellular communication in rodent, monkey and human hepatocyte by nongenotoxic compounds. Prog Clin Biol Res, 391, 71–80
   PubMedGoogle Scholar
• Barrass N, Stewart M, Warburton S, et al. (1993). Cell proliferartion in the liver and thyroid of C57Bl/10J mice after dietary administration of chlordane. Environ Health Perspect, 101, 219–23
   PubMedGoogle Scholar
• Becker FF. (1982). Morphological classification of mouse liver tumors based on biological characteristics. Cancer Res, 42, 3918–23
   PubMed Web of Science ®Google Scholar
• Boobis AR, Cohen SM, Dellarco V, et al. (2006). IPCS framework for analyzing the relevance of a cancer mode of action for humans. Crit Rev Toxicol, 36, 781–92
   PubMed Web of Science ®Google Scholar
• Boobis AR, Cohen SM, Doerrer NG, et al. (2009). A data-based assessment of alternative strategies for identification of potential human cancer hazards. Toxicol Pathol, 37, 714–32
   PubMed Web of Science ®Google Scholar
• Bullock P, Pearce R, Draper A, et al. (1995). Induction of liver microsomal cytochrome P450 in Cynomolgus monkeys. Drug Metab Dispos, 23, 736–48
   PubMed Web of Science ®Google Scholar
• Bursch W, Chabicovsky M, Wastl U, et al. (2005a). Apoptosis in early stages of mouse hepatocarcinogenesis: failure to counterbalance cell proliferation and to account for strain differences in tumor susceptibility. Toxicol Sci, 85, 515–29
   PubMed Web of Science ®Google Scholar
• Bursch W, Wastl U, Hufnagl K, Schulte-Hermann R. (2005b). No increase in apoptosis in regressing mouse liver after withdrawal of growth stimuli or food restriction. Toxicol Sci, 85, 507–14
   PubMed Web of Science ®Google Scholar
• Butler WH. (1978). Long-term effects of phenobarbitone-Na on male Fischer rats. Brit J Cancer, 37, 418–23
   PubMedGoogle Scholar
• Carthew P, Edwards RE, Nolan BM. (1998). The quantitative distinction of hyperplasia from hypertrophy in hepatomegaly in the rat liver by phenobarbital. Toxicol Sci, 44, 46–51
   PubMed Web of Science ®Google Scholar
• Cerminara C, Bagnolo V, De Leonardis F, et al. (2012). Hepatocellular adenoma associated with long-term exposure to phenobarbital: a paediatric case report. Childs Nerv Syst, 28, 939–41
   PubMedGoogle Scholar
• Chiang JY, Steggles AW. (1983). Identification and partial purification of hamster microsomal cytochrome P-450 isoenzymes. Biochem Pharmacol, 32, 1389–97
   PubMed Web of Science ®Google Scholar
• Chipman JK, Mally A, Edwards GO. (2003). Disruption of gap junctions in toxicity and carcinogenicity. Toxicol Sci, 71, 146–53
   PubMed Web of Science ®Google Scholar
• Christensen JG, Gonzales AJ, Cattley RC, Goldsworthy TL. (1998). Regulation of apoptosis in mouse hepatocytes and alteration of apoptosis by nongenotoxic carcinogens. Cell Growth Differ, 9, 815–25
   PubMedGoogle Scholar
• Cohen SM, Meek ME, Klaunig JE, et al. (2003). The human relevance of information on carcinogenic modes of action: overview. Crit Rev Toxicol, 33, 581–9
   PubMed Web of Science ®Google Scholar
• Crampton RF, Gray TJB, Grasso P, Parke DV. (1977). Long-term studies on chemically induced liver enlargement in the rat. I. Sustained induction of microsomal enzymes with absence of liver damage on feeding phenobarbitone or butylated hydroxytoluene. Toxicology, 7, 289–306
   PubMedGoogle Scholar
• Dickins M. (2004). Induction of cytochromes P450. Curr Topics Med Chem, 4, 1745–66
   PubMed Web of Science ®Google Scholar
• Di Mizio G, Gambardella A, Labate A, et al. (2007). Hepatonecrosis and cholangitis related to long-term phenobarbital therapy: an autopsy report of two patients. Seizure, 16, 653–6
   PubMed Web of Science ®Google Scholar
• Diwan BA, Ward JM, Anderson LM, et al. (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
