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

Critical Reviews in Toxicology

Volumn 44, Issue 1, 2014, Pages 64-82

  Elcombe, Clifford R ^a   Peffer, Richard C ^b   Wolf, Douglas C ^c   Bailey, Jason ^d   Bars, Remi ^e   Bell, David ^f   Cattley, Russell C ^g   Ferguson, Stephen S ^h   Geter, David ⁱ   Goetz, Amber ^b   Goodman, Jay I ^j   Hester, Susan ^c   Jacobs, Abigail ^k   Omiecinski, Curtis J ^l   Schoeny, Rita ^c   Xie, Wen ^m   Lake, Brian G ⁿ  

^a CXR Biosciences Ltd   (United Kingdom)

^b SYNGENTA CROP PROTECTION   (United States)

^c U S ENVIRONMENTAL PROTECTION AGENCY   (United States)

^d DOW AGROSCIENCES LLC   (United States)

^e BAYER CROPSCIENCE   (United States)

^f EUROPEAN CHEMICALS AGENCY   (Finland)

^g AUBURN UNIVERSITY   (United States)

^h CellzDirect Life Technologies   (United States)

ⁱ DOW CHEMICAL COMPANY   (United States)

^j MICHIGAN STATE UNIVERSITY   (United States)

^k CENTER FOR DRUG EVALUATION AND RESEARCH   (United States)

^l PENNSYLVANIA STATE UNIVERSITY   (United States)

^m UNIVERSITY OF PITTSBURGH   (United States)

ⁿ UNIVERSITY OF SURREY   (United Kingdom)

more..

Author keywords

Constitutive androstane receptor; Dose response assessment; Human relevance framework; Key and associative events; Liver cancer; Mode of action; Modulating factors; Phenobarbital; Pregnane X receptor

Indexed keywords

CELL NUCLEUS RECEPTOR; PHENOBARBITAL;

ANIMAL CELL CULTURE; APOPTOSIS; CANCER RISK; CARCINOGENICITY; CASE STUDY; CELL COMMUNICATION; CELL PROLIFERATION; DISEASE ASSOCIATION; ENZYME ACTIVATION; EPIGENETICS; GAP JUNCTION; GENE EXPRESSION; HUMAN; LIVER ADENOMA; LIVER CARCINOGENESIS; LIVER CELL; LIVER CELL CARCINOMA; LIVER HYPERTROPHY; LIVER TOXICITY; LIVER TUMOR; NONHUMAN; OXIDATIVE STRESS; REVIEW; RODENT MODEL; SPECIES DIFFERENCE;

ANIMALS; ARYL HYDROCARBON HYDROXYLASES; CELL PROLIFERATION; HEPATOCYTES; HUMANS; LIVER; LIVER NEOPLASMS; PHENOBARBITAL; RECEPTORS, CYTOPLASMIC AND NUCLEAR; RECEPTORS, STEROID; XENOBIOTICS;

EID: 84891503154     PISSN: 10408444     EISSN: 15476898     Source Type: Journal    
DOI: 10.3109/10408444.2013.835786     Document Type: Review

References (129)

