Effect of the separate and combined administration of mestranol and phenobarbital on the development of altered hepatic foci expressing placental form of glutathione S-transferase in the rat

Carcinogenesis

Volumn 17, Issue 9, 1996, Pages 2043-2052

  Dragan, Yvonne P ^a   Singh, Jyoti ^a   Pitot, Henry C ^a  

^a UNIVERSITY OF WISCONSIN MADISON   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETONE; BROXURIDINE; DIETHYLNITROSAMINE; GLUTATHIONE TRANSFERASE; MESTRANOL; PHENOBARBITAL; PLACENTA ENZYME; TRIOCTANOIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; FEMALE; LIVER CARCINOGENESIS; NONHUMAN; PHARMACODYNAMICS; PHARMACOKINETICS; PRIORITY JOURNAL; RAT; STEREOLOGY;

EID: 0029837680     PISSN: 01433334     EISSN: None     Source Type: Journal    
DOI: 10.1093/carcin/17.9.2043     Document Type: Article

References (123)

1. Pitot, H.C. and Dragan, Y.P. (1991) Facts and theories concerning the mechanism of carcinogenesis. FASEB J., 5, 2280-2286.
2. Boutwell, R. (1964) Some biological aspects of skin carcinogenesis. Prog. Exp. Tumor Res., 4, 207-250.
3. Dragan, Y., Sargent, L., Xu, Y.-D., Xu, Y.-H. and Pitot, H.C. (1993) The initiation-promotion-progression model of rat hepatocarcinogenesis. Proc. Soc. Exp. Biol. Med., 202, 16-24.
4. Knudson, A., Hethcote, H. and Brown, B. (1975) Mutation and childhood cancer: a probabilistic model for the incidence of retinoblastoma. Proc. Natl Acad. Sci. USA, 72, 5116-5120.
5. Moolgavkar, S. and Venzon, D. (1979) Two event models for carcinogenesis: incidence curves for childhood and adult tumors. Math. Biosci., 47, 55-77.
6. Moolgavkar, S. and Knudson, A. (1981) Mutations and cancer: a model for carcinogenesis. J. Natl Cancer Inst., 66, 1037-1052.
7. Hennings, H., Shores, R., Wenk, M., Spangler, E., Tarone, R. and Yuspa, S. (1985) Malignant conversion of mouse skin tumours is increased by tumor initiators and unaffected by tumor promoters. Nature, 304, 67-69.
8. Hennings, H., Shores, R., Mitchell, P., Spangler, E. and Yuspa, S. (1985) Induction of papillomas with a high probability of conversion to malignancy. Carcinogenesis, 6, 1607-1610.
9. Scherer, E., Feringa, A. and Emmelot, P. (1984) Initiation-promotion-initiation. Induction of neoplastic foci within islands of precancerous liver cells in the rat. In Borzonski, M., Lapis, K., Day, N. and Yamasaki, H. (eds), Models, Mechanisms, and Etiology of Tumor Promotion. IARC Scientific Publication no. 56, International Agency for Research on Cancer, Lyon, France, pp. 57-66.
10. Pitot, H.C. and Dragan, Y.P. (1995) The instability of tumor promotion in relation to human cancer risk. In McClain, R.M., Slaga, T., LeBoeuf, R. and Pitot, H.C. (eds), Growth Factors and Tumor Promotion: Implications for Risk Assessment. Wiley-Liss, New York, pp. 21-38.
11. Potter, V.R. (1981) A new protocol and its rationale for the study of initiation and promotion of carcinogenesis in the rat liver. Carcinogenesis, 2, 1375-1379.
12. Moolgavkar, S. and Luebeck, E. (1992) Multistage carcinogenesis: population-based model for colon cancer. J. Natl Cancer Inst., 84, 610-618.
13. Pitot, H.C. (1990) Altered hepatic foci: their role in murine hepatocarcinogenesis. Annu. Rev. Pharmacol. Toxicol., 30, 465-500.
14. Goldsworthy, T. and Pitot, H. (1986) An approach to the development of whole-animal bioassay to distinguish initiating (incomplete) carcinogens, complete carcinogens, and non-carcinogens in the rat. Toxicol. Pathol., 17, 594-612.