   PubMed Web of Science ®Google Scholar
• Dostalek M, Brooks JD, Hardy KD, et al. (2007). In vivo oxidative damage in rats is associated with barbiturate response but not other cytochrome P450 inducers. Mol Pharmacol, 72, 1419–24
   PubMed Web of Science ®Google Scholar
• Evans JG, Collins MA, Lake BG, Butler WH. (1992). The histology and development of hepatic nodules and carcinoma in C3H/He and C57BL/6 mice following chronic phenobarbitone administration. Toxicol Pathol, 20, 585–94
   PubMedGoogle Scholar
• Evans JG, Collins MA, Savage SA, et al. (1986). The histology and development of hepatic nodules in C3H/He mice following chronic administration of phenobarbitone. Carcinogenesis, 7, 627–31
   PubMedGoogle Scholar
• Foster JR. (2000). Cell death and cell proliferation in the control of normal and neoplastic tissue growth. Toxicol Pathol, 28, 441–6
   PubMed Web of Science ®Google Scholar
• Foster GR, Goldin RD, Freeth CJ, et al. (1991). Liver damage in long-term anticonvulsant therapy: a serological and histological study. Quart J Med, 79, 315–22
   PubMedGoogle Scholar
• Friedman GD, Jiang S-F, Udaltsova N, et al. (2009). Epidemiological evaluation of pharmaceuticals with limited evidence of carcinogenicity. Int J Cancer, 125, 2173–8
   PubMed Web of Science ®Google Scholar
• Gold LS, Manley NB, Slone TH, Ward JM. (2001). Compendium of chemical carcinogens by target organ: results of chronic bioassays in rats, mice, hamsters, dogs, and monkeys. Toxicol Pathol, 29, 639–52
   PubMed Web of Science ®Google Scholar
• Goldsworthy TL, Fransson-Steen R. (2002). Quantitation of the cancer process in C57BL/6J, B6C3F1 and C3H/HeJ mice. Toxicol Pathol, 20, 97–105
   Google Scholar
• Gollapudi B, Kan H, Wood A, et al. (2011). Dose response characterization of dietary phenobarbital-induced gene expression, enzyme induction, and cell proliferation in the livers of male and female mice. Toxicol Sci, 120, 565–6
   Google Scholar
• Goodman JI, Watson RE. (2002). Altered DNA methylation: a secondary mechanism involved in carcinogenesis. Annu Rev Pharmacol Toxicol, 42, 501–25
   PubMed Web of Science ®Google Scholar
• Grasso P, Hinton RH. (1991). Evidence for and possible mechanisms of non-genotoxic carcinogenesis in rodent liver. Mutat Res, 248, 271–90
   PubMed Web of Science ®Google Scholar
• Hagiwara A, Miyata E, Tamano S, et al. (1999). Non-carcinogenicity, but dose-related increase in preneoplastic hepatocellular lesions, in a two-year feeding study of phenobarbital sodium in male F344 rats. Food Chem Toxicol, 37, 869–79
   PubMedGoogle Scholar
• Hamadeh HK, Bushel PR, Jayadev S, et al. (2002). Gene expression analysis reveals chemical-specific profiles. Toxicol Sci, 67, 219–31
   PubMed Web of Science ®Google Scholar
• Hasmall SC, Roberts RA. (1999). The perturbation of apoptosis and mitosis by drugs and xenobiotics. Pharmacol Ther, 82, 63–70
   PubMed Web of Science ®Google Scholar
• Hill A.B. (1965). The environment and disease: association or causation? President’s Address. Proc Royal Soc Med, 9, 295–300
   Google Scholar
• Hirose Y, Nagahori N, Yamada T, et al. (2009). Comparison of the effects of the synthetic pyrethroid Metofluthrin and phenobarbital on CYP2B form induction and replicative DNA synthesis in cultured rat and human hepatocytes. Toxicology, 258, 64–9
   PubMed Web of Science ®Google Scholar
• Holsapple MP, Pitot HC, Cohen SH, et al. (2006). Mode of action in relevance of rodent liver tumors to human cancer risk. Toxicol Sci, 89, 51–6
   PubMed Web of Science ®Google Scholar
• Hosseinpour F, Moore R, Negishi M, Sueyoshi T. (2006). Serine 202 regulates the nuclear translocation of constitutive active/androstane receptor. Mol Pharmacol, 69, 1095–102
