Phenobarbital mechanistic data and risk assessment: Enzyme induction, enhanced cell proliferation, and tumor promotion

Pharmacology and Therapeutics

Volumn 71, Issue 1-2, 1996, Pages 153-191

  Whysner, John ^a   Ross, Peter M ^a   Williams, Gary M ^a  

^a AMERICAN HEALTH FOUNDATION   (United States)

Author keywords

cell proliferation; intercellular communication; neoplasia; phenobarbital; tumor promotion

Indexed keywords

PHENOBARBITAL;

ANIMAL EXPERIMENT; ANIMAL MODEL; APOPTOSIS; CANCER RISK; CARCINOGENICITY; CELL COMMUNICATION; CELL PROLIFERATION; ENZYME INDUCTION; GENOTOXICITY; HAMSTER; HUMAN; LIVER ADENOMA; MONKEY; MOUSE; NONHUMAN; PRIORITY JOURNAL; RAT; REVIEW; RISK ASSESSMENT; SIDE EFFECT; TUMOR PROMOTION;

EID: 0029762765     PISSN: 01637258     EISSN: None     Source Type: Journal    
DOI: 10.1016/0163-7258(96)00067-8     Document Type: Review

References (221)

1. Aaron, C. S., Bolcsfoldi, G., Glatt, H. R., Moore, M., Nishi, Y., Stankowski, L., Theiss, J. and Thompson, E. (1994) Mammalian cell gene mutation assays working group report. Environ. Mutagen. 312: 235-239.
2. Abanobi, S. E., Lombardi, B. and Shinozuka, H. (1982) Stimulation of DNA synthesis and cell proliferation in the liver of rats fed a choline-devoid diet and their suppression by phenobarbital. Cancer Res. 42: 412-415.
3. 2+-ATPase activity of the rat liver endoplasmic reticulum by the liver tumour promoters 1,1,1-trichloro-2,2-bis(p-chlorophenyl )-ethane and phenobarbital. Toxicology 71: 1-6.
4. Adesnik, M. and Atchison, M. (1986) Genes for cytochrome P-450 and their regulation. CRC Crit. Rev. Biochem. 19: 247-305.
5. Albertini, S. and Gocke, E. (1992) Phenobarbital: does the positive result in TA1535 indicate genotoxic properties? Environ. Mol. Mutagen. 19: 161-166.
6. Amacher, D. E. and Turner, G. N. (1985) Tests for gene mutational activity in the L5178Y/TK assay system. Prog. Mutat. Res. 5: 487-496.
7. Andersen, D. and Styles, J. A. (1978) The bacterial mutation test. Br. J. Cancer 37: 924-930.
8. Appel, K. E., Menden, M., Buchmann, A. and Schwarz, M. (1991) Effect of varying the concentration of phenobarbital and its duration of treatment on the evolution of carcinogen induced enzyme-altered foci in rat liver. Cancer Lett. 57: 75-82.
9. Auletta, A. E., Dearfield, K. L. and Cimino, M. C. (1993) Mutagenicity test schemes and guidelines: U.S. EPA Office of Pollution Prevention and Toxics and Office of Pesticide Programs. Environ. Mol. Mutagen. 21: 38-45.
10. Bachmann, K. A., Martin, N. M. and Jaregui, L. (1991) The use of single sample clearance estimates to probe hepatic drug metabolism: handprinting the influence of phenobarbitone on human hepatic drug metabolism. Xenobiotica 21: 1385-1392.
11. Baker, R. S. U. and Bonin, A. M. (1985) Tests with the Salmonella plate-incorporation assay. Prog. Mutat. Res. 5: 177-180.
12. Barbason, H., Rassenfosse, C. and Betz, E. H. (1983) Promotion mechanism of phenobarbital and partial hepatectomy in DENA hepatocarcinogenesis cell kinetics effect. Br. J. Cancer 47: 517-525.
13. Bauer-Hofmann, R., Buchmann, A., Mahr, J., Kress, S. and Schwarz, M. (1992) The rumour promoters dieldrin and phenobarbital increase the frequency of c-Ha-ras wild-type, but not of c-Ha-ras mutated focal liver lesions in male C3H/He mice. Carcinogenesis 13: 477-481.
14. Becker, F. F. (1982) Morphological classification of mouse liver tumors based on biological characteristics. Cancer Res. 42: 3918-3923.
15. Benet, L. Z. and Sheiner, L. B. (1985) Design and optimization of dosage regimens: pharmacokinetic data. Br. J. Clin. Pharmacol. 15:71-76.
16. Bradley, M. O. (1985) Measurement of DNA single-strand breaks by alkaline elution in rat hepatocytes. Prog. Mutat. Res. 5: 353-357.
17. Brockenbrough, J. S., Meyer, S. A., Li, C. and Jirtle, R. L. (1991) Reversible and phorbol ester-specific defect of protein kinase c translocation in hepatocytes isolated from phenobarbital-treated rats. Cancer Res. 51: 130-136.
18. Budunova, I. V. and Williams, G. M. (1994) Cell culture assays for chemicals with tumor-promoting or tumor-inhibiting activity based on the modulation of intercellular communication. Cell Biol. Toxicol. 10: 71-116.
19. Bursch, W., Lauer, B., Timmermann-Trosiener, I., Barthel, G., Schuppler, J. and Schulte-Hermann, R. (1984) Controlled death (apoptosis) of normal and putative preneoplastic cells in rat liver following withdrawal of tumor promoters. Carcinogenesis 5: 453-458.
20. Büsser, M. T. and Lutz, W. K. (1987) Stimulation of DNA synthesis in rat and mouse liver by various tumor promoters. Carcinogenesis 8: 1433-1437.
21. Butler, T. C. (1956) The metabolic hydroxylation of phenobarbital. Pharmacol. Exp. Ther. 116: 326-337.
22. Butler, W. H. (1978) Long-term effects of phenobarbitone-Na on male Fischer rats. Br. J. Cancer 37: 418-423.
23. Cattley, R. C. and Glover, S. E. (1993) Elevated 8-hydroxydeoxy-guanosine in hepatic DNA of rats following exposure to peroxisome proliferators: relationship to carcinogenesis and nuclear localization. Carcinogenesis 14: 2495-2499.
24. Chen, Z. Y. and Eaton, D. L. (1993) Association between responsiveness to phenobarbital induction of CYP2B1/2 and 3A1 in rat hepatic hyperplastic nodules and their zonal origin. Environ. Health Perspect. 101: 185-190.
25. Chen, Z. Y., Farin, F., Omiecinski, C. J. and Eaton, D. L. (1992) Association between growth stimulation by phenobarbital and expression of cytochromes P450 1A1, 1A2, 2B1/2 and 3A1 in hepatic hyperplastic nodules in male F344 rats. Carcinogenesis 13: 675-682.
