© 1986 Oxford University Press
research-article |
Interstrain differences in susceptibility to liver carcinogenesis initiated by N-nitrosodiethylamine and its promotion by phenobarbital in C57BL/6NCr, C3H/HeNCrMTV- and DBA/2NCr mice
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility Frederick, MD 21701, USA
1To whom reprint requests should be sent
Selected inbred strains of mice were compared with respect to their susceptibility to two-stage liver carcinogenesis. Five-week-old male mice of strains C57BL/6NCr (C57), C3H/HeNCrMTV- (C3H) and DBA/2NCr (DBA) were given a single i.p. injection of N-nitrosodiethylamine (DEN, 90 mg/kg body weight) or the solvent tricaprylin (10 ml/kg). Beginning 2 weeks later, half of the DEN-treated and half of the control mice were given drinking water containing 0.05% phenobarbital (PB). Ten mice from each treatment group were killed at 12, 24, 36 and 52 weeks of age (5, 17, 29 and 45 weeks exposure to PB). PB significantly increased both the number of hepatocellular foci/cm2 and the incidence of hepatocellular tumors after 17 weeks of treatment in 24-week-old DEN-initiated mice of strains C3H (0.11 ± 0.07 versus 2.9 ± 0.3 foci/cm2 and 20 versus 70% incidence of hepatocellular tumors) and DBA (0.09 ± 0.09 versus 3.72 ± 0.6 foci/cm2 and 0 versus 90% incidence of hepatocellular tumors) but was ineffective in C57 mice (0.04 ± 0.04 versus 0.07 ± 0.07 foci/cm2). At 36 weeks of age the incidence of liver cell tumors in mice given DEN but not PB was 10 (DBA), 10 (C57) and 50% (C3H); the incidence was increased by PB to 90% in DBA and 100% in C3H mice, but there was no increase in C57 mice. Even at 52 weeks, the low incidence of hepatocellular tumors in C57 mice given DEN only (20%) was not significantly increased by subsequent exposure to PB. Serum PB levels observed at 12, 24 and 36 weeks of age were significantly higher in DBA mice than in C57 or C3H mice. Similar results were observed in a separate study in which PB was administered in drinking water to 7-week-old male mice of these three strains for 20 days, during which period serum PB levels were measured at shorter intervals. DBA mice thus appear to be unable to metabolize PB, which itself rather than its metabolites is probably responsible for tumor-promoting effects. DBA mice were especially sensitive, while C57 mice were refractory to promotion of hepatocar-cinogenesis by PB. These two strains, which differ with respect to other significant parameters for chemical carcinogenesis including inducibility for aryl hydrocarbon hydroxylase and susceptibility to promotion of hydrocarbon-initiated skin tumors by 12-O-tetradecanoyl-phorbol-13-acetate, thus also provide a means for analysis of the pharmacogenetics of susceptibility to hepatocellular tumor promotion.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. S. Tien, K. Matsui, R. Moore, and M. Negishi The Nuclear Receptor Constitutively Active/Androstane Receptor Regulates Type 1 Deiodinase and Thyroid Hormone Activity in the Regenerating Mouse Liver J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 307 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Bai, H.-M. Ni, X. Chen, D. DiFrancesca, and X.-M. Yin Deletion of Bid Impedes Cell Proliferation and Hepatic Carcinogenesis Am. J. Pathol., May 1, 2005; 166(5): 1523 - 1532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yamamoto, R. Moore, T. L. Goldsworthy, M. Negishi, and R. R. Maronpot The Orphan Nuclear Receptor Constitutive Active/Androstane Receptor Is Essential for Liver Tumor Promotion by Phenobarbital in Mice Cancer Res., October 15, 2004; 64(20): 7197 - 7200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Warner, M. J. Fernstrom, and R. J. Ruch Inhibition of Mouse Hepatocyte Gap Junctional Intercellular Communication by Phenobarbital Correlates with Strain-Specific Hepatocarcinogenesis Toxicol. Sci., February 1, 2003; 71(2): 190 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.-H. Lee Review Article: Paradoxical Effects of Phenobarbital on Mouse Hepatocarcinogenesis Toxicol Pathol, March 1, 2000; 28(2): 215 - 225. [Abstract] [PDF]
|
|
|
|
|
|
J. E. Sagartz, S. W. Curtiss, R. T. Bunch, J. C. Davila, D. L. Morris, and C. L. Alden Phenobarbital Does Not Promote Hepatic Tumorigenesis in a Twenty-Six-Week Bioassay in p53 Heterozygous Mice Toxicol Pathol, July 1, 1998; 26(4): 492 - 500. [Abstract] [PDF]
|
|
|
|
|
|
K. Mitsumori, H. Koizumi, T. Nomura, and S. Yamamoto Pathological Features of Spontaneous and Induced Tumors in Transgenic Mice Carrying a Human Prototype c-Ha-ras Gene Used for Six-Month Carcinogenicity Studies Toxicol Pathol, July 1, 1998; 26(4): 520 - 531. [Abstract] [PDF]
|
|
|
|
|
|
B. A. Diwan, J. M. Ward, D. Ramljak, and L. M. Anderson Promotion by Helicobacter hepaticus-Induced Hepatitis of Hepatic Tumors Initiated by N-Nitrosodimethylamine in Male A/JCr Mice Toxicol Pathol, November 1, 1997; 25(6): 597 - 605. [Abstract] [PDF]
|
|
|
|
 |
|
 R. W. Nims, R. A. Prough, C. R. Jones, D. L. Stockus, K. H. Dragnev, P. E. Thomas, and R. A. Lubet In Vivo Induction and in Vitro Inhibition of Hepatic Cytochrome P450 Activity by the Benzodiazepine Anticonvulsants Clonazepam and Diazepam Drug Metab. Dispos., June 1, 1997; 25(6): 750 - 756. [Abstract] [Full Text]
|
|
|
|
|
|
B. A. Diwan, J. M. Ward, Y. Kurata, and J. M. Rice Dissimilar Frequency of Hepatoblastomas and Hepatic Cystadenomas and Adenocarcinomas Arising in Hepatocellular Neoplasms of D2B6F1 Mice Initiated with N-Nitrosodiethylamine and Subsequently Given Aroclor-1254, Dichlorodiphenyltrichloroethane, or Phenobarbital Toxicol Pathol, July 1, 1994; 22(4): 430 - 439. [Abstract] [PDF]
|
|