   PubMed Web of Science ®Google Scholar
• Huang W, Zhang J, Wahington M, et al. (2005). Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol Endocrinol, 19, 1646–53
   PubMed Web of Science ®Google Scholar
• Huff J, Cirvello J, Haseman J, Bucher J. (1991). Chemicals associated with site-specific neoplasia in 1394 long-term carcinogenesis experiments in laboratory rodents. Environ Health Perspect, 93, 247–70
   PubMed Web of Science ®Google Scholar
• IARC (International Agency for Research on Cancer). (2001). IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 79. Lyon: Some Thyrotropic Agents, IARC Press
   Google Scholar
• Imaoka S, Osada M, Minamiyama Y, et al. (2004). Role of phenobarbital-inducible cytochrome P450s as a source of active oxygen species in DNA-oxidation. Cancer Lett, 203, 117–25
   PubMed Web of Science ®Google Scholar
• Isenberg JS, Kamendulis LM, Ackley DC, et al. (2001). Reversibility and persistence of di-2-ethylhexyl phthalate (DEHP)- and phenobarbital-induced hepatocellular changes in rodents. Toxicol Sci, 64, 192–9
   PubMed Web of Science ®Google Scholar
• James NH, Roberts RA. (1996). Species differences in response to peroxisome proliferators correlate in vitro with induction of DNA synthesis rather than suppression of apoptosis. Carcinogenesis, 17, 1623–32
   PubMed Web of Science ®Google Scholar
• Jones CR, Lubet RA. (1992). Induction of a pleiotropic response by phenobarbital and related compounds. Response of various inbred strains of rats, response in various species and the induction of aldehyde dehydrogenase in Copenhagen rats. Biochem Pharmacol, 44, 1651–60
   PubMedGoogle Scholar
• Jones HB, Orton TC, Lake BG. (2009). Effect of chronic phenobarbitone administration on liver tumour formation in the C57BL/10J mouse. Food Chem Toxicol, 47, 1333–40
   PubMed Web of Science ®Google Scholar
• Kasper P. (2001). Cyproterone acetate: a genotoxic carcinogen? Pharmacol Toxicol, 88, 223–31
   PubMedGoogle Scholar
• Kitano M, Ichihara T, Matsuda T, et al. (1998). Presence of a threshold for promoting effects of phenobarbital on diethylnitrosamine-induced hepatic foci in the rat. Carcinogenesis, 19, 1475–80
   PubMed Web of Science ®Google Scholar
• Klaunig JE, Babich MA, Baetcke KP, et al. (2003). PPAR-alpha agonist-induced rodent tumors: modes of action and human relevance. Crit Rev Toxicol, 33, 655–780
   PubMed Web of Science ®Google Scholar
• Klaunig JE, Kamendulis LM, Hocevar BA. (2010). Oxidative stress and oxidative damage in carcinogenesis. Toxicol Pathol, 38, 96–109
   PubMed Web of Science ®Google Scholar
• Klaunig JE, Ruch RJ. (1987). Strain and species effects on the inhibition of hepatocyte intercellular communication by liver tumor promoters. Cancer Lett, 36, 161–8
   PubMed Web of Science ®Google Scholar
• Klaunig JE, Ruch RJ, Weghorst CM. (1990). Comparative effects of phenobarbital, DDT, and lindane on mouse hepatocyte gap junctional intercellular communication. Toxicol Appl Pharmacol, 102, 553–63
   PubMed Web of Science ®Google Scholar
• Kolaja KL, Stevenson DE, Johnson JT, et al. (1996a). Subchronic effects of dieldrin and phenobarbital on hepatic DNA synthesis in mice and rats. Fundam Appl Toxicol, 29, 219–28
   PubMedGoogle Scholar
• Kolaja KL, Stevenson DE, Johnson JT, et al. (1996b). Dose dependence of phenobarbital promotion of preneoplastic hepatic lesions in F344 rats and B6C3F1 mice: effects on DNA synthesis and apoptosis. Carcinogenesis, 17, 947–54
   PubMed Web of Science ®Google Scholar
• Kolaja KL, Stevenson DE, Walborg EF Jr, Klaunig JE. (1996c). Reversibility of promoter induced hepatic focal lesion growth in mice. Carcinogenesis, 17, 1403–9
   PubMedGoogle Scholar