15. Dragan, Y.P. and Pitot, H.C. (1992) Multistage hepatocarcinogenesis in the rat: insights into risk estimation. In D'Amato, R., Slaga, T., Farland, W. and Henry, C. (eds), Relevance of Animal Studies to the Evaluation of Human Cancer Risk. Wiley-Liss, New York, pp. 261-279.
16. Doll, R. and Peto, R. (1981) The Causes of Cancer. Oxford University Press, New York.
17. Pitot, H. (1993) Multistage carcinogenesis: the role of tumor promotion. Cancer Detect. Prevent., 17, 567-573.
18. Dragan, Y.P. and Pitot, H.C. (1992) The role of the stages of initiation and promotion in phenotypic diversity during hepatocarcinogenesis in the rat. Carcinogenesis, 13, 739-750.
19. Peraino, C., Fry, M. and Stuffeldt, G. (1971) Reduction and enhancement of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. Cancer Rex., 31, 1506-1512.
20. Pitot, H., Barness, L., Goldsworthy, T. and Kitagawa, J. (1978) Biochemical characterization of stages of hepatocarcinogenesis after a single oral dose of diethylnitrosamine. Nature, 271, 456-458.
21. Kitagawa, T. and Sugano, H. (1978) Enhancing effect of phenobarbital on the development of enzyme-altered islands and hepatocellular carcinomas initiated by 3′-methyl-4-(dimethylamino)azobenzene or diethylnitrosamine. Gann, 69, 679-687.
22. Weisburger, J., Madison, R., Ward, J., Viguera, C. and Weisburger, E. (1975) Modification of diethylnitrosamine liver carcinogenesis with phenobarbital but not immunosuppression. J. Natl Cancer Inst., 54, 1185-1188.
23. Schulte-Hermann, R., Ohde, G., Schuppler, J. and Timmermann-Trosnier, 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.
24. Schulte-Hermann, R., Timmermann-Trosnier, I. and Schuppler, J. (1986) Facilitated expression of adaptive responses to phenobarbital in putative pre-stages of liver cancer. Carcinogenesis, 7, 1651-1655.
25. Yager, J. and Yager, R. (1980) Oral contraceptive steroids as promoters of hepatocarcinogenesis in female Sprague-Dawley rats. Cancer Res., 40, 680-685.
26. Cameron, R., Imaida, K., Tsuda, H. and Ito, N. (1982) Promotive effects of steroids and bile acids on hepatocarcinogenesis initiated by diethylnitrosamine. Cancer Res., 42, 2426-2428.
27. Wanless, I. and Medline, A. (1982) Role of estrogens as promoters of hepatic neoplasia. Lab Invest., 46, 313-320.
28. Yager, J., Campbell, H., Longnecker, D., Roebuck, B. and Benoit, M. (1984) Enhancement of hepatocarcinogenesis in female rats by ethinyl estradiol and mestranol but not estradiol. Cancer Res., 46, 1224-1232.
29. Yager, J., Roebuck, B., Paluszyck, T. and Memoli, V. (1986) Effects of ethinyl estradiol and tamoxifen on liver DNA turnover and new synthesis and appearance of gamma glutamyl transpeptidase-positive foci in female rats. Carcinogenesis, 7, 2007-2014.
30. Campen, D., Sloop, T., Maronpot, R. and Lucier, G. (1987) Continued development of hepatic γ-glutamyl transpeptidase positive foci upon withdrawal of 17α ethinyl estradiol in diethylnitrosamine-initiated rats. Cancer Res., 47, 2328-2333.
31. Vickers, A. and Lucier, G. (1991) Estrogen receptor, epidermal growth factor receptor, and cellular ploidy in elutriated subpopulations of hepatocytes during liver tumor promotion by 17α-ethinylestradiol in rats. Carcinogenesis, 12, 391-399.
32. Vickers, A., Nelson, K., McCoy, Z. and Lucier, G. (1989) Changes in estrogen receptor. DNA-ploidy and estrogen metabolism in rat hepatocytes during liver tumor promotion by 17α-ethinylestradiol in rats. Cancer Res., 47, 2328-2333.
33. Schulte-Hermann, R. (1985) Tumor promotion in the rat liver. Arch. Toxicol., 57, 147-158.
34. Yager, J. and Shi, Y. (1991) Synthetic estrogens and tamoxifen as promoters of hepatocarcinogenesis. Prev. Med., 20, 27-37.
