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Carcinogenesis Advance Access originally published online on April 22, 2006
Carcinogenesis 2006 27(8):1713-1720; doi:10.1093/carcin/bgl050
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Effect of long-term tamoxifen exposure on genotoxic and epigenetic changes in rat liver: implications for tamoxifen-induced hepatocarcinogenesis

Volodymyr P. Tryndyak, Levan Muskhelishvili1, Olga Kovalchuk2, Rocio Rodriguez-Juarez2, Beverly Montgomery, Mona I. Churchwell, Sharon A. Ross3, Frederick A. Beland and Igor P. Pogribny*

Division of Biochemical Toxicology, National Center for Toxicological Research Jefferson, AR 72079, USA
1 Toxicologic Pathology Associates, National Center for Toxicological Research Jefferson, AR 72079, USA
2 Department of Biological Sciences, University of Lethbridge AB T1K 3M4, Canada
3 Division of Cancer Prevention, National Cancer Institute Bethesda, MD 20892, USA

*To whom correspondence should be addressed at: Division of Biochemical Toxicology, NCTR, 3900 NCTR Road, Jefferson, AR 72079, USA. Tel: +1 870 543 7096; Fax: +1 870 543 7720; Email: igor.pogribny{at}fda.hhs.gov

Tamoxifen is a non-steroidal anti-estrogen used for the treatment of breast cancer and, more recently, as a chemopreventive agent in healthy women at high risk of developing breast cancer. On the other hand, tamoxifen is a potent hepatocarcinogen in rats, with both tumor-initiating and tumor-promoting properties. There is substantial evidence that hepatic tumors in rats are initiated as a result of formation of tamoxifen–DNA adducts; however, events subsequent to DNA adduct formation are not clear. Recently, it has been demonstrated that genotoxic carcinogens, in addition to exerting genotoxic effects, often cause epigenetic alterations. In the current study, we investigated whether or not the mechanism of tamoxifen-induced hepatocarcinogenesis includes both genotoxic and epigenetic components. Female Fisher 344 rats were fed a 420 p.p.m. tamoxifen diet for 6, 12, 18 or 24 weeks. Hepatic tamoxifen–DNA adduct levels, as assessed by high-performance liquid chromatography and electrospray tandem mass spectrometry, were 580 adducts/108 nt at 6 weeks, and increased to ~1700 adducts/108 nt by 18 weeks. Global liver DNA hypomethylation, as determined by an HpaII-based cytosine extension assay, was increased at all time points, with the maximum increase (~200%) occurring at 6 weeks. Protein expressions of maintenance (DNMT1) DNA methyltransferase and de novo DNA methyltransferases DNMT3a and DNMT3b were decreased at all time points. Likewise, trimethylation of histone H4 lysine 20 was significantly decreased at all time points. In contrast, non-target tissues (i.e. mammary gland, pancreas and spleen) did not show any changes in global DNA methylation or DNA methyltransferase activity. These data indicate the importance of genotoxic and epigenetic alterations in the etiology of tamoxifen-induced hepatocarcinogenesis.


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