• Kostka G, Urbanek K, Ludwicki JK. (2007). The effect of phenobarbital on the methylation level of the p16 promoter region in rat liver. Toxicology, 239, 127–35
   PubMedGoogle Scholar
• Lake BG. (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
   PubMed Web of Science ®Google Scholar
• Lake BG, Longland RC, Harris RA, et al. (1978). The effect of prolonged sodium phenobarbitone treatment on hepatic xenobiotic metabolism and the urinary excretion of metabolites of the D-glucuronic acid pathway in the rat. Biochem Pharmacol, 27, 2357–61
   PubMed Web of Science ®Google Scholar
• Lake BG, Renwick AB, Cunningham ME, et al. (1998). Comparison of the effects of some CYP3A and other enzyme inducers on replicative DNA synthesis and some cytochrome P450 isoforms in rat liver. Toxicology, 131, 9–20
   PubMed Web of Science ®Google Scholar
• Lamminpää A, Pukkala E, Teppo L, Neuvonen PJ. (2002). Cancer incidence among patients using antiepileptic drugs: a long-term follow-up of 28,000 patients. Eur J Clin Pharmacol, 58, 137–41
   PubMed Web of Science ®Google Scholar
• La Vecchia C, Negri E. (2013). A review of epidemiological data on epilepsy, phenobarbital, and risk of liver cancer. Eur J Cancer Prevent, in press
   Google Scholar
• Lehman-McKeeman LD, Caudill D, Vassallo JD, Fix AS. (1999). Increased spontaneous liver tumor susceptibility in cytochrome P450 2B1 (CYP2B1) transgenic mice. Toxicol Sci, 48, 253
   Google Scholar
• Ma X, Shah Y, Cheung C, et al. (2007). The pregnane X receptor gene-humanized mouse: a model for investigating drug-drug interactions mediated by cytochromes P450 3A. Drug Metab Dispos, 35, 194–200
   PubMed Web of Science ®Google Scholar
• Maglich JM, Stoltz CM, Goodwin BM, et al. (2002). Nuclear pregnane X receptor and consititutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic metabolism. Mol Pharmacol, 62, 638–46
   PubMed Web of Science ®Google Scholar
• Martignoni M, Groothuis GMM, de Kanter R. (2006). Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol, 2, 875–94
   PubMed Web of Science ®Google Scholar
• Meek ME, Bucher JR, Cohen SM, et al. (2003). A framework for human relevance analysis of information on carcinogenic modes of action. Crit Rev Toxicol, 33, 591–653
   PubMed Web of Science ®Google Scholar
• Moennikes O, Buchmann A, Romualdi A, et al. (2000). Lack of phenobarbital-mediated promotion of hepatocarcinogenensis in Connexin32-null mice. Cancer Res, 60, 5087–91
   PubMed Web of Science ®Google Scholar
• Moore JT, Moore LB, Maglich JM, Kliewer SA. (2003). Functional and structural comparison of PXR and CAR. Biochim Biophys Acta, 1619, 235–8
   PubMed Web of Science ®Google Scholar
• Moore LB, Parks DJ, Jones SA, et al. (2000). Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem, 275, 15122–7
   PubMed Web of Science ®Google Scholar
• Munro A. (1993). The paradoxical lack of interspecies correlation between plasma concentrations and chemical carcinogenicity. Regul Toxicol Pharmacol, 18, 115–35
   PubMedGoogle Scholar
• Mutoh S, Osabe M, Inoue K, et al. (2009). Dephosphorylation of threonine 38 is required for nuclear translocation and activation of human xenobiotic receptor CAR (NR113). J Biol Chem, 284, 34785–92
   PubMed Web of Science ®Google Scholar
• Mutoh S, Sobhany M, Moore R, et al. (2013). Phenobarbital indirectly activates the constitutive androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling. Sci Signal, 6, ra31
   PubMed Web of Science ®Google Scholar
• Navarro VJ, Senior JR. (2006). Drug-related hepatotoxicity. New Eng J Med, 354, 731–9
   PubMed Web of Science ®Google Scholar
• Neveu MJ, Babcock KL, Hertzberg EL, et al. (1994). Colocalized alterations in connexin32 and cytochrome P450IIB1/2 by phenobarbital and related liver tumor promoters. Cancer Res, 54, 3145–52