26. Clemmesen, J. and Hjalgrim-Jensen, S. (1977) On the absence of carcinogenicity to man of phenobarbital. ACTA Pathol. Microbiol. Scand. 261: 38-50.
27. Clemmesen, J. and Hjalgrim-Jensen, S. (1978) Is phenobarbital carcinogenic? A follow-up of 8078 epileptics. Ecotoxicol. Environ. Safety 1: 457-470.
28. Clemmesen, J. and Hjalgrim-Jensen, S. (1981) Does phenobarbital cause intracranial tumors? A follow-up through 35 years. Ecotoxicol. Environ. Safety 5: 255-260.
29. Collins, M. A., Lake, B. G., Evans, J. G., Walker, R., Gangolli, S. D. and Conning, D. M. (1984) Sustained induction of hepatic xenobiotic metabolising enzyme activities by phenobarbitone in C3H/He mice: relevance to nodule formation. Toxicology 33: 129-144.
30. Conney, A. H. (1967) Pharmacological implications of microsomal enzyme induction. Pharmacol. Rev. 19: 317-366.
31. Crayford, J. V. and Hutson, D. H. (1980) Comparative metabolism of phenobarbitone in the rat (CFE) and mouse (CF1). Food Cosmet. Toxicol. 18: 503-509.
32. Crespi, C. L., Ryan, C. G., Seixas, G. M., Turner, T. R. and Penman, B. W. (1985) Tests for mutagenic activity using mutation assays at two loci in the human lymphoblast cell lines TK6 and AHH-1. Prog. Mutat. Res. 5: 497-516.
33. Cunninghame, M. E., Evans, J. G. and Butler, W. H. (1991) An ultrastructural study of spontaneous and phenobarbitone-induced nodules in the mouse liver. Int. J. Exp. Pathol. 72: 695-703.
34. Danford, N. (1985) Tests for chromosome aberrations and aneuploidy in the Chinese hamster fibroblast cell line CH1 -L. Prog. Mutat. Res. 5: 397-411.
35. Denda, A., Ura, H., Tsujiuchi, T., Tsutsumi, M., Eimoto, H., Takashima, Y., Kitazawa, S., Kinugasa, T. and Konishi, Y. (1989) Possible involvement of arachidonic acid metabolism in phenobarbital promotion of hepatocarcinogenesis. Carcinogenesis 10: 1929-1935.
36. 1 mice. Cancer Lett. 23: 223-234.
37. MTV-and DBA/2NCr mice. Carcinogenesis 7: 215-220.
38. Diwan, B. A., Ward, J. M., Anderson, L. M., Hagiwara, A. and Rice, J. M. (1986b) 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.
39. Diwan, B. A., Rice, J. M., Nims, R. W., Lubert, R. A., Hu, H. and Ward, J. M. (1988) P-450 enzyme induction by 5-ethyl-5-phenylhydantoin and 5,5-diethylhydantoin, analogues of barbiturate tumor promoters phenobarbital and barbital and promotion of liver and thyroid carcinogenesis initiated by N-nitrosodiethylamine in rats. Cancer Res. 48: 2492-2497.
40. Diwan, B. A., Rice, J. M. and Ward, J. M. (1990) Strain-dependent effects of phenobarbital on liver tumor promotion in inbred mice. In: Mouse Liver Carcinogenesis: Mechanisms and Species Comparisons, pp. 69-83, Stevenson, D. E. (ed.) Alan R. Liss, Inc., New York.
41. Diwan, B. A., Henneman, J. R. and Rice, J. M. (1995) Further evidence for promoter-dependent development of hepatoblastoma in the mouse. Cancer Lett. 89: 29-35.
42. Donato, M. T., Gomez-Lechon, M. J. and Castell, J. V. (1990) Effect of xenobiotics on monooxygenase activities in cultured human hepatocytes. Biochem. Pharmacol. 39: 1321-1326.
43. Doostdar, H., Grant, M. H., Melvin, W. T., Wolf, C. R. and Burke, M. D. (1993) The effects of inducing agents on cytochrome P450 and UDP-glucuronyltransferase activities in human HEFG2 hepatoma cells. Biochem. Pharmacol. 46: 629-635.
44. Douglas, G. R., Blakey, D. H., Liu-Lee, V. W., Bell, R. D. L. and Bayley, J. M. (1985) Alkaline sucrose sedimentation, sister-chromatid exchange and micronucleus assays in CHO cells. Prog. Mutat. Res. 5: 359-366.
45. Drinkwater, N. R. and Ginsler, J. J. (1986) Genetic control of hepatocarcinogenesis in C57B1/6J and C3H/HeJ inbred mice. Carcinogenesis 7: 1701-1707.
46. Driver, H. E. and McLean, A. E. M. (1986a) Dose-response relationships for initiation of rat liver tumours by diethylnitrosamine and promotion by phenobarbitone or alcohol. Food Chem.Toxicol. 24: 241-245.
47. Driver, H. E. and McLean, A. E. M. (1986b) Dose-response relationship tor phenobarbitone promotion of liver tumours initiated by single dose dimethylnitrosamine. Br. J. Exp. Pathol. 67: 131-139.
48. Eckl, P. M., Meyer, S. A., Whitcombe, W. R. and Jirtle, R. E. (1988) Phenobarbital reduces EGF receptors and the ability of physiological concentrations of calcium to suppress hepatocyte proliferation. Carcinogenesis 9: 479-483.
49. Edwards, A. M. and Lucas, C. M. (1985) Phenobarbital and some other liver tumor promoters stimulate DNA synthesis in cultured rat hepatocytes. Biochem. Biophys. Res. Commun. 131: 103-108.
50. Elmore, E. and Nelmes, A. J. (1985) Summary report on the performance of the inhibition of metabolic cooperation assay. Prog. Mutat. Res. 5: 95-102.
51. Evans, J. G., Collins, M. A., Savage, S. A., Lake, B. G. and Butler, W. H. (1986) The histology and development of hepatic nodules in C3H/He mice following chronic administration of phenobarbitone. Carcinogenesis 7: 627-631.
52. Evans, J. G., Collins, M. A., Eake, B. G. and Butler, W. H. (1992) The histology and development of hepatic nodules and carcinoma in C3H/He and C57B1/6 mice following chronic phenobarbitone administration. Toxicol. Pathol. 20: 585-594.
53. Fox, T. R., Schumann, A. M., Watanabe, P. G., Yano, B. E., Maher, V. M. and McCormick, J. J. (1990) Mutational analysis of the H-ras oncogene in spontaneous C57BE/6 x C3H/He mouse liver tumors and tumors induced with genotoxic and nongenotoxic hepatocarcinogens. Cancer Res. 50: 4014-4019.
54. Friedman, G. D. (1981) Barbiturates and lung cancer in humans. J. Natl. Cancer Inst. 67: 291-295.
55. Fullerton, F. R., Hoover, K., Mikol, Y. B., Creasia, D. A. and Porier, E. A. (1990) The inhibition by methionine and choline of liver carcinoma formation in male C3H mice dosed with diethylnitrosamine and fed phenobarbital. Carcinogenesis 11: 1301-1305.