35. Peraino, C., Staffeldt, E., Haugen, D., Lombard, L., Stevens, F. and Fry, R. (1980) Effects of varying the dietary concentration of phenobarbital on its enhancement of 2-acetylaminofluorene-induced hepatic tumorigenesis. Cancer Res., 40, 3268-3273.
36. Goldsworthy, T., Campbell, H. and Pitot, H. (1984) The natural history and dose-response characteristics of enzyme-altered foci in rat liver following phenobarbital and diethylnitrosamine administration. Carcinogenesis, 5, 67-71.
37. Driver, H. and McLean, A. (1986) Dose response relationships for the initiation of rat liver tumors by diethylnitrosamine and their promotion by phenobarbital. Food Chem. Toxicol., 24, 241-245.
38. Driver, H. and McLean, A. (1986) Dose-response relationship for phenobarbitone promotion of liver tumors initiated by single dose dimethylnitrosamine. Br. J. Exp. Pathol., 67, 131-139.
39. Pereira, M., Herren-Freund, S. and Long, R. (1986) Dose-response relationship of phenobarbital promotion of diethylnitrosamine initiated tumors in rat liver. Cancer Lett., 32, 305-311.
40. 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 diethylnitrosamine. Carcinogenesis, 13, 501-503.
41. Xu, Y.D., Dragan, Y., Young, T. and Pitot, H. (1991) The format of administration of phenobarbital on altered hepatic foci following initiation in female rats with diethylnitrosamine. Carcinogenesis, 12, 1009-1016.
42. Campen, D., Maronpot, R. and Lucier, G. (1990) Dose-response relationships in promotion of rat hepatocarcinogenesis by 17α-ethinylestradiol. J. Toxicol. Environ. Health, 29, 257-268.
43. Peraino, C., Fry, R., Staffeldt, E. and Christopher, J. (1973) Effects of varying the exposure to phenobarbital on its enhancement of 2-acetylaminofluorene induced hepatic tumorigenesis in the rat. Cancer Res., 33, 2701-2705.
44. Laconi, E., Li, F., Semple, E., Rao, P., Rajalakshmi, S. and Sarma, D. (1988) Inhibition of DNA synthesis in primary cultures of hepatocytes by orotic acid. Carcinogenesis, 9, 675-677.
45. Abonobi, S., 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.
46. Barbason, H. and Betz, E. (1981) Proliferation of preneoplastic lesions after discontinuation of chronic DEN feeding in the development of hepatomas in the rat. Br. J. Cancer, 44, 561-566.
47. Jirtle, R., Meyer, S. and Brockenbrough, J. (1991) Liver tumor promoter phenobarbital: a biphasic modulator of hepatocyte proliferation. In Butterworth, B., Slaga, T., Farland, W. and McClain, M. (eds), Chemically Induced Cell Proliferation: Implications for Risk Assessment. Wiley-Liss, New York, Vol. 369, pp. 209-216.
48. Jirtle, R. and Meyer, S. (1991) Liver tumor promotion: effect of phenobarbital on EGF and protein kinase C signal transduction and TGFβ1 expression. Dig. Dis. Sci., 36, 659-668.
49. Jirtle, R. (1995) Liver tumor promotion: a process of natural selection. In McClain, R.M., Slaga, T., LeBoeuf, R. and Pitot, H. (eds), Growth Factors and Tumor Promotion: Implications for Risk Assessment. Wiley-Liss, New York, pp. 149-159.
50. Lingroos, P. and Michalopoulos, G. (1993) Response of phenobarbital- and ciprofibrate-exposed hepatocytes to growth factors in type 1 collagen gels. Carcinogenesis, 14, 731-735.
51. Tsai, W. and Michalopoulos, G. (1991) Responsiveness of hepatocytes to epidermal growth factor, transforming growth factor beta, and norepinephrine during treatment with xenobiotic hepatic tumor promoters. Cancer Lett., 57, 83-90.
52. Hendrich, S., Campbell, H. and Pitot, H. (1987) Quantitative stereological evaluation of four histochemical markers of altered hepatic foci in multistage hepatocarcinogenesis in the rat. Carcinogenesis, 8, 1245-1250.