   PubMed Web of Science ®Google Scholar
• Nims RW, Lubet RA. (1996). The CYP2B subfamily. In: Ioannides C, ed. Cytochromes P450: metabolic and toxicological aspects. Boca Raton: CRC Press, 135–60
   Google Scholar
• Olsavsky KM, Page JL, Johnson MC, et al. (2007). Gene expression profiling and differentiation assessment in primary human hepatocyte cultures, established hepatoma cell lines, and human liver tissues. Toxicol Appl Pharmacol, 222, 42–56
   PubMed Web of Science ®Google Scholar
• Olsen JH, Boice JD Jr, Jensen JPA, Fraumeni JF Jr. (1989). Cancer among epileptic patients exposed to anticonvulsant drugs. J Natl Cancer Inst, 81, 803–8
   PubMed Web of Science ®Google Scholar
• Olsen JH, Schulgen G, Boice JD Jr, et al. (1995). Antiepileptic treatment and risk for hepatobiliary cancer and malignant lymphoma. Cancer Res, 55, 294–7
   PubMed Web of Science ®Google Scholar
• Omiecinski CJ, Vanden Heuvel JP, Perdew GH, Peters JM. (2011a). Xenobiotic metabolism, disposition, and regulation by receptors: from biochemical phenomenon to predictors of major toxicities. Toxicol Sci, 120, 9–75
   Google Scholar
• Omiecinski CJ, Coslo DM, Chen T, et al. (2011b). Multi-species analyses of direct activators of the constitutive androstane receptor. Toxicol Sci, 123, 550–62
   PubMed Web of Science ®Google Scholar
• Orton TC, Doughty SE, Kalinowski AE, et al. (1996). Expression of growth factors and growth factor receptors in the liver of C57BL/10J mice following administration of phenobarbitone. Carcinogenesis, 17, 973–81
   PubMed Web of Science ®Google Scholar
• Osimitz TG, Lake BG. (2009). Mode-of-action analysis for induction of rat liver tumors by pyrethrins: relevance to human cancer risk. Crit Rev Toxicol, 39, 501–11
   PubMed Web of Science ®Google Scholar
• Parzefall W, Erber E, Sedivy R, Schulte-Hermann R. (1991). Testing for induction of DNA synthesis in human hepatocyte primary cultures by rat liver tumor promoters. Cancer Res, 51, 1143–7
   PubMed Web of Science ®Google Scholar
• Pelkonen O, Turpeinen M, Hakkola J, et al. (2008). Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol, 82, 667–715
   PubMed Web of Science ®Google Scholar
• Peraino C, Fry RJM, Staffeldt E. (1973). Enhancement of spontaneous hepatic tumorigenesis in C3H mice by dietary phenobarbital. J Natl Cancer Inst, 51, 1349–50
   PubMedGoogle Scholar
• Phillips JC, Price RJ, Cunninghame ME, et al. (1997). Effect of piperonyl butoxide on cell replication and xenobiotic metabolism in the livers of CD-1 mice and F344 rats. Fundam Appl Toxicol, 38, 64–74
   PubMedGoogle Scholar
• Phillips JM, Goodman JI. (2008). Identification of genes that may play critical roles in phenobarbital (PB)-induced liver tumorigenesis due to altered DNA methylation. Toxicol Sci, 104, 86–99
   PubMedGoogle Scholar
• Phillips JM, Yamamoto Y, Negishi M, et al. (2007). Orphan nuclear receptor constitutive active/androstane receptor-mediated alterations in DNA methylation during phenobarbital promotion of liver tumorigenesis. Toxicol Sci, 96, 72–82
   PubMed Web of Science ®Google Scholar
• Pirttiaho HI, Sotaniemi EA, Ahokas JT, Pitkänen U. (1978). Liver size and indices of drug metabolism in epileptics. Brit J Clin Pharmacol, 6, 273–8
   PubMed Web of Science ®Google Scholar
• Pirttiaho HI, Sotaniemi EA, Pelkonen RO, Pitkänen U. (1982). Hepatic blood flow and drug metabolism in patients on enzyme-inducing anticonvulsants. Eur J Clin Pharmacol, 22, 441–5
   PubMed Web of Science ®Google Scholar
• Plant NJ, Horley NJ, Dickins M, et al. (1998). The coordinate regulation of DNA synthesis and suppression of apoptosis is differentially regulated by the liver growth agents, phenobarbital and methylclofenapate. Carcinogenesis, 22, 441–5