56. Furukawa, K., Numoto, S., Furuya, K., Furukawa, N. T. and Williams, G. M. (1985) Effects of the hepatocarcinogen nafenopin, a peroxisome proliferator on the activities of rat liver glutathione requiring enzymes and catalase in comparison to the action of phenobarbital. Cancer Res. 45: 5011-5019.
57. Glauert, H. P., Kennan, W. S., Sattler, G. E. and Pitot, H. C. (1985) Assays to measure the induction of unscheduled DNA synthesis in cultured hepatocytes. Prog. Mutat. Res. 5: 371-373.
58. Glauert, H. P., Schwarz, M. and Pitot, H. C. (1986) The phenotypic stability of altered hepatic foci: effect of the short-term withdrawal of phenobarbital and of the long-term feeding of purified diets after the withdrawal of phenobarbital. Carcinogenesis 7: 117-121.
59. Gold, E., Gordis, L., Tonascia, J. and Szklo, M. (1978) Increased risk of brain tumors in children exposed to barbiturates. J. Natl. Cancer Inst. 61: 1031-1034.
60. Goldhaber, M. K., Selby, J. V., Hiatt, R. A. and Quesenberry, C. P. (1990) Exposure to barbiturates in utero and during childhood and risk of intracranial and spinal cord tumors. Cancer Res. 50: 4600-4603.
61. Goldsworthy, T., Campbell, H. A. and Pitot, H. C. (1984) The natural history and dose-response characteristics ot enzyme-altered foci in rat liver following phenobarbital and diethylnitrosamine administration. Carcinogenesis 5: 67-71.
62. Goodman, J. I. and Counts, J. L. (1993) Hypomethylation of DNA: a possible nongenotoxic mechanism underlying the role of cell proliferation in carcinogenesis. Environ. Health Perspect. 101: 169-172.
63. Grasl-Kraupp, B., Waldhor, T., Huber, W. and Schuhe-Hermann, R. (1993) Glutathione S-transferase isoenzyme patterns in different subtypes of enzyme-altered rat liver foci treated with the peroxisome proliferator nafenopin or with phenobarbital. Carcinogenesis 14:2407-2412.
64. Grasso, P. and Hardy, J. (1975) Strain difference in natural incidence and response to carcinogens. In: Mouse Hepatic Neoplasia, pp. 111-142, Butler, W. H. and Newberne, P. M. (eds.) Elsevier, Amsterdam.
65. Griffin, R. J., Dudley, C. N. and Cunningham, M. L. (1996) Biochemical effects of the mouse hepatocarcinogen oxazepam: similarities to phenobarbital. Fundam. Appl. Toxicol. 29: 147-154.
66. Gulati, D. K., Sabharwal, P. S. and Shelby, M. D. (1985) Tests for the induction of chromosomal aberrations and sister chromatid exchanges in cultured Chinese hamster ovary (CHO) cells. Prog. Mutat. Res. 5: 413-426.
67. Guppy, M. J., Wilton, J. C., Sharma, R., Coleman, R. and Chipman, J. K. (1994) Modulation of phenobarbitone-induced loss of gap junctional intercellular communication in hepatocyte couplets. Carcinogenesis 15: 1917-1921.
68. Gupta, C., Hattori, A., Betschart, J. M., Virji, M. A. and Shinozuka, H. (1988) Modulation of epidermal growth factor receptors in rat hepatocytes by two liver tumor-promoting regimens, a choline-deficient and a phenobarbital diet. Cancer Res. 48: 1162-1165.
69. Hanigan, M. H., Kemp, C. J., Ginsler, J. J. and Drinkwater, N. R. (1988) Rapid growth of preneoplastic lesions in hepatocarcinogen-sensitive C3H/HeJ male mice relative to C57BL/6J male mice. Carcinogenesis 9: 885-890.
70. Hanigan, M. H., Winkler, M. L. and Drinkwater, N. R. (1990) Partial hepatectomy is a promoter of hepatocarcinogenesis in C57BL/6J male mice but not in C3H/HeJ male mice. Carcinogenesis 11: 589-594.
71. Harvey, D. J., Glazener, L., Stratton, C., Nowlin, J., Hill, R. M. and Horning, M. G. (1972) Detection of a 5-(3,4-dihydroxy-1,5-cyclobexadien-1-y1)-metabolite of phenobarbital and mephobarbital in rat, guinea pig and human. Res. Commun. Chem. Pathol. Pharmacol. 3: 557-565.
72. Hayes, M. A., Lee, G., Tatematsu, M. and Farber, E. (1987) Influences of diethylnitrosamine on longevity of surrounding hepatocytes and progression of transplanted persistent nodules during phenobarbital promotion ot hepatocarcinogenesis. Int. J. Cancer 40: 58-63.
73. He, J. S. and Fulco, A. J. (1991) A barbiturate-regulated protein binding to a common sequence in the cytochrome P450 genes of rodents and bacteria. J. Biol. Chem. 266: 7864-7869.
74. Hendrich, S., Glauert, H. P. and Pitot, H. C. (1986) The phenotypic stability of altered hepatic foci: effects of withdrawal and subsequent readministration of phenobarbital. Carcinogenesis 7: 2041-2045.
75. Hiasa, Y., Kitahori, Y., Ohshima, M., Fujita, T., Yuasa, T., Konishi, N. and Miyashiro, A. (1982) Promoting effects of phenobarbital and harbital on development of thyroid tumors in rats treated with N-bis(2-hydroxypropyl)nitrosamine. Carcinogenesis.3: 1187-1190.
76. Hobbs, C. H. and McClellan, R. O. (1986) Toxic effects of radi-tion and radioactive materials. In: Casarett and Doull's Toxicology. The Basic Science of Poisons, 3rd edn., Ch. 21, pp. 669-705, Klaassen, C. D., Amdur, M. O. and Doull, J. (eds.) Macmillan Publishing Company, New York.
77. Holder, M. J., Wang, H., Milner, A. E., Casamayor, M., Armitage, R., Spriggs, M. K., Fanslow, W. C., MacLennan, I. C., Gregory, C. D. and Gordon, J. ( 1993) Suppression of apoptosis in normal and neoplastic human B lymphocytes by CD40 ligand is independent of Bcl-2 induction. Eur. J. Immunol. 23: 2368-2371.
78. Honkakosi, P., Auriola, S. and Lang, M. A. ( 1992) Distinct induction profiles of three phenobarbital-responsive mouse liver cytochrome P450 isozymes. Biochem. Pharmacol. 43: 2121-2128.
79. Howe, G. R., Burch, J. D., Miller, A. B., Cook, G. M, Esteve, J., Morrison, B., Gordon, P., Chambers, L. W., Fodor, G. and Winsor, G. M. (1980) Tobacco use, occupation, coffee, various nutrients, and bladder cancer. J. Natl. Cancer Inst. 64: 701-713.