53. Tatematsu, M., Mera, Y., Ito, N., Satoh, K. and Sato, K. (1985) Relative merits of immunohistochemical demonstrations of placental, A, B, and C forms of glutathione S-transferase and histochemical demonstration of γ-glutamyltranspeplidase as markers of altered hepatic foci during liver Carcinogenesis in rats. Carcinogenesis, 6, 1621-1626.
54. Peraino, C., Staffeldt, E., Carnes, B., Ludeman, V., Blomquist, J. and Vesslinovitch, S. (1984) Characterization of histochemically detectable altered hepatocyte foci and their relationship to hepatic tumorigencsis in rats treated once with diethylnitrosamine or benzo(a)pyrene within one day after birth. Cancer Res., 44, 3340-3347.
55. Dragan, Y., Xu, Y.-H. and Pitot, H. (1993) The effect of the dose of diethylnitrosamine on the initiation of altered hepatic foci in neonatal female rats. Carcinogenesis, 14, 385-391.
56. Hendrich, S., Glauert, H. and Pitot, H. (1988) Dietary effects on initiation and promotion of hepatocarcinogenesis in rat. J. Cancer Res. Clin. Oncol., 114, 149-157.
57. 3H-thymidine for studies of hepatocellular proliferation in rodents. Carcinogenesis, 10, 1341-1343.
58. 3H]thymidine administered by injection or osmotic pump. Carcinogenesis, 11, 2245-2251.
59. Kaku, T., Ekem, J., Lindayen, C., Bailey, D., van Nostrand, A. and Farber, E. (1983) Comparison of formalin- and acetone-fixation for immunohistochemical detection of carcinoembryonic antigen (CEA) and keratin. Am. J. Clin. Pathol., 80, 806-815.
60. Satoh, K., Kitahara, A., Soma, Y., Inaba, Y., Hatayama, I. and Sato, K. (1985) Purification, induction, and distribution of placental glutathione transferase: a new marker enzyme for preneoplastic cells in rat chemical hepatocarcinogenesis. Proc. Natl Acad. Sci., USA, 82, 3964-3968.
61. Hsu, S., Raine, L. and Fanger, H. (1981) Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques. A comparison between ABC and unlabeled antibody (PAP) procedures. J. Histochem. Cytochem., 29, 577-580.
62. Bondi, A., Chieregatti, G., Eusebi, V., Fulcheri, E. and Bussolati, G. (1982) The use of β-galactosidase stain as a tracer in immunocytochemistry. Histochemistry, 76, 153-158.
63. De Lesse, M. (1848) Procede mechanique pour determiner Ia composition des roches. Ann. Mines, 13, 379-388.
64. Saltykov, S. (1967) The determination of the sire distribution of particles in an opaque material from measurement of the size distribution of their sections. In Elias, H. (ed.). Proceedings of the Second International Congress for Stereology. Springer-Verlag, Berlin, Germany, pp. 163-173.
65. Campbell, H., Hanigan, M., Xu, Y.-H. and Pitot, H. (1986) Application of quantitative stereology to the analysis of heterogeneous EAF in the rat liver. J. Natl Cancer Inst., 76, 751-767.
66. Campbell, H., Potter, V., Laishes, B. and Pitot, H. (1982) Application of quantitative stereology to the evaluation of enzyme-altered foci in rat liver. Cancer Res., 42, 465-472.
67. Kitagawa, T., Hirakawa, T., Ishikawa, T., Nemoto, N. and Takayama, S. (1980) Induction of hepatocellular carcinoma in ral liver after partial hepatectomy and promotion by phenobarbital. Toxicol. Lett., 6, 167-171.
68. Nakanishi, K., Fukushima, S., Hagiwara, A., Tamano, S. and Ito, N. (1982) Organ specific promoting effects of phenobarbital sodium and sodium saccharin in the induction of liver and urinary bladder tumors in male F344 rats. J. Natl Cancer Inst., 68, 497-500.
69. Hiasa, Y., Kitahori, V., Oshima, M., Fujita, T., Yuasa, T., Konishi, N. and Miyashiro, A. (1982) Promoting effects of phenobarbital and barbital on development of thyroid tumors in rats treated with N-bis(2-hydroxypropyl)nitrosamine. Carcinogenesis, 3, 1187-1190.
70. Xu, Y.-H., Campbell, H., Sattler, G., Hendrich, S., Maronpot, R., Sato, K. and Pitot, H. (1990) Quantitative stereological analysis of the effects of age and sex on multistage hepatocarcinogenesis in the rat by use of four cytochemical markers. Cancer Res., 50, 472-179.