1. 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.
2. 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.
3. Bachman AN, Kamendulis LM, Goodman JI. (2006). Diethanolamine and Phenobarbital produce an altered pattern of methylation in GCrich regions of DNA in B6C3F1 mouse hepatocytes similar to that resulting from choline deficiency. Toxicol Sci, 90, 317-25.
4. 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.
5. 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.
6. Becker FF. (1982). Morphological classification of mouse liver tumors based on biological characteristics. Cancer Res, 42, 3918-23.
7. 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.
8. 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.
9. Bullock P, Pearce R, Draper A, et al. (1995). Induction of liver microsomal cytochrome P450 in Cynomolgus monkeys. Drug Metab Dispos, 23, 736-48.
10. 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.
11. 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.
12. Butler WH. (1978). Long-term effects of phenobarbitone-Na on male Fischer rats. Brit J Cancer, 37, 418-23.
13. 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.
14. 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.
15. Chiang JY, Steggles AW. (1983). Identification and partial purification of hamster microsomal cytochrome P-450 isoenzymes. Biochem Pharmacol, 32, 1389-97.
16. Chipman JK, Mally A, Edwards GO. (2003). Disruption of gap junctions in toxicity and carcinogenicity. Toxicol Sci, 71, 146-53.
17. 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.
18. 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.
19. 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.
20. Dickins M. (2004). Induction of cytochromes P450. Curr Topics Med Chem, 4, 1745-66.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. Foster JR. (2000). Cell death and cell proliferation in the control of normal and neoplastic tissue growth. Toxicol Pathol, 28, 441-6.
27. Foster GR, Goldin RD, Freeth CJ, et al. (1991). Liver damage in longterm anticonvulsant therapy: a serological and histological study. Quart J Med, 79, 315-22.
28. 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.
29. 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.
30. Goldsworthy TL, Fransson-Steen R. (2002). Quantitation of the cancer process in C57BL/6J, B6C3F1 and C3H/HeJ mice. Toxicol Pathol, 20, 97-105.
31. 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.
32. Goodman JI, Watson RE. (2002). Altered DNA methylation: a secondary mechanism involved in carcinogenesis. Annu Rev Pharmacol Toxicol, 42, 501-25.
33. Grasso P, Hinton RH. (1991). Evidence for and possible mechanisms of non-genotoxic carcinogenesis in rodent liver. Mutat Res, 248, 271-90.
34. Hagiwara A, Miyata E, Tamano S, et al. (1999). Non-carcinogenicity, but dose-related increase in preneoplastic hepatocellular lesions, in a twoyear feeding study of phenobarbital sodium in male F344 rats. Food Chem Toxicol, 37, 869-79.
35. Hamadeh HK, Bushel PR, Jayadev S, et al. (2002). Gene expression analysis reveals chemical-specific profiles. Toxicol Sci, 67, 219-31.
36. Hasmall SC, Roberts RA. (1999). The perturbation of apoptosis and mitosis by drugs and xenobiotics. Pharmacol Ther, 82, 63-70.
37. Hill A.B. (1965). The environment and disease: association or causation? President's Address. Proc Royal Soc Med, 9, 295-300.
38. 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.
39. 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.
40. 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.
41. 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.
42. 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.
43. 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.
44. 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.
45. Isenberg JS, Kamendulis LM, Ackley DC, et al. (2001). Reversibility and persistence of di-2-ethylhexyl phthalate (DEHP)-and phenobarbitalinduced hepatocellular changes in rodents. Toxicol Sci, 64, 192-9.
46. 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.
47. 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.
48. 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.
49. Kasper P. (2001). Cyproterone acetate: a genotoxic carcinogen? Pharmacol Toxicol, 88, 223-31.
50. 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.
51. Klaunig JE, Babich MA, Baetcke KP, et al. (2003). PPAR-alpha agonistinduced rodent tumors: modes of action and human relevance. Crit Rev Toxicol, 33, 655-780.
52. Klaunig JE, Kamendulis LM, Hocevar BA. (2010). Oxidative stress and oxidative damage in carcinogenesis. Toxicol Pathol, 38, 96-109.
53. 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.
54. 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.
55. 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.
56. 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.
57. Kolaja KL, Stevenson DE, Walborg Jr EF, Klaunig JE. (1996c). Reversibility of promoter induced hepatic focal lesion growth in mice. Carcinogenesis, 17, 1403-9.
58. 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.
59. 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.
60. 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 Dglucuronic acid pathway in the rat. Biochem Pharmacol, 27, 2357-61.
61. 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.
62. 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.
63. 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.
64. 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.
65. Ma X, Shah Y, Cheung C, et al. (2007). The pregnane X receptor genehumanized mouse: a model for investigating drug-drug interactions mediated by cytochromes P450 3A. Drug Metab Dispos, 35, 194-200.