80. Hsieh, L. L., Peraino, C. and Weinstein, I. B. (1988) Expression of endogenous retrovirus-like sequences and cellular oncogenes during phenobarbital treatment and regeneration in rat liver. Cancer Res. 48: 265-269.
81. IARC (1987) 1ARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Suppl. 7. Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs. Vol. 1-42. IARC, Lyon.
82. Ishidate, M. and Sofuni, T. (1985) The in vitro chromosomal aberration test using Chinese hamster lung (CHL) fibroblast cells in culture. Prog. Mutat. Res. 5: 427-432.
83. Japundžič, M. M. (1969) The goitrogenic effect of phenobarbital on the rat thyroid. Acta Anat. 74: 88-96.
84. Jirtle, R. L. and Meyer, S. A. (1991) Liver tumor promotion: effect of phenobarbital on EGF and protein kinase c signal transduction and transforming growth factor-β1 expression. Dig. Dis. Sci. 36: 659-668.
85. Jones, H. B. and Clarke, N. A. B. (1993) Assessment of the influence of subacute phenobarbitone administration on multitissue cell proliferation in the rat using bromodeoxyundine immunocytochemisrry. Archiv. Toxicol. 67: 622-628.
86. 1 mice. Proc. Am. Assoc. Cancer Res. 34: 171.
87. Kanno, J., Matsuoka, C., Furuta, K., Onodera, H., Miyajima, H., Maekawa, A. and Hayashi, Y. (1990) Tumor promoting effect of goitrogens on the rat thyroid. Toxicol. Pathol. 18: 239-246.
88. Kemp, C. J. and Drinkwater, N. R. ( 1990) The androgen receptor and liver tumor development in mice. Prog. Clin. Biol. Res. 131: 109-120.
89. Kew, M. C. (1989) Role of cirrhosis in hepatocarcinogenesis. In: Liver Cell Carcinoma, pp. 37-45, Bannasch, P., Keppler, D. and Weber, G. (eds.) Kluwer Academic, Boston.
90. Kitagawa, T., Watanabe, R. and Sugano, H. (1980) Induction of γ-glutamyl transpeptidase activity by dietary phenobarbital in "spontaneous" hepatic tumors of C3H mice. Gann 71: 536-542.
91. Kitagawa, T., Hino, O., Nomura, K. and Sugano, H. (1984) Dose-response studies on promoting and anticarcinogenic effects of phenobarbital and DDT in the rat hepatocarcinogenesis. Carcinogenesis 5: 1653-1656.
92. Kitchin, K. T. and Brown, J. L. (1994) Dose-response relationship for rat liver DNA damage caused by 49 rodent carcinogens. Toxicology 88: 31-49.
93. Klaunig, J. E. (1993) Selective induction of DNA synthesis in mouse preneoplastic and neoplastic hepatic lesions after exposure to phenobarbital. Environ. Health Perspect. 101: 235-240.
94. 1 mice on phenobarbital promotion of diethylnitrosamine-initiated liver tumors. Toxicol. Appl. Pharmacol. 90: 79-85.
95. Klaunig, J. E., Ruch, R. J. and Weghorst, C. M. (1990) Comparative effects of phenobarbital, DDT, and lindane on mouse hepatocyte gap junctional intercellular communication. Toxicol. Appl. Pharmacol. 102: 553-563.
96. Klaunig, J. E., Siglin, J. C., Schafer, L. D., Hartnett, J. A., Weghorst, C. M., Olson, M. J. and Hampton, J. A. (1991) Correlation between species and tissue sensitivity to chemical carcinogenesis in rodents and the induction of DNA synthesis. In: Chemically Induced Cell Proliferation: Implications for Risk Assessment, pp. 185-194, Butterworth, B. E. (ed.) Wiley-Liss, New York.
97. Kocarek, T. A., Schuetz, E. G. and Guzelian, P. S. (1990) Differentiated induction of cytochrome P450b/e and P450p mRNAs by dose of phenobarbital in primary cultures of adult rat hepatocytes. Mol. Pharmacol. 38: 440-444.
98. Kunz, H. W., Buchmann, A., Schwarz, M., Schmitt, R., Kuhlmann, W. D., Wolf, C. R. and Oesch, R. (1987) Expression and inducibility of drug-metabolizing enzymes in preneoplastic and neoplastic lesions of rat liver during nitrosamine-induced hepatoearcinogenesis. Arch. Toxicol. 60: 198-203.
99. Kunz, W., Appel, K. E., Rickart, R., Schwarz, M. and Stückle, G. (1978) Enhancement and inhibition of carcinogenic effectiveness of nitrosamines. In: Primary Liver Tumors, pp. 261-285, Remmer, H., Bolt, H. M., Bannasch, P. and Popper, H. (eds.) University Park Press, Baltimore.
100. Kuroda, Y., Yokoiyama, A. and Kada, T. (1985) Assays for the induction of mutations to 6-thioguanine resistance in Chinese hamster V79 cells in culture. Prog. Mutat. Res. 5: 537-542.
101. Lee, C. G. and Webber, T. D. (1985) The induction of gene mutations in the mouse lymphoma L5178Y/TK+/-assay and the Chinese hamster V79/HGPRT assay. Prog. Mutat. Res. 5: 547-554.
102. Leibold, E. and Schwarz, L. R. (1993a) Intercellular communication in primary cultures of putative preneoplastic and normal hepatocytes. Carcinogenesis 14: 2127-2129.
103. Leibold, E. and Schwarz, L. R. (1993b) Inhibition of intercellular communication in rat hepatocytes by phenobarbital, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) and γ-hexachlorocyclohexane (lindane): modification by antioxidants and inhibitors of cyclo-oxygenase. Carcinogenesis 14: 2377-2382.
104. Levin, S. S., Vars, H. M., Schleyer, H. and Cooper, D. Y. (1986) The metabolism and excretion of enzyme-inducing doses of phenobarbital by rats with bile fistulas. Xenobiotica 16: 213-224.
105. Li, D., Moorthy, B., Chen, S. and Randerath, K. (1992) Effects of cytochrome P450 inducers on 1-compounds in rat liver and kidney DNA. Carcinogenesis 13: 1191-1198.
106. Liber, H. L. (1985) Mutation tests with Salmonella using 8-azaguanine resistance as the genetic marker. Prog. Mutat. Res. 5: 213-216.
107. Lin, E. L. C., Klaumg, J. E., Mattox, J. K., Weghorst, C. M., McFarland, B. H. and Pereira, M. A. (1989) Comparison of the effects of acute and suhacute treatment of phenobarbital in different strains of mice. Cancer Lett. 48: 4.3-51.
108. Lindroos, P., Tsai, W. H., Zarnegar, R. and Michalopoulos, G. K. (1992) Plasma levels of HGF in rats treated with tumor promoters. Carcinogenesis 13: 139-141.