71. Peraino, C., Fry, M., Staffeldt, E. and Christopher, E. (1975) Comparative enhancing effects of phenobarbital, amobarbital, diphenylhydantoin, and dichlorodiphenyl-trichloroethane on 2-acetylaminofluorene-induced hepatic tumorigenesis in the rat. Cancer Res., 35, 2884-2890.
72. Solt, D. and Farber, E. (1976) New principles for the analysis of chemical carcinogenesis. Nature, 263, 701-703.
73. Farber, E. and Sarma, D. (1986) Chemical carcinogenesis: the liver as a model. Pathol. Immunol. Res., 5, 1-28.
74. Rao, P., Nagamine, Y., Roomi, M., Rajalakshima, S. and Sarma, D. (1984) Orotic acid, a new promoter for experimental liver carcinogenesis. Toxicol. Pathol., 12, 173-178.
75. Nims, R., Devor, D., Henneman, J. and Lubet, R. (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.
76. Lubet, R., Nims, R., Ward, J., Rice, J. and Diwan, B. (1989) Induction of cytochrome P450b and its relationship to liver tumor promotion. J. Am. Coll. Toxicol., 8, 259-268.
77. Rice, J., Diwan, B., Ward, J., Nims, R. and Lubet, R. (1992) Phenobarbital and related compounds: approaches to interspecies extrapolation. In D'Amato, R., Slaga, T., Farland, W. and Henry, C. (eds), Relevance of Animal Studies to the Evaluation of Human Cancer Risk. Wiley-Liss, New York, pp. 231-249.
78. Liang, Q. and Fulco, A. (1995) Transcriptional regulation of the genes encoding cytochromes P450BM-1 and P450BM-3 in Bacillus megaterium by the binding of Bm3R1 repressor to barbie box elements and operator sites. J. Biol. Chem., 270, 18606-18614.
79. He, J.-S., Liang, Q. and Fulco, A. (1995) The molecular cloning and characterization of BM1P1 and BM1P2 proteins, putative positive transcription factors involved in barbiturate-mediated induction of the genes encoding cytochrome P450BM-1 of Bacillus megaterium. J. Biol. Chem., 270, 18615-18625.
80. Liang, Q., He, J.-S. and Fulco, A. (1995) The molecular cloning and characterization of BMP1 and BMP2 proteins, putative positive transcription factors involved in barbiturate-mediated induction of the genes encoding cytochrome P450BM1 of Bacillus megaterium. J. Biol. Chem., 270, 4438-4450.
81. Upadhya, R., Rao, M., Venkateswar, V., Rangerajn, P. and Padmanaban, G. (1992) Identification and functional characterization of a cis acting positive DNA element regulating CYP2B1/B2 gene transcription in rat liver. Nucleic Acids Res., 20, 557-562.
82. Hahn, C., Hansen, A. and May, B. (1991) Transcriptional regulation of the chicken CYPH1 gene; localization of a phenobarbital-responsive enhancer domain. J. Biol. Chem., 266, 17031-17039.
83. Shervington, A., Shephard, E.A. and Phillips, I.R. (1994) Identification of DNA sequences involved in the transcription of a CYP2B2 gene. Biochem. Soc. Trans., 22, 1215.
84. Shephard, E.A., Forrest, L.A., Shervington, A., Fernandez, L.M., Ciaramella, G. and Phillips, I.R. (1994) Interaction of proteins with a cytochrome P450 2B2 gene promoter: identification of two DNA sequences that bind proteins that are enriched or activated in response to phenobarbital. DNA Cell Biol., 13, 793-804.
85. Waxman, D. and Azaroff, L. (1992) Phenobarbital induction of cytochrome P450 gene expression. Biochem. J., 281, 577-592.
86. Preat, V., Lans, M., de Gerlache, J., Taper, H. and Roberfroid, M. (1987) Influence of the duration and delay of administration of phenobarbital on its modulating influences on rat hepatocarcinogenesis. Carcinogenesis, 8, 333-335.
87. Tsai, W., Zarnegar, R. and Michalopoulos, G. (1991) Long-term treatment with hepatic tumor promoters inhibits mitogenic responses of hepatocytes to acidic fibroblast growth factor and hepatocyte growth factor. Cancer Lett., 59, 103-108.