   Google Scholar
• Ponomarkov V, Tomatis L, Turusov V. (1976). The effect of long-term administration of phenobarbitone in CF-1 mice. Cancer Lett, 1, 165–72
   Web of Science ®Google Scholar
• Ross J, Plummer SM, Scheer N, et al. (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, 452–66
   PubMed Web of Science ®Google Scholar
• Ross PK, Woods CG, Bradford BU, et al. (2009). Time-course comparison of xenobiotic activators of CAR and PPARα in mouse liver. Toxicol Appl Pharmacol, 235, 199–207
   PubMedGoogle Scholar
• Rossi L, Ravera M, Repetti G, Santi L. (1977). Long-term administration of DDT or phenobarbital-Na in Wistar rats. Int J Cancer, 19, 179–85
   PubMed Web of Science ®Google Scholar
• Ruch RJ, Klaunig JE. (1988). Kinetics of phenobarbital inhibition of intercellular communication in mouse hepatocytes. Cancer Res, 48, 2519–23
   PubMed Web of Science ®Google Scholar
• Scheer N, Ross J, Kapelyukh Y, et al. (2010). In vivo responses of the human and murine pregnane X receptor to dexamethasone in mice. Drug Metab Dispos, 38, 1046–53
   PubMed Web of Science ®Google Scholar
• Scheer N, Ross J, Rode A, et al. (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, 3228–39
   PubMed Web of Science ®Google Scholar
• Schulte-Hermann R, Timmermann-Trosiener I, Schuppler J. (1983). Promotion of spontaneous preneoplastic cells in rat liver as a possible explanation of tumor production by nonmutagenic compounds. Cancer Res, 43, 839–44
   PubMed Web of Science ®Google Scholar
• Selby JV, Friedman GD, Fireman BH. (1989). Screening prescription drugs for possible carcinogenicity: eleven to fifteen years of follow-up. Cancer Res, 49, 5736–47
   PubMed Web of Science ®Google Scholar
• Sonich-Mullin C, Fielder R, Wiltse J, et al. (2001). IPCS conceptual framework for evaluating a mode of action for chemical carcinogenesis. Regul Toxicol Pharmacol, 34, 146–52
   PubMed Web of Science ®Google Scholar
• Stanley L, Horsburgh B, Ross J, et al. (2006). PXR and CAR: nuclear receptors which play a pivotal role in drug disposition and chemical toxicity. Drug Metabolism Reviews, 38, 515–97
   PubMed Web of Science ®Google Scholar
• Staudinger J, Lui Y, Madan A, et al. (2001). Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor. Drug Metab Dispos, 29, 1467–72
   PubMed Web of Science ®Google Scholar
• Staudinger JL, Madan A, Carol KM, Parkinson A. (2003). Regulation of drug transporter gene expression by nuclear receptors. Drug Metab Dispos, 31, 523–7
   PubMed Web of Science ®Google Scholar
• Stenbäck F, Mori H, Furuya K, Williams GM. (1986). Pathogenesis of dimethylnitrosamine-induced hepatocellular cancer in hamster liver and lack of enhancement by phenobarbital. J Natl Cancer Inst, 76, 327–33
   PubMedGoogle Scholar
• Tanaka T, Mori H, Williams GM. (1987). Enhancement of dimethylnitrosamine-initiated hepatocarcinogenesis in hamsters by subsequent administration of carbon tetrachloride but not by phenobarbital or p,p′-dichlorodiphenyltrichoroethane. Carcinogenesis, 8, 1171–8
   PubMed Web of Science ®Google Scholar
• Thorpe E, Walker AIT. (1973). The toxicology of dieldrin (HEOD). II. Comparative long-term oral toxicity studies in mice with dieldrin, DDT, phenobarbitone, β-BHC and γ-BHC. Food Chem Toxicol, 11, 433–42
   Google Scholar
• Tien ES, Negishi M. (2006). Nuclear receptors CAR and PXR in the regulation of hepatic metabolism. Xenobiotica, 36, 1152–63
   PubMed Web of Science ®Google Scholar
• Trottier E, Belzil A, Stoltz C, Anderson A. (1995). Localization of a phenobarbital-responsive element (PBRE) in the 5′-flanking region of the rat CYP2B2 gene. Gene, 158, 263–2688
   PubMed Web of Science ®Google Scholar
