Toxicological Sciences 68, 51-58 (2002)
Copyright © 2002 by the Society of Toxicology
CARCINOGENICITY |
Effects of Phenobarbital on DNA Methylation in GC-Rich Regions of Hepatic DNA from Mice That Exhibit Different Levels of Susceptibility to Liver Tumorigenesis
Department of Pharmacology and Toxicology, Michigan State University, B440 Life Sciences Building, East Lansing, Michigan 48824
DNA methylation is an important epigenetic mechanism involved in transcriptional control and altered patterns of methylation may lead to the aberrant gene expression contributing to carcinogenesis. Three groups of mice were used in the current study: the relatively liver-tumor-sensitive C3H/He strain and B6C3F1 stock (C57BL/6xC3H/He), as well as the relatively resistant C57BL/6 strain. For a 2-week period, animals from each group were given drinking water containing a tumor-promoting dose of phenobarbital (PB), a nongenotoxic rodent carcinogen. Methylation-sensitive restriction digests using HpaII or MspI were followed by PCR amplification using an arbitrary primer or primer pair, binding preferentially to guanine and cytysine (GC)-rich regions of DNA, including CpG islands. This procedure allows for assessment of methylation at the internal and/or external cytosine of the 5`-CCGG-3` sites recognized by MspI and HpaII. Results with the single primer indicated marked differences in PB-induced hypermethylation at external and internal cytosines of 5`-CCGG-3` sites: C3H/He >> B6C3F1 > C57BL/6. Results with the arbitrary primer pair indicated PB-induced hypermethylation at the external cytosine of 5`-CCGG-3` site: B6C3F1 > C3H/He, and a low level of hypomethylation at internal and external cytosine sites in C57BL/6. Thus, there was a clear indication of more methylation changes in GC-rich regions of DNA, primarily hypermethylation, in the tumor-sensitive groups of mice in response to PB treatment. Therefore, this study supports our hypothesis that the capacity to maintain normal methylation patterns is related inversely to tumor susceptibility.
Key Words: B6C3F1; carcinogenesis; C3H/He; C57BL/6; CpG islands; DNA methylation; GC-rich regions; liver; non-CpG methylation; phenobarbital; susceptibility; tumorigenesis.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. M. Phillips and J. I. Goodman Identification of Genes that May Play Critical Roles in Phenobarbital (PB)-Induced Liver Tumorigenesis due to Altered DNA Methylation Toxicol. Sci., July 1, 2008; 104(1): 86 - 99. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Phillips, Y. Yamamoto, M. Negishi, R. R. Maronpot, and J. I. Goodman Orphan Nuclear Receptor Constitutive Active/Androstane Receptor-Mediated Alterations in DNA Methylation during Phenobarbital Promotion of Liver Tumorigenesis Toxicol. Sci., March 1, 2007; 96(1): 72 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Allen, D. C. Wolf, M. H. George, S. D. Hester, G. Sun, S.-F. Thai, D. A. Delker, T. Moore, C. Jones, G. Nelson, et al. Toxicity Profiles in Mice Treated with Hepatotumorigenic and Non-Hepatotumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil Toxicol Pathol, December 1, 2006; 34(7): 853 - 862. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. P. Tryndyak, L. Muskhelishvili, O. Kovalchuk, R. Rodriguez-Juarez, B. Montgomery, M. I. Churchwell, S. A. Ross, F. A. Beland, and I. P. Pogribny Effect of long-term tamoxifen exposure on genotoxic and epigenetic changes in rat liver: implications for tamoxifen-induced hepatocarcinogenesis Carcinogenesis, August 1, 2006; 27(8): 1713 - 1720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. N. Bachman, J. M. Phillips, and J. I. Goodman Phenobarbital Induces Progressive Patterns of GC-Rich and Gene-Specific Altered DNA Methylation in the Liver of Tumor-Prone B6C3F1 Mice Toxicol. Sci., June 1, 2006; 91(2): 393 - 405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. N. Bachman, L. M. Kamendulis, and J. I. Goodman Diethanolamine and Phenobarbital Produce an Altered Pattern of Methylation in GC-Rich Regions of DNA in B6C3F1 Mouse Hepatocytes Similar to That Resulting from Choline Deficiency Toxicol. Sci., April 1, 2006; 90(2): 317 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Watson, J. M. McKim, G. L. Cockerell, and J. I. Goodman The Value of DNA Methylation Analysis in Basic, Initial Toxicity Assessments Toxicol. Sci., May 1, 2004; 79(1): 178 - 188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Watson, G. M. Curtin, D. J. Doolittle, and J. I. Goodman Progressive Alterations in Global and GC-Rich DNA Methylation during Tumorigenesis Toxicol. Sci., October 1, 2003; 75(2): 289 - 299. [Abstract] [Full Text] [PDF]
|
|