109. 450b and its relationship to liver tumor promotion. J. Am. Col. Toxicol. 8: 259-268.
110. Maekawa, A., Onodera, H., Ogasawara, H., Matsushima, Y., Mitsumori, K. and Hayashi, Y. (1992) Threshold dose dependence in phenobarbital promotion of rat hepatocarcinogenesis initiated by diethyinitrosamine. Carcinogenesis 13: 501-503.
111. Maniara, W., Levin, S. S., Schleyer, H. and Cooper, D. Y. (1988) Biophysical and catalytic properties of the phenobarbital p-hydroxylase, a cytochrome P-450 dependent mixed function oxidase. Xenobiotica 18: 545-550.
112. Manjeshwar, S., Rao, P. M, Rajalakshmi, S. and Sarma, D. S. R. (1992) Inhibition of DNA synthesis by phenobarbital in primary cultures of hepatocytes from normal rat liver and from hepatic nodules. Carcinogenesis 13: 2287-2291.
113. Maronpot, R. R., Montgomery, C. A., Jr., Boorman, G. A. and McConnell, E. E. (1986) National toxicology program nomenclature for hepatoproliferative lesions of rats. Toxicol. Pathol. 14: 263-273.
114. Martin, C. N. and Campbell, J. (1985) Tests for the induction of unscheduled DNA repair synthesis in HeLa cells. Prog. Mutat. Res. 5: 375-379.
115. Matsushima, T., Muramatsu, M. and Haresaku, M. (1985) Mutation tests on Salmonella typhimurium by the preincubation method. Prog. Mutat. Res. 5: 181-186.
116. McCann, J., Choi, E., Yamasaki, E. and Ames, B. N. (1975) Detection of carcinogens as mutagens in the Salmonella/ microsome test: assay of 300 chemicals. Proc. Natl. Acad. Sci. USA 72: 5135-5139.
117. McClain, R. M. (1989) The significance of hepatic microsomal enzyme induction and altered thyroid function in rats: implications for thyroid gland neoplasia. Toxicol. Pathol. 17: 294-306.
118. McClain, R. M. (1990) Mouse liver tumors and microsomal enzyme-inducing drugs: experimental and clinical perspectives with phenobarbital. Prog. Clin. Biol. Res. 331: 345-365.
119. McClain, R. M., Posch, R. C., Bosakowski, T. and Armstrong, J. M. (1988) Studies on the mode of action for thyroid gland tumor promotion in rats by phenobarbital. Toxicol. Appl. Pharmacol. 94: 254-265.
120. McClain, R. M., Levin, A. A., Posch, R. and Downing, J. C. (1989) The effect of phenobarbital on the metabolism and excretion of thyroxine in rats. Toxicol. Appl. Pharmacol. 99: 216-228.
121. McLean, A. E. M., Driver, H. E. and Sutherland, I. A. (1992) Liver tumour promotion by phenobarbital: comparison of rat and human studies. In: Relevance of Animal Studies to the Evaluation of Human Cancer Risk, pp. 251-259, D'Amato, R., Slaga, T. J., FarLand, W. H. and Henry, C. (eds.) Wiley-Liss, New York.
122. Mesnil, M., Fitzgerald, D. J. and Yamasaki, H. (1988) Phenobarbital specifically reduces gad junction protein mRNA level in rat liver. Mol. Carcinog. 1: 79-81.
123. Meyer, S. A., Gibbs, T. A. and Jirtle, R. L. (1989) Independent mechanisms for tumor promoters phenobarbital and 12-O-tet-radecanoylphorbol-13-acetate in reduction ot epidermal growth factor binding by rat hepatocytes. Cancer Res. 49: 5907-5912.
124. Miyazaki, M., Handa, Y., Oda, M., Yabe, T., Miyano, K. and Sato, J. (1985) Long-term survival of functional hepatocytes from adult rat in the presence of phenobarbital in primary culture. Exp. Cell Res. 159: 176-190.
125. Monro, A. (1993) The paradoxical lack of interspecies correlation between plasma concentrations and chemical carcinogenicity. Reg. Toxicol. Pharmacol. 18: 115-135.
126. Myhr, B., Bowers, L. and Caspary, W. J. (1985) Assays for the induction of gene mutations at the thymidine kinase locus in L5178Y mouse lymphoma cells in culture. Prog. Mutat. Res. 5: 555-568.
127. Natarajan, A. T., Bussmann, C. J. M., van Kesteren-van Leeuwen, A. C., Meijers, M. and van Rijn, J. L. S. (1985) Tests for chromosome aberrations and sister-chromatid exchanges in Chinese hamster ovary (CHO) cells in culture. Prog. Mutat. Res. 5: 433-437.
128. Neveu, M. J., Babcock, K. L, Hertzberg, E. L, Paul, D. L, Nicholson, B. J. and Pitot, H. C. (1994) Colocalized alterations in connexin32 and cytochrome P450HB1/2 by phenobarbital and related liver tumor promoters. Cancer Res. 54: 3145-3152.
129. Nims, R. W., Devor, D. E., Henneman, J. R. and Lubet, R. A. (1987) Induction of alkoxyresorufin O-dealkylases, epoxide hydrolase and liver weight gain: correlation with liver tumor-promoting potential in a series of barbiturates. Carcinogenesis 8:67-71.
130. Nims, R. W., Lubet, R. A., Jones, C. R., Mellini, D. W. and Thomas, P. E. (1993a) Comparative pharmacodynamics of CYP2B induction by phenobarbital in the male and female F344/NCr rat. Biochem. Pharmacol. 45: 521-526.
131. Nims, R. W., Syi, J. L, Wink, D. A., Nelson, V. C., Thomas, P. E., Jones, C. R., Diwan, B. A., Keefer, L. K., Rice, J. M. and Lubet, R. A. (1993b) Hepatic cytochrome P450 2B-type induction by ethyl/phenyl-substituted congeners of phenobarbital in the rat. Chem. Res. Toxicol. 6: 180-187.
132. Obe, G., Hille, A., Jonas, R., Schmidt, S. and Thenhaus, U. (1985) Tests for the induction of sister-chromatid exchanges in human peripheral lymphocytes in culture. Prog. Mutat. Res. 5: 439-442.
133. Oberly, T. J., Bewsey, B. J. and Probst, G. S. (1985) Tests for the induction of forward mutation at the thymidine kinase locus of L5178Y mouse lymphoma cells in culture. Prog. Mutat. Res. 5: 569-582.
134. 6-methylguanine from hepatic DNA. Carcinogenesis 9: 2033-2038.
135. Ohmori, T., Rice, J. M. and Williams, G. M. (1981) Histochemical characteristics of spontaneous and chemically induced hepatocellular neoplasms in mice and the development of neoplasms with γ-glutamyl transpeptidase activity during phenobarbitral exposure. Histochem. J. 13: 85-99.
136. Ohnhaus, E. E. and Studer, H. (1983) A link between microsomal enzyme activity and thyroid hormone metabolism in man. Br. J. Clin. Pharmacol. 15: 71-76.