• Tucker MJ, Kalinowski AE, Orton TC. (1996). Carcinogenicity of cyproterone acetate in the mouse. Carcinogenesis, 17, 1473–6
   PubMedGoogle Scholar
• Ueda A, Hamadeh HK, Webb HK, et al. (2002). Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol Pharmacol, 61, 1–6
   PubMed Web of Science ®Google Scholar
• U.S. EPA (United States Environmental Protection Agency). (2005). Guidelines for carcinogen risk assessment and supplemental guidance for assessing susceptibility from early-life exposure to carcinogens. Fed Reg, 70, 17765–817
   Google Scholar
• Ward JM. (1983). Increased susceptibility of livers of aged F344/NCr rats to the effects of phenobarbital on the incidence, morphology, and histochemistry of hepatocellular foci and neoplasms. J Natl Cancer Inst, 71, 815–23
   PubMed Web of Science ®Google Scholar
• Ward JM, Lynch P, Riggs C. (1988). Rapid development of hepatocellular neoplasms in aging male C3H/HeNCr mice given phenobarbital. Cancer Lett, 39, 9–18
   PubMed Web of Science ®Google Scholar
• Waterman CL, Currie RA, Cottrell LA, et al. (2010). An integrated functional genomic study of acute phenobarbital exposure in the rat. BMC Genomics, 11, 1–17
   PubMedGoogle Scholar
• Weaver RJ, Thompson S, Smith G, et al. (1994). A comparative study of constitutive and induced alkoxyresorufin O-dealkylation and individual cytochrome P450 forms in Cynomolgus monkey (Macaca fascicularis), human, mouse, rat and hamster liver microsomes. Biochem Pharmacol, 47, 763–73
   PubMed Web of Science ®Google Scholar
• Wei P, Zhang J, Egan-Hafley M, et al. (2000). The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature, 407, 920–3
   PubMed Web of Science ®Google Scholar
• White SJ, McLean AEM, Howland C. (1979). Anticonvulsant drugs and cancer. A cohort study in patients with severe epilepsy. Lancet, ii: 458–61
   Google Scholar
• Whysner J, Montandon F, McClain RM, et al. (1998). Absence of DNA adduct formation by phenobarbitol, polychlorinated biphenols, and chlordane in mouse liver using the 32P-postlabelling assay. Toxicol Appl Pharmacol, 148, 14–23
   PubMed Web of Science ®Google Scholar
• Whysner J, Ross PM, Williams GM. (1996). Phenobarbital mechanistic data and risk assessment: enzyme induction, enhanced cell proliferation, and tumor promotion. Pharmacol Ther, 71, 153–91
   PubMed Web of Science ®Google Scholar
• Williams GM. (1997a). Chemicals with carcinogenic activity in the rodent liver; mechanistic evaluation of human risk. Cancer Lett, 117, 175–88
   PubMed Web of Science ®Google Scholar
• Williams GM. (1997b). Carcinogenic responses to toxic liver injury in rodents. In: Comprehensive Toxicology, Volume 9, Hepatic and Gastrointestinal Toxicology. McCuskey RS, Earnest DL, eds. Oxford: Pergamon Press, 165–79
   Google Scholar
• Wolf DC, Mann PC. (2005). Confounders in interpreting pathology for safety and risk assessment. Toxicol Appl Pharmacol, 202, 302–8
   PubMed Web of Science ®Google Scholar
• Xie W, Barwick JL, Simon CM, et al. (2000). Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature, 406, 435–9
   PubMed Web of Science ®Google Scholar
• Yamada T, Uwagawa S, Okuno Y, et al. (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
   PubMed Web of Science ®Google Scholar
• Yamamoto Y, Moore R, Goldsworthy TL, et al. (2004). The orphan nuclear receptor constitutive active/androstane receptor is essential for liver tumor promotion by phenobarbital in mice. Cancer Res, 64, 7197–200
   PubMed Web of Science ®Google Scholar
• Yoshinari K, Tien E, Negishi M, Honkakoski P. (2008). Receptor-mediated regulation of cytochromes P450. In: Ioannides C, ed. Cytochromes P450: role in the metabolism and toxicity of drugs and other xenobiotics. Cambridge: RSC Publishing, 417–48
   Google Scholar