88. Meyer, S., Gibbs, T. and Jirtle, R. (1989) Independent mechanisms for tumor promoters phenobarbital and 12-O-tetradecanoylphorbol-13-acetate in reduction of epidermal growth factor binding by rat hepatocytes. Cancer Res., 49, 5907-5912.
89. Meyer, S. and Jirtle, R. (1989) Phenobarbital decreases hepatocyte EGF receptor expression independent of protein kinase C activation. Biochem. Biophys. Res. Commun., 158, 652-659.
90. Meyer, S., Li, C. and Jirtle, R. (1990) Cytochrome P450-independent down regulation of hepatocyte EGF receptors by liver tumor promoter phenobarbital. Proc. Am. Assoc. Cancer Res., 31, 150.
91. Stenius, U. (1993) Different inhibition of DNA synthesis by transforming growth factor β1 and phenobarbital on GST-P positive and GST-P negative hepatocytes. Carcinogenesis, 14, 159-161.
92. Manjeshwar, S., Laconi, E., Sheikh, A., Rao, P., Rajalakshmi, S. and Sarma, D. (1994) In vitro and in vivo response of hepatocytes from hepatic nodules to the mitoinhibitory effects of phenobarbital. Carcinogenesis, 15, 1963-1968.
93. Pugh, T. and Goldfarb, S. (1978) Quantitative histochemical and autoradiographic studies of hepatocarcinogenesis in rats fed 2-acetylaminofluorene followed by phenobarbital. Cancer Res., 38, 4450-4457.
94. Schulte-Hermann, R., Timmermann-Trosiener, I. and Schuppler, J. (1982) Response of liver foci in rats to hepatic tumor promoters. Toxicol. Pathol., 10, 63-70.
95. Schulte-Hermann, R., Timmermann-Trosiener, I. and Schuppler, J. (1984) Aberrant expression of adaptation to phenobarbital may cause selective growth of foci of altered cells in rat liver. In Borzsrony, M., Lapis, K. and Day, N.E. (eds), Models, Mechanisms, and Etiology of Tumor Promotion. IARC Scientific Publication no. 56. International Agency for Research on Cancer, Lyon, France, pp. 67-75.
96. Kappus, H., Bolt, H. and Remmer, H. (1972) Demethylation of mestranol to ethylestradiol in vitro and in vivo. Acta Endocrinol., 71, 374-384.
97. Breuer, H. (1977) Metabolic pathways of steroid contraceptive drugs. In Garattini, S. and Berendes, H.W. (eds), Pharmacology of Steroid Contraceptive Drugs. Raven Press, New York, pp. 73-88.
98. Helton, E.D. and Goldzieher, J. (1977) The pharmacokinetics of ethynyl estrogens. Contraception, 15, 255-284.
99. Bolt, H., Kappus, H. and Kasbohrer, R. (1974) Metabolism of 17α-ethinylestradiol by human liver microsomes in vitro: aromatic hydroxylation and irreversible protein binding of metabolites. J. Clin. Endocrinol. Metab., 39, 1072-1080.
100. Khan, F. and Fotherby, K. (1979) In vitro metabolism of 17α-ethynylsteroids. J. Steroid Biochem., 10, 437-442.
101. Guengerich, F.P. (1988) Oxidation of 17α ethynylestradiol by human liver cytochrome P450. Mol. Pharmacol., 33, 500-508.
102. Longcope, C. and Williams, K. (1977) Ethynylestradiol and mestranol: their pharmacodynamics and effects on natural estrogens. In Garattini, S. and Berendes, H.W. (eds), Pharmacology of Steroid Contraceptive Drugs. Raven Press, New York, pp. 89-98.
103. Mayol, X., Perez-Tomas, R., Cullere, X., Romero, A., Estradella, M. and Domingo, J. (1991) Cell proliferation and tumor promotion by ethinyl estradiol in rat hepatocarcinogenesis. Carcinogenesis, 12, 1133-1136.
104. Mishkin, S., Farber, E., Ho, R., Mulay, S. and Mishkin, S. (1983) Evidence for the hormone dependency of transformation after exogenous 17β-estradiol and tamoxifen. Hepatology, 3, 308-316.