137. Okey, A. B. (1990) Enzyme induction in the cytochrome P-450 system. Pharmacol. Ther. 45: 241-298.
138. Olsen, J. H., Boice, J. D., Jr., Jensen, J. P. A. and Fraumeni, J. F., Jr. (1989) Cancer among epileptic patients exposed to anticonvulsant drugs. Reports 81: 803-808.
139. Olsen, J. H., Boice, J. D., Jr. and Fraumeni, J. F., Jr. (1990) Cancer in children of epileptic mothers and the possible relation to maternal anticonvulsant therapy. Br. J. Cancer 62: 996-999.
140. Olsen, J. H., Wallin, H., Boice, J. D., Jr., Rask, K., Schulgen, G. and Fraumeni, J. F., Jr. (1993) Phenobarbital, drug metabolism, and human cancer. Cancer Epidemiol. Biomarkers Preven. 2: 449-452.
141. Olsen, J. H., Schulgen, G., Boice, J. D., Jr., Whysner, J., Travis, L. B, Williams, G. M., Johnson, F. B. and McGee, J. O. (1995) Antiepileptic treatment and risk for hepatobiliary cancer and malignant lymphoma. Cancer Res. 55: 294-297.
142. Oppenheimer, J. H., Bernstein, G. and Surks, M. I. (1968) Increased thyroxine turnover and thyroidal function after stimulation of hepatocellular binding of thyroxine by phenobarbital. J. Clin. Invest. 47: 1399-1406.
143. Parzefall, W., Erber, E., Sedivy, R. and Schuhe-Hermann, R. (1991) Testing for induction of DNA synthesis in human hepatocytc primary cultures by rat liver tumor promoters. Cancer Res. 51: 1143-1147.
144. Peraino, C., Fry, R. J. M. and Staffeldt, E. (1971) Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. Cancer Res. 31: 1506-1512.
145. Peraino, C., Fry, R. J. M. and Staffeldt, E. (1973) Brief communication: enhancement of spontaneous hepatic tumorigenesis in C3H mice by dietary phenobarbital. J. Natl. Cancer Inst. 51: 1349-1350.
146. Peraino, C., Fry, R. J. M., Staffeldt, E. and Christopher, J. P. (1975) Comparative enhancing effects of phenobarbital, amoharbital, diphenylhydantoin and dichlorodiphenyltrichloroethane on 2-acetylaminofluorene-induced hepatic tumorigenesis in the rat. Cancer Res. 35: 2884-2890.
147. Peraino, C., Fry, R. J. M. and Staffeldt, E. (1977) Effects of varying the onset and duration of exposure to phenobarbital on its enhancement of 2-acetylaminofluorene-induced hepatic tumorigenesis. Cancer Res. 37: 3623-3627.
148. Peraino, C., Staffeldt, E. F., Haugen, D. A., Eombard, E. S., Stevens, F. J. and Fry, R. J. M. (1980) Effects of varying the dietary concentration of phenobarbital on its enhancement of 2-acetylaminofluorene-induced hepatic tumorigenesis. Cancer Res. 40: 3268-3273.
149. 1 mice of the sensitivity to diethylnitrosamine-initiation and phenobarbital-promotion to the extent of cell proliferation. Carcinogenesis 14: 299-302.
150. Pereira, M. A., Knutsen, G. E. and Herren-Freund, S. E. (1985) Effect of subsequent treatment of chloroform or phenobarbital on the incidence of liver and lung tumors initiated by ethylnitrosourea in 15 day old mice. Carcinogenesis 6: 203-207.
151. Pereira, M. A., Herren-Freund, S. E. and Eong, R. E. (1986a) Dose-response relationship of phenobarbital promotion of diethylnitrosamine mitated tumors in rat liver. Cancer Eett. 32: 305-311.
152. Pereira, M. A., Klaunig, J. E., Herren-Freund, S. E. and Ruch, R. J. (1986b) Effect of phenobarbital on the development of liver tumors in juvenile and adult mice. J. Natl. Cancer Inst. 77: 449-452.
153. Pirttiaho, H. I., Sotaniemi, E. A., Ahokas, J. T. and Pitkänen, U. (1978) Liver size and indices of drug metabolism in epileptics. Br. J. Clin. Pharmacol. 6: 273-278.
154. Pitot, H. C., Goldsworthy, T. E., Moran, S., Kennan, W., Glauert, H. P., Maronpot, R. R. and Campbell, H. A. (1987) A method to quantitate the relative initiating and promoting potencies of hepatocarcinogenic agents in their dose-response relationships to altered hepatic foci. Carcinogenesis 8: 1491-1499.
155. Ponomarkov, V. and Tomatis, L. (1976) The effect of long-term administration of phenobarbitone in CF-1 mice. Cancer Lett. 1: 165-172.
156. Prabhu, L, Upadhya, P., Ram, N., Nirodi, C. S., Sultana, S., Vatsala, P. G., Mani, S. A., Rangarajan, P. N., Surolia, A. and Padmanaban, G. (1995) A model for the transcriptional regulation of the CYP2B1/B2 gene in rat liver. Proc. Natl. Acad. Sci. USA 92: 9628-9632.
157. Priston, R. A. J. and Dean, B. J. (1985) Tests for the induction of chromosome aberrations, polyploidy and sister-chromatid exchanges in rat liver (RL4) cells. Prog. Mutat. Res. 5: 387-395.
158. Probst, G. S. and Hill, L. E. (1985) Tests tor the induction of DNA-repair synthesis in primary cultures of adult rat hepatocytes. Prog. Mutat. Res. 5: 381-386.
159. Pugh, T. D. and Goldfarb, S. (1978) Quantitative histochemical and autoradiographic studies of hepatocarcinogenesis in rats fed 2-acetylaminofluorene followed by phenobarbital. Cancer Res. 38: 4450-4457.
160. Randerath, K., van Golen, K. L., Dragan, Y. P. and Pitot, H. C. (1992) Effects of phenobarbital on 1-compounds in liver DNA as a function of age in male rats fed two different diets. Carcinogenesis 13: 125-130.
161. Razin, A. and Cedar, H. (1991) DNA methylation and gene expression. Microbiol. Rev. 55: 451-458.
162. Ray, J. S., Harbison, M. L., McClain, R. M. and Goodman, J. I. (1994) Alterations in the methylation status and expression of the raf oncogene in phenobarbital-induced and spontaneous B6C3F1 mouse liver tumors. Mol. Carcinog. 9: 155-166.
163. Reidenberg, P., Glue, P., Banfield, C. R., Colucci, R. D., Meehan, J. W., Radwanski, E., Mojavarian, P., Lin, C. C., Nezamis, J. and Guillaume, M. (1995) Effects of felbamate on the pharmacokinetics of phenobarbital. Clin. Pharmacol. Ther. 58: 279-287.