66. 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.
67. 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.
68. 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.
69. 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.
70. Moore JT, Moore LB, Maglich JM, Kliewer SA. (2003). Functional and structural comparison of PXR and CAR. Biochim Biophys Acta, 1619, 235-8.
71. 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.
72. Munro A. (1993). The paradoxical lack of interspecies correlation between plasma concentrations and chemical carcinogenicity. Regul Toxicol Pharmacol, 18, 115-35.
73. 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.
74. 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.
75. Navarro VJ, Senior JR. (2006). Drug-related hepatotoxicity. New Eng J Med, 354, 731-9.
76. 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.
77. Nims RW, Lubet RA. (1996). The CYP2B subfamily. In: Ioannides C, ed. Cytochromes P450: metabolic and toxicological aspects. Boca Raton: CRC Press, 135-60.
78. 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.
79. Olsen JH, Boice Jr JD, Jensen JPA, Fraumeni Jr JF. (1989). Cancer among epileptic patients exposed to anticonvulsant drugs. J Natl Cancer Inst, 81, 803-8.
80. Olsen JH, Schulgen G, Boice Jr JD, et al. (1995). Antiepileptic treatment and risk for hepatobiliary cancer and malignant lymphoma. Cancer Res, 55, 294-7.
81. 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.
82. 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.
83. 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.
84. 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.
85. 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.
86. Pelkonen O, Turpeinen M, Hakkola J, et al. (2008). Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol, 82, 667-715.
87. 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.
88. 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.
89. 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.
90. 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.
91. 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.
92. 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.
93. 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.
94. Ponomarkov V, Tomatis L, Turusov V. (1976). The effect of long-term administration of phenobarbitone in CF-1 mice. Cancer Lett, 1, 165-72.
95. 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.
96. Ross PK, Woods CG, Bradford BU, et al. (2009). Time-course comparison of xenobiotic activators of CAR and PPARa in mouse liver. Toxicol Appl Pharmacol, 235, 199-207.
97. 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.
98. Ruch RJ, Klaunig JE. (1988). Kinetics of phenobarbital inhibition of intercellular communication in mouse hepatocytes. Cancer Res, 48, 2519-23.
99. 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.
100. 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.
101. 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.
102. Selby JV, Friedman GD, Fireman BH. (1989). Screening prescription drugs for possible carcinogenicity: eleven to fifteen years of followup. Cancer Res, 49, 5736-47.
103. 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.
104. 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.
105. 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.
106. Staudinger JL, Madan A, Carol KM, Parkinson A. (2003). Regulation of drug transporter gene expression by nuclear receptors. Drug Metab Dispos, 31, 523-7.
107. 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.
108. 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,p0-dichlorodiphenyltrichoroethane. Carcinogenesis, 8, 1171-8.
109. Thorpe E, Walker AIT. (1973). The toxicology of dieldrin (HEOD). II. Comparative long-term oral toxicity studies in mice with dieldrin, DDT, phenobarbitone, b-BHC and g-BHC. Food Chem Toxicol, 11, 433-42.
110. Tien ES, Negishi M. (2006). Nuclear receptors CAR and PXR in the regulation of hepatic metabolism. Xenobiotica, 36, 1152-63.
111. Trottier E, Belzil A, Stoltz C, Anderson A. (1995). Localization of a phenobarbital-responsive element (PBRE) in the 50-flanking region of the rat CYP2B2 gene. Gene, 158, 263-2688.
112. Tucker MJ, Kalinowski AE, Orton TC. (1996). Carcinogenicity of cyproterone acetate in the mouse. Carcinogenesis, 17, 1473-6.
113. 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.
114. 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.
115. 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.
116. 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.
117. 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.
118. 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.
119. 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.
120. White SJ, McLean AEM, Howland C. (1979). Anticonvulsant drugs and cancer. A cohort study in patients with severe epilepsy. Lancet, ii: 458-61.
121. 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.
122. 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.
123. Williams GM. (1997a). Chemicals with carcinogenic activity in the rodent liver; mechanistic evaluation of human risk. Cancer Lett, 117, 175-88.
124. 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.
125. Wolf DC, Mann PC. (2005). Confounders in interpreting pathology for safety and risk assessment. Toxicol Appl Pharmacol, 202, 302-8.
126. Xie W, Barwick JL, Simon CM, et al. (2000). Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature, 406, 435-9.
127. 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.
128. 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.
129. 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.