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Carcinogenesis Advance Access published online on April 22, 2006
Carcinogenesis, 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
Received February 6, 2006
Revised April 11, 2006
Accepted April 13, 2006

CARCINOGENESIS

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

Volodymyr P. Tryndyak 1, Levan Muskhelishvili 2, Olga Kovalchuk 3, Rocio Rodriguez-Juarez 3, Beverly Montgomery 1, Mona I. Churchwell 1, Sharon A. Ross 4, Frederick A. Beland 1, and Igor P. Pogribny 1 *

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

* To whom correspondence should be addressed.
Igor P. Pogribny, E-mail: igor.pogribny{at}fda.hhs.gov


  Abstract

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 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 ppm tamoxifen diet for 6, 12, 18, or 24 weeks. Hepatic tamoxifen DNA adduct levels, as assessed by HPLC and electrospray tandem mass spectrometry, were 580 adducts/108 nucleotides at 6 weeks, and increased to ~1,700 adducts/108 nucleotides 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.

Keywords: Tamoxifen; rat hepatocarcinogenesis; DNA adducts; DNA hypomethylation; DNA methyltransferases; histone methylation.
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