164. Rexroat, M. A. and Probst, G. S. (1985) Mutation tests with Salmonella using the plate-incorporation assay. Prog. Mutat. Res. 5: 210-212.
165. Rice, J. M., Rehm, S., Donovan, P. J. and Perantoni, A. O. (1989) Comparative transplacental carcinogenesis by directly acting and metabolism-dependent alkylating agents in rodents and nonhuman primates. IARC Sci. Publ. 96: 17-34.
166. Rice, J. M., Diwan, B. A., Ward, J. M., Nims, R. W. and Lubet, R. A. (1992) Phenobarbital and related compounds: approaches to interspecies extrapolation. In: Relevance of Animal Studies to the Evaluation of Human Cancer Risk, pp. 231-249, D'Amato, R., Slaga, T. J., Farland, W. H. and Henry, C. (eds.) Wiley-Liss, New York.
167. Rice, J. M., Diwan, B. A, Hu, H., Ward, J. M., Nims, R. W. and Lubet, R. A. (1994) Enhancement of hepatocarcinogenesis and induction of specific cytochrome P450-dependent monooxygenase activities by the barbiturates allobarbital, aprobarbital, pentobarbital, secobarbital and 5-phenyl-and 5-ethyibarbituric acids. Carcinogenesis 15: 395-402.
168. Roberts, C. J. C., Jackson, L., Halliwell, M. and Branch, R. A. (1976) The relationship between liver volume, antipyrine clearance an dindocyanine green clearance before and after phenobarbitone administration in man. Br. J. Clin. Pharmacol. 3: 907-913.
169. Rossi, L., Ravera, M., Repetti, G. and Santi, L. (1977) Long-term administration of DDT or phenobarbital-Na in Wistar rats. Int. J. Cancer 19:179-185.
170. Ruch, R. J. and Klaunig, J. E. (1986) Effects of tumor promoters, genotoxic carcinogens and hepatocytotoxins on mouse hepatocyte intercellular communication. Cell Biol. Toxicol. 2: 469-483.
171. Rumsby, P. C., Barrass, N. C., Phillimore, H. E. and Evans, J. G. (1991) Analysis of the Ha-ras oncogene in C3H/He mouse liver tumours derived spontaneously or induced with diethylnitrosamine or phenobarbitone. Carcinogenesis 12: 2331-2336.
172. Rumsby, P. C., Davies, M. J. and Evans, J. G. (1994) Screening for p53 mutations in C3H/He mouse liver tumors derived spontaneously or induced with diethylnitrosamine or phenobarbitone. Mol. Carcinog. 9:71-75.
173. Ruttimann, G. (1972) Effect of phenobarbital on hepatocyte proliferation in rats following partial hepatectomy. Experientia 15: 1196-1197.
174. Saito, K., Kaneko, H-, Sato, K., Yoshitake, A. and Yamada, H. (1991) Hepatic UDP-glucuronyltransferase(s) activity toward thyroid hormones in rats: induction and effects on serum thyroid hormone levels following treatment with various enzyme inducers. Toxicol. Appl. Pharmacol. 111: 99-106.
175. Saito, R., Chandar, N., Janosky, J. E. and Lombardi, B. (1990) No enhancement by phenobarbital of the hepatocarcinogenicity of a choline-devoid diet in the rat. Res. Commun. Chem. Pathol. Pharmacol. 69: 197-207.
176. Sawada, N., Staecker, J. L. and Pitot, H. C. (1987) Effects of tumor-promoting agents 12-O-tetradecanoylphorbol-l 2-acetate and phenobarbital on DNA synthesis of rat hcpatocytes in pri-mary culture. Cancer Res. 47: 5665-5671.
177. Schmähl, D. and Habs, M. (1976) Life-span investigations for carcinogenicity of some immune-stimulating, immunodepressive and neurotropic substances in Sprague-Dawley rats. Z. Krebsforsch. 86: 77-84.
178. Scholz, W., Schütze, K., Kunz, W. and Schwarz, M. (1990) Phenobarbital enhances the formation of reactive oxygen in neoplastic rat liver nodules. Cancer Res. 50: 7015-7022.
179. Schülte-Hermann, R., Ohde, G., Schuppler, J. and Timmermann-Trosiener, I. (1981) Enhanced proliferation of putative preneoplastic cells in rat liver following treatment with the tumor promoters phenobarbital, hexachlorocyclohexane, steroid compounds and nafenopin. Cancer Res. 41: 2556-2562.
180. Schülte-Hermann, R., Timmermann-Trosiener, I. and Schuppler, J. (1986) Facilitated expression of adaptive responses to phenobarbital in putative pre-stages of liver cancer. Carcinogenesis 7:1651-1655.
181. Schülte-Hermann, R., Timmermann-Trosiener, L, Barthel, G. and Bursch, W. (1990) DNA synthesis, apoptosis, and phenotypic expression as determinants of growth of altered foci in rat liver during phenobarbital promotion. Cancer Res. 50: 5127-5135.
182. Selby, J. V., Friedman, G. D. and Fireman, B. H. (1989) Screening prescription drugs for possible carcinogenicity: eleven to fifteen years of follow-up. Cancer Res. 49: 5736-5747.
183. Seltzer, C. C., Friedman, G. D. and Siegelaub, A. B. (1974) Smoking and drug consumption in White, Black and Oriental men and women. Am. J. Public Health 64: 466-473.
184. Shirts, S. B., Annegers, J. F., Hauser, W. A. and Kurland, L. T. (1986) Cancer incidence m a cohort of patients with seizure disorders. J. Natl. Cancer Inst. 77: 83-87.
185. Siglin, J. C, Weghorst, C. M. and Klaunig, J. E. (1991) Role of hepatocyte proliferation in a-hexachlorocyclohexane and phenobarbital tumor promotion in B6C3F, mice. Prog. Clin. Biol. Res. 369:407-416.
186. Smith, P. F., O'Brien, K. A. and Keenan, K. P. (1991) Evaluation of bromodeoxyuridine labeling in hepatomegaly produced by peroxisomal proliferation of P-450 induction in rodents. Prog. Clin. Biol. Res. 369: 285-289.
187. Soine, W. H., Soine, P. J., England, T. M., Ferkany, J. W. and Agriesti, B. E. (1991 ) Identification of phenobarbital N-glucosides as urinary metabolites of phenobarbital in mice. J. Pharm. Sci. 80: 99-103.
188. Stenbäck, F., Mori, H., Furuya, K. and Williams, G. M. (1986) Pathogenesis of dimethylnitrosamine-induced hepatocellular cancer in hamster liver and lack of enhancement by phenobarbital. J. Natl. Cancer Inst. 76: 327-333.
189. 1 mice and Fischer 344 rats. Carcinogenesis 9: 271-276.
190. Styles, J. A., Clay, P. and Cross, J. F. (1985) Assays for the induction of gene mutations at the thymidine kinase and the Na+/ K+ ATPase loci in two different mouse lymphoma cell lines in culture. Prog. Mutat. Res. 5: 587-596.