105. Sumi, C., Yokoro. K. and Matsushima, R. (1984) Inhibitory effect of antiestrogen on hepatic tumorigenesis in WF rats treated with diethylstilbestrol alone or in combination with N-nitrosobutylurea. J. Natl Cancer Inst., 72, 949-953.
106. Mayol, X., Neal, G., Davies, R., Romero, A. and Domingo, J. (1992) Ethinyl estradiol-induced cell proliferation in rat liver. Involvement of specific populations of hepatocytes. Carcinogenesis, 13, 2381-2388.
107. Ochs, H., Dusterberg, B., Gunzel, P. and Schulte-Hermann, R. (1986) Effect of tumor promoting contraceptive steroids on growth and drug metabolism enzymes in rat liver. Cancer Res., 46, 1224-1232.
108. Yager, J., Zurlo, J., Sewall, C., Lucier, G. and He, H. (1994) Growth stimulation followed by growth inhibition in livers of female rats treated with ethinyl estradiol. Carcinogenesis, 15, 2117-2123.
109. Welch, R., Levin, W. and Conney, A. (1968) Stimulatory effect of phenobarbital on the metabolism in vivo of estradiol-17β and estrone in the rat. J. Pharmacol. Exp. Ther., 160, 171-178.
110. Levin, W., Welcj, R. and Conney, A. (1968) Decreased uterotropic potency of oral contraceptives in rats pretreated with phenobarbital. Endocrinology, 83, 149-156.
111. Kraek, M., Peterson, R., Sleisenger, M. and Jeffries, G. (1969) Effects of ethinylestradiol-induced cholestasis on bile flow and biliary excretion of estradiol and estradiol glucuronide by the rat. Proc. Soc. Exp. Biol. Med., 131, 646-650.
112. Back, D. et al. (1980) The interaction of phenobarbital and other anticonvulsants with oral contraceptives steroid therapy. Contraception, 22, 495-503.
113. Michalopoulos, G. et al. (1987) Mechanisms of rodent liver carcinogenesis. Toxicol. Indust. Health, 3, 119-128.
114. Yager, J., Zurlo, J. and He, H. (1992) Inhibition of liver growth by chronic treatment with the tumor promoter ethinyl estradiol. Toxicologist, 12, 203.
115. Luebeck, E.G., Grasl-Kraupp, B., Timmermann-Trosiener, I., Bursch, W., Schulte-Hermann, R. and Moolgavkar, S. (1995) Growth kinetics of enzyme-altered foci in rats treated with phenobarbital or α-hexachlorocyclohexane. Toxicol. Appl. Pharmacol., 130, 304-315.
116. Schulte-Hermann, R., Timmermann-Trosiener, I., 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.
117. Stinchcombe, S., Buchman, A., Bock, K. and Schwarz, M. (1995) Inhibition of apoptosis during 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated tumour promotion in rat liver. Carcinogenesis, 16, 1271-1275.
118. Berger, M., Schmal, D. and Zerban, H. (1987) Combination experiments with very low doses of three genotoxic N-nitrosamines with similar organotropic carcinogenicity in rats. Carcinogenesis, 8, 1635-1643.
119. Hasegawa, R., Mutai, M., Imaida, K., Tsuda, H., Yamaguchi, S. and Ito, N. (1989) Synergistic effects of low dose hepatocarcinogens in induction of glutathione S-transferase P-positive foci in the rat liver. Jpn J. Cancer Res., 80, 945-951.
120. Ito, N. et al. (1991) Enhancement of GST-P positive liver cell foci development by combined treatment of rats with five heterocyclic amines at low doses. Carcinogenesis, 12, 767-772.
121. Warshawsky, D., Barkley, W. and Bingham, E. (1993) Factors affecting carcinogenic potential of mixtures. Fund. Appl. Toxicol., 20, 376-382.
122. Ito, N., Hasegawa, R., Imaida, K., Kurata, Y., Hagiwara, A. and Shirai, T. (1996) Ingestion of 20 pesticides in combination of acceptable daily intake levels exerts no effects on rat liver Carcinogenesis. Carcinogenesis, in press.
123. Sargent, L., Dragan, Y., Erickson, C., Laufer, C. and Pitot, H. (1991) Study of the separate and combined effects of the non-planar 2,5,2′,5′ and the planar 3,4,3′,4′ tetrachlorobiphenyl in liver and lymphocytes in vivo. Carcinogenesis, 12, 793-800.