191. Sugie, S., Mori, H. and Takahashi, M. (1987) Effect of in vivo exposure to the liver tumor promoters phenobarbital or DDT on the gap junctions of rat hepatocytes: a quantitative freeze-fracture analysis. Carcinogenesis 8: 45-51.
192. Sunshine, I. (1986) Analytic toxicology. In: Casarett and Doull's Toxicology. The Basic Science of Poisons, 3rd edn., Ch. 27, pp. 857-878, Klaassen, C. D., Amdur, M. O. and Doull, J. (eds.) Macmillan Publishing Company, New York.
193. Tanaka, T., Mori, H. and Williams, C. M. (1987) Enhancement of dimethylnitrosamine-initiated hepatocarcinogenesis in hamsters by subsequent administration of carbon tetrachloride but not phenobarbital or p,p'-dichlorodiphenyltrichloroethane. Carcinogenesis 8: 1171-1178.
194. Tang, B. K., Kalow, W. and Grey, A. A. (1979) Metabolic fate of phenobarbital in man. Drug Metab. Dispos. 7: 315-318.
195. Tavoloni, N., Jones, M. J. T. and Berk, P. D. (1983) Dose-related effects of phenobarbital on hepatic microsomal enzymes. Proc. Soc. Exp. Biol. Med. 174: 20-27.
196. Thorpe, E. and Walker, A. I. T. (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 Cosmet. Toxicol. 11: 433-442.
197. Treston, A. M. and Hooper, W. D. (1992) Urinary metabolites of phenobarhitone, primidone, and their N-methyl and N-ethyl derivatives in humans. Xenobiotica 22: 385-394.
198. Trosko, J. E., Yotti, L. P., Warren, S. T., Tsushimoto, G. and Chang, C. C. (1982) Inhibition of cell-cell communication by tumor promoters. Carcinogenesis 7: 565-585.
199. Umeda, M., Noda, K. and Ono, T. (1980) Inhibition of metabolic cooperation in Chinese hamster cells by various chemicals including tumor promoters. Gann 71: 614-620.
200. Vecchini, F., Mace, K., Magdalou, J., Mahe, Y., Bernard, B. A. and Shroot, B. ( 1995) Constitutive and inducible expression of drug metabolizing enzymes in cultured human keratinocytes. Br. J. Dermatol. 132:14-21.
201. Ward, J. M. (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: 815-823.
202. Ward, J. M. and Ohshima, M. (1985) Evidence for lack of promotion of the growth of the common naturally occurring basophilic focal hepatocellular proliferative lesions in aged F344/ NCr rats by phenobarbital. Carcinogenesis 6: 1255-1259.
203. Ward, J. M., Lynch, P. and Riggs, C. (1988) Rapid development of hepatocellular neoplasms in aging male C3H/HeNCr mice given phenobarbital. Cancer Lett. 39: 9-18.
204. Watanabe, K. and Williams, G. M. (1978) Enhancement of rat hepatocellular-altcred foci by the liver tumor promoter phenobarbital: evidence that foci are precursors of neoplasms and that the promoter acts on carcinogen-induced lesions. J. Natl. Cancer Inst. 61: 1311-1314.
205. Waxman, D. J. and Azaroff, L. (1992) Phenobarbital induction of cytochrome P-450 gene expression. Biochem. J. 281: 577-592.
206. 1 mice: influence of gender. Carcinogenesis 10: 609-612.
207. Weisburger, J. H., Madison, R. M., Ward, J. M., Viguera, C. and Weishurger, E. K. (1975) Modification of diethylnitrosamine liver carcinogenesis with phenobarbital hut not with immunosuppression. J. Natl. Cancer Inst. 54: 1185-1188.
208. White, S. J., McLean, A. E. M. and Rowland, C. (1979) Anticonvulsant drugs and cancer: a cohort study in patients with severe epilepsy. Lancet ii: 458-461.
209. 32P-postlabeling assay for detection of adduct formation by phenobarbital, chlordane and polychlorinated biphenyls in mouse liver DNA. The Toxicologist 15: 83.
210. Whyte, M. P. and Dekaban, A. S. (1977) Metabolic fate of phenobarbital. A quantitative study of p-hydroxyphenobarbital elimination in man. Drug Metab. Dispos. 5: 6.3-70.
211. Williams, G. M. (1980) Classification of genotoxic and epigenetic hepatocarcinogens using liver culture assays. Ann. NY Acad. Sci. 349: 273-282.
212. Williams, G. M. (1981) Liver carcinogenesis: the role for some chemicals in an epigenetic mechanism of liver-tumour promotion involving modification of the cell membrane. Food Cosmet. Toxicol. 19: 577-583.
213. Williams, G. M. and Furuya, K. (1984) Distinction between liver neoplasm promoting and syncarcinogenic effects demonstrated by exposure to phenobarbital or diethylnitrosamine either before or after N - 2-fluorenylacetamide. Carcinogenesis 5: 171-174.
214. Williams, G. M., Ohmori, T., Katayama, S. and Rice, J. M. (1980) Alteration by phenobarbital of membrane-associated enzymes including gamma glutamyl transpeptidase in mouse liver neoplasms. Carcinogenesis 1: 813-818.
215. Williams, G. M., Telang, S. and Tong, C. (1981) Inhibition of intercellular communication between liver cells by the liver tumor promoter 1,1,1 -trichloro-2,2-bis(p-chlorophenyl)ethane. Cancer Lett. 11: 339-344.
216. Williams, G. M., Tong, C. and Ved Brat, S. (1985) Tests with the rat hepatocyte primary culture/DNA-repair test. Prog. Mutat. Res. 5: 341-345.
217. Wolff, G. L., Morrissey, R. L. and Chen, J. J. (1986a) Amplified response to phenobarbital promotion of hepatotumorigenesis in obese yellow A[+vy]/A (C3H x VY) F-1 hybird mice. Carcinogenesis 7:1895-1898.
218. Wolff, G. L., Morrissey, R. L. and Chen, J. J. ( 1986b) Susceptible and resistant subgroups in genetically identical populations: response of mouse liver neoplasia and body weight to phenobarbital. Carcinogenesis 7: 1935-1937.
219. Xu, Y., Maronpot, R. and Pitot, H. C. (1990) Quantitative stereologic study of the effects of varying the time between initiation and promotion on four histochemical markers in rat liver during hepatocarcinogenesis. Carcinogenesis 11: 267-272.
220. Xu, Y., Dragan, Y. P., Young, T. and Pitot, H. C. (1991) The effect of the format of administration and the total dose of phenobarbital on altered hepatic foci following initiation in female rats with diethylnitrosamine. Carcinogenesis 12: 1009-1016.
221. Zeiger, E. and Haworth, S. (1985) Tests with a preincubation modification of the Salmonella/microsome assay. Prog. Mutat. Res. 5